Primary Care articles

Bisphosphonates in the management of osteoporosis in postmenopausal women

2009-01-14T09:43:00.000-08:00

Bisphosphonates in the management of osteoporosis in postmenopausal women

Author
Hillel N Rosen, MD
Section Editors
Clifford J Rosen, MD
Kenneth E Schmader, MD
Deputy Editor
Jean E Mulder, MD

Last literature review version 16.3: October 2008 | This topic last updated: October 16, 2008 (More)

INTRODUCTION — Osteoporosis is caused by the cumulative effect of bone resorption in excess of bone formation. Bisphosphonates, one of the available therapeutic options for the management of osteoporosis, inhibit bone resorption with relatively few side effects. As a result, they are widely used for the prevention and treatment of osteoporosis.

Bisphosphonates are also used in the management of hypercalcemia, Paget disease, and in a number of malignancies including multiple myeloma, breast cancer, and prostate cancer. These topics are all reviewed separately in the appropriate topic reviews.

The use of bisphosphonates for osteoporosis in women is reviewed here. The pharmacology of bisphosphonates, role of bisphosphonates for osteoporosis in men and premenopausal women, and an overview of other treatment options for osteoporosis in women are reviewed separately. (See "Pharmacology of bisphosphonates" and see "Overview of the management of osteoporosis in postmenopausal women" and see "Treatment of osteoporosis in men", section on Bisphosphonates and see "Evaluation and treatment of premenopausal osteoporosis").

ALENDRONATE — Alendronate is effective for both the treatment and prevention of osteoporosis in postmenopausal women. Alendronate is also effective for African-American women [1] and for men with osteoporosis. (See "Treatment of osteoporosis in men").

Treatment — A number of randomized, clinical trials have demonstrated that alendronate increases bone mineral density (BMD) and decreases the risk of osteoporotic fractures [2-7]. The optimal suppression of bone turnover and increase in bone density with minimal side effects is achieved at an alendronate dose of approximately 10 mg/day (show figure 1) [2,4].

In one trial of 994 women with postmenopausal osteoporosis who were randomly assigned to receive placebo or different doses of alendronate (all groups also were supplemented with calcium (500 mg/day) [2]), the results at three years were (show figure 1):

Bone density fell slightly in the placebo group but increased in the alendronate groups.

The differences in bone density between alendronate (10 mg/day) and placebo were 8.8 percent in the spine, 5.9 percent in the femoral neck, and 7.8 percent in the greater trochanter. Thus, alendronate increased bone density at sites rich in cortical bone (mid-forearm and femoral neck) and at sites rich in trabecular bone (spine).

Alendronate was associated with fewer vertebral fractures (3.2 versus 6.2 percent), less loss of height, and, at the dose of 10 mg/day, no increase in side effects as compared with placebo.

The Fracture Intervention Trial (FIT), a larger, randomized trial in postmenopausal women with low bone density, had two study arms comparing daily alendronate and placebo.

In the vertebral fracture study arm, in 2027 women with a low femoral neck bone density (T-score < -2.1) and at least one vertebral fracture at baseline, alendronate therapy increased femoral neck and spine BMD by 4.1 and 6.2 percent, respectively, and reduced the risk of vertebral fracture by approximately 50 percent, and hip and wrist fractures by approximately 30 percent [6].

The clinical fracture study arm included 4432 postmenopausal women with a low femoral neck bone density (T-score < -1.6), but no vertebral fracture at baseline [8]. Alendronate therapy (5 mg per day for two years followed by 10 mg per day for the remainder of the trial) increased bone mineral density and reduced the risk of vertebral fractures (diagnosed by x-ray) by 44 percent, but did not significantly decrease the risk of hip, wrist, or all clinical fractures. However, in a subgroup of the subjects who had osteoporosis (baseline femoral neck T score of -2.5 or less), alendronate reduced the risk of hip and all clinical fractures by 56 and 36 percent, respectively.

In a meta-analysis of 11 trials of alendronate therapy in postmenopausal women, the relative risk (RR) of vertebral fractures in patients given 5 mg or more of alendronate was 0.52 [95% CI 0.43-0.65] [7]. The RR of nonvertebral fractures in patients given ≥10 mg of alendronate was 0.51, a greater reduction than with 5 mg (RR 0.87). Improvements in bone density with alendronate increased with both dose and time. The risk of side effects was similar for 5 mg and doses ≥ 10 mg. For all doses combined, there was no evidence of an excess risk of gastrointestinal side effects.

Elderly women — Alendronate appears to be equally effective in older and younger postmenopausal women with osteoporosis. In the FIT trial, alendronate reduced fracture rate even in women at highest risk for fracture (older than age 75 years, or severe osteoporosis) [9]. The reduction in fracture rate was similar in women older and younger than age 75 years, suggesting that even elderly women benefit from treatment of their osteoporosis [9]. In a randomized, trial of 327 elderly women with osteoporosis in long-term care facilities, alendronate increased bone density when compared to placebo and was well-tolerated [10].

Long-term efficacy — Alendronate is well tolerated and effective for at least 10 years. In an extension study of 247 postmenopausal women with osteoporosis, alendronate (5 or 10 mg/day) resulted in continued increases in bone mineral density over a 10-year period [11].

The total 10-year increase in lumbar spine density was 13.7 and 9.3 percent for the 10 and 5 mg/day groups, respectively. Increases in bone mineral density were greatest in the initial five years of the study (10 and 6.8 percent for the 10 and 5 mg/day groups, respectively).

Fractures were not a primary outcome, and were captured only as adverse events. However, fracture reduction appeared to be maintained throughout the study.
The safety and tolerability of alendronate were similar to those of placebo.
How long to treat? — There is currently no consensus on how long to continue bisphosphonate therapy. However, for some women, stopping therapy after five years may be reasonable, as there appears to be a residual benefit on BMD and fractures for up to five years. This was illustrated in the Fracture Intervention Trial Long-term Extension (FLEX), in 1099 postmenopausal women who had previously received alendronate for five years in the Fracture Intervention Trial (FIT) [12].

At the completion of FIT, women were randomly assigned to an additional five years of alendronate (5 or 10 mg daily) or placebo. Women at highest risk for fracture were excluded from FLEX (those with FLEX baseline T-scores either below -3.5, or below their FIT baseline). The BMD, bone marker, and fracture data in the women who continued alendronate for ten years were similar to those described above [11].

In women who were switched to placebo after five years of alendronate, the following results were seen:

There was a gradual decline in BMD (-2.4 and -3.7 percent, at the total hip and spine, respectively), but mean BMD remained at or higher than levels 10 years earlier.

There was a gradual rise in biochemical markers of bone turnover. However, the values were still lower than ten years previously.

In the placebo compared to alendronate groups, the rate of nonvertebral fracture (19 and 18.9 percent) or morphometric vertebral fractures (detected by lateral spine radiographs) (11.3 and 9.8 percent) were not significantly different. However, there was a slightly higher risk of clinically detected vertebral fractures (by participant's physician and spine radiograph) (5.3 and 2.4 percent for placebo and alendronate, respectively).

There were no differences in adverse events between the groups, and there were no cases of osteonecrosis of the jaw. No qualitative abnormalities were seen on bone biopsy in either group.

In summary, stopping alendronate after five years of therapy results in a gradual decline in BMD and increase in biochemical markers of bone turnover, but no significantly higher risk of fracture (except for clinical vertebral fracture). Thus, stopping bisphosphonate therapy after five years (with careful BMD and risk factor assessment follow-up) may be reasonable for some women.

However, the FLEX trial does not address the impact of stopping therapy in women at highest risk for fracture as they were excluded from the trial. In these women, we suggest continuing alendronate for up to ten years, as BMD and fracture benefits were maintained with no increased risk of adverse events.

Weekly dosing — Weekly administration of alendronate is as effective as daily dosing. In a two-year randomized trial comparing once-weekly (70 mg) and daily alendronate (10 mg), the regimens were similar for increasing BMD and had similar low rates of side effects [13]. The rates of clinical fractures were captured as adverse experiences, and were similar among the groups.

Prevention — In addition to its efficacy in the treatment of osteoporosis in postmenopausal women, alendronate is useful for the prevention of osteoporosis [14-18]. The approved prevention dose with alendronate is one-half the dose for treatment (5 mg/day or 35 mg/week).

As an example, in a double-blind, randomized trial of 447 women who had been menopausal for 6 to 36 months, alendronate for three years at 5, 10, and 20 mg/day increased bone mineral density at the lumbar spine, femoral neck, and trochanter by 1 to 4 percent [14]. In comparison, those receiving placebo lost 2 to 4 percent at these sites. The protective effect of alendronate disappeared relatively rapidly after cessation of therapy [15].

A second randomized study found similar efficacy (3.5 percent increase in bone mineral density at the lumbar spine and 1.9 percent increase at the hip) with the 5 mg dose of alendronate administered to postmenopausal women under the age of 60 years for two years [16]. In a follow-up study of this cohort for four [17] and six years [18], the positive effects of continued therapy on bone density were maintained (show figure 2) [17]. This dose was as, or perhaps slightly less, beneficial than estrogen-progestin therapy. Women receiving alendronate during years one and two who then received placebo in years three and four had the expected fall in bone density (show figure 2).

Although alendronate increases bone mineral density in postmenopausal women without osteoporosis [14,18], there is no consensus on when to initiate therapy in postmenopausal women with osteopenia (femoral neck T-scores between -1.5 and -2.4) and no other independent risk factors for fracture (previous fracture, age, tendency to fall). One group of investigators calculated that treating these women would not be cost-effective from a societal standpoint [19]. However, this does not imply that an individual postmenopausal woman with osteopenia would not derive fracture benefit.

Combination therapy — Although estrogen and bisphosphonates both inhibit bone resorption, they do so through different mechanisms. Their effects on BMD appear to be similar, and the combination of the two may be slightly more effective, although the additional benefit is modest [20-23]. The rate of bone loss may be accelerated after withdrawing estrogen therapy, but not after withdrawal of alendronate or combination therapy [24].

The combination of alendronate and raloxifene has a greater effect on bone mineral density and markers of bone turnover, when compared to either drug alone [25]. However, the benefit of combined versus monotherapy for fracture reduction is unknown.

We do not suggest combination bisphosphonate-estrogen therapy or bisphosphonate-raloxifene therapy, as the additional benefits are small. In addition, the indications for using estrogen have been diminished since the results of the Women's Health Initiative were published. (See "Postmenopausal hormone therapy: Benefits and risks" and See "Overview of the management of osteoporosis in postmenopausal women").

With PTH — Because teriparatide (PTH) stimulates bone formation and bisphosphonates reduce bone resorption, it has been hypothesized that combining the two therapies would increase bone density more than either therapy alone. However, addition of alendronate to teriparatide therapy provides no additional benefits for bone mineral density, and reduces the anabolic effect of teriparatide in both women and men. (See "Parathyroid hormone therapy for osteoporosis", section on Combination therapy, and see "Treatment of osteoporosis in men", section on Combination therapy).

Formulations — Several formulations of alendronate are available:

For treatment of osteoporosis, a 10 mg daily or 70 mg once weekly formulation are available. Most patients prefer the convenience of the once-weekly regimen.
For prevention of osteoporosis: 5 mg daily or 35 mg once-weekly tablets.
A liquid formulation of alendronate is also available (70 mg/75 mL). This may be useful for patients who are unable to swallow pills.

Instructions for administration are found below. (See "Oral regimen" below).

Other indications — Alendronate is also effective and approved for use in male osteoporosis, Paget disease (30 mg once daily dose), and glucocorticoid-induced osteoporosis. (See "Treatment of osteoporosis in men", section on Bisphosphonates, and see "Treatment of Paget disease of bone", section on Alendronate, and see "Prevention and treatment of glucocorticoid-induced osteoporosis", section on Alendronate).

RISEDRONATE

Treatment — Risedronate (Actonel) improves BMD, reduces fracture risk, and is well-tolerated in postmenopausal women with osteoporosis [26,27]. This was illustrated in the Vertebral Efficacy with Risedronate (VERT) study of 2458 postmenopausal women with osteoporosis (either two or more vertebral fractures, or one vertebral fracture and lumbar spine T-score of -2.0 or less) who were randomly assigned to risedronate (5 mg/day) or placebo for three years with the following results [28]:

Bone density at the lumbar spine, femoral neck, and trochanter increased by 5.4, 1.6, and 3.3 percent, respectively, in the risedronate group, as compared with 1.1 percent, -1.2 percent, and -0.7 percent, respectively, in the placebo group.
The risk of vertebral and nonvertebral fractures was reduced by 41 and 39 percent, respectively, with risedronate. The three-year rates of new vertebral fractures with risedronate versus placebo were 11 and 16 percent, respectively, and 5 and 8 percent, respectively, for nonvertebral fractures.

Gastrointestinal and other adverse effects occurred with similar (low) frequency in both groups.

In a two-year extension study in 265 subjects, the effects of risedronate on vertebral fracture and bone mineral density appeared to be maintained [29].
In a second three-year randomized trial in postmenopausal women with osteoporosis, a similar overall reduction in vertebral and nonvertebral fracture risk was observed; the vertebral fracture risk reduction was evident during the first year of the trial [30].

Risedronate reduces the risk of hip fracture among elderly women with confirmed osteoporosis, but not among elderly women selected primarily on the basis of risk factors. This was illustrated in a randomized trial of 5445 women aged 70 to 79 years with osteoporosis (Group 1), and 3886 women aged 80 years or older selected primarily on the basis of nonskeletal risk factors (poor gait, smoking, propensity to fall) (Group 2) [31]. Although risedronate decreased overall hip fracture risk by 30 percent, the rate of hip fracture was reduced only in Group 1 (1.9 and 3.2 percent of women experienced hip fracture in the drug and placebo groups, respectively, RR 0.6), but not in Group 2, where hip fracture rate was similar (4.2 and 5.1 percent of women, respectively).

A meta-analysis of eight randomized trials of risedronate confirmed the fracture risk reduction in early postmenopausal women and in women with established osteoporosis [26]. For risedronate versus placebo, the pooled relative risk (RR) for vertebral and nonvertebral fractures with risedronate was 0.64 and 0.73, respectively.

Long term efficacy — Risedronate is effective and well-tolerated for up to seven years, as illustrated in a trial of 164 women, in whom improvements in BMD continued over the seven years of therapy, with no apparent loss of fracture risk reduction [32].

How long to treat? — As discussed previously, there is currently no consensus on how long to continue bisphosphonate therapy. In the FLEX trial described above, stopping alendronate after five years of therapy resulted in a gradual decline in BMD and increase in biochemical markers of bone turnover over a five year period.

When risedronate is discontinued, its beneficial effects on BMD and markers of bone turnover appear to revert partially or completely within one year, as reported in an extension of the VERT trial [28,33]. In this extension study, women who received risedronate or placebo for three years were reassessed one year after stopping therapy (but continuing vitamin D supplementation) [33]. BMD of the lumbar spine and femoral neck decreased (0.83 and 1.23 percent, respectively) in the group previously taking risedronate, although mean values remained higher than baseline (lumbar spine) and placebo (lumbar spine and femoral neck). However, markers of bone turnover returned to baseline and were the same as the placebo group within one year. Nonetheless, the incidence of new vertebral fractures in patients previously treated with risedronate remained lower (6.5 versus 11.6 percent).

Given these results, stopping risedronate after three years of therapy may be an option for some women, but because bone turnover markers revert to the untreated state within one year, we do not suggest discontinuing risedronate after three years of use, especially in those individuals at high risk for fracture.

Weekly dose — Weekly risedronate (35 mg) is as effective and well tolerated as daily administration of 5 mg [34-36].

Monthly dose — Monthly risedronate (150 mg once monthly or 75 mg tablets on two consecutive days each month) has similar efficacy for increasing spine and hip BMD as daily administration of 5 mg [37-39].

Prevention — Risedronate is also effective for prevention of bone loss in postmenopausal women with normal bone density [40], and postmenopausal women with low bone density but no fractures [26,41].

Other indications for risedronate include osteoporosis in men, glucocorticoid-induced osteoporosis, and Paget disease. (See "Treatment of osteoporosis in men", section on Bisphosphonates, and see "Prevention and treatment of glucocorticoid-induced osteoporosis", section on alendronate, and see "Treatment of Paget disease of bone", section on alendronate).

Combination therapy — Addition of estrogen therapy to risedronate may provide a modest additional benefit [42], but we do not suggest the routine use of combined risedronate-estrogen therapy, given the known risks of estrogen therapy. (See "Postmenopausal hormone therapy: Benefits and risks").

Formulation — Risedronate formulations available for clinical use include: a daily (5 mg), weekly (35 mg) and monthly (single 150 mg tablet or 75 mg tablets on two consecutive days each month) dose (all used for the treatment and prevention of postmenopausal and glucocorticoid-induced osteoporosis).

In addition, a 30 mg once daily formulation is available for the treatment of Paget disease. (See "Treatment of Paget disease of bone", section on Bisphosphonates).

Risedronate may also be effective for men with osteoporosis, but it is less well studied. (See "Treatment of osteoporosis in men", section on Bisphosphonates).

Instructions for administration are found below. (See "Oral regimen" below).

Alendronate versus risedronate — Alendronate and risedronate have been compared in one prospective randomized and some retrospective observational trials. In the randomized trial, alendronate increased bone density more than risedronate at all sites after 12 months [43]. Results persisted in year two of the study [44]. However, there were no differences in the incidence of fractures, which were reported only as adverse events. In one observational study, treatment with risedronate was associated with a decreased risk of fracture in the first year of therapy [45]. However, this study was limited by the inability to accurately characterize fracture risk at baseline between the two groups. Thus, although alendronate may have a greater effect on bone mineral density when compared to risedronate, the clinical relevance of this finding is unclear. A prospective randomized trial with fracture as a defined endpoint is necessary to determine if there is a difference in fracture prevention efficacy between the two bisphosphonates.

IBANDRONATE — Ibandronate is a newer bisphosphonate that is approved for prevention and treatment of osteoporosis [46]. A daily regimen (2.5 mg/day), and intermittent regimen (20 mg every other day for 12 doses every 3 months) are equally effective for increasing bone mineral density and reducing vertebral fracture risk, when compared to placebo [47]. However, a significant reduction in hip fracture was not seen. The daily formulation was approved for use in 2003, but was never marketed.

Monthly dose — A once-monthly 150 mg oral formulation is available for both prevention and treatment of osteoporosis [48]. In a trial of 1609 postmenopausal women with osteoporosis randomly assigned to receive daily ibandronate (2.5 mg), ibandronate 50 + 50 mg once-monthly [single doses given on consecutive days], 100 mg once-monthly, or 150 mg once-monthly, the following results were seen after two years of follow-up [49]:

Increases in lumbar spine bone density were observed in all treatment groups (5.0, 5.3, 5.6, and 6.6 percent in the daily, 50 + 50 mg, 100 mg, and 150 mg groups, respectively). The increases in the 50 + 50 and 100 mg group were not statistically different from the daily 2.5 mg group, while the increase in the 150 mg group was significantly greater than the 2.5 mg daily group.
Similar results were seen for hip bone density.
No differences in adverse events were noted.
Fracture data were not reported.

Thus, monthly ibandronate (150 mg) appears to improve BMD more than daily administration (2.5 mg). The manufacturer of the monthly formulation will also provide monthly reminders for patients. The monthly formulation may therefore increase overall compliance with therapy [49].

In the absence of consistent clinical trial data that ibandronate reduces hip fracture risk, we continue to suggest alendronate or risedronate as our first choice for bisphosphonate therapy in patients at high risk for fractures.

Intravenous — An intravenous formulation of ibandronate (3 mg every three months) appears to improve BMD to a similar or greater degree than daily oral ibandronate (2.5 mg/day) [50,51]. This formulation provides an alternative option for patients who cannot tolerate oral bisphosphonates, or who have difficulty with dosing requirements, including an inability to sit upright for 30 to 60 minutes and/or to swallow a pill.

Meta-analyses of phase III studies, in which fracture data were collected as adverse effects, have shown a reduction in nonvertebral fractures with higher doses of ibandronate (pooled data from IV dosing [2 or 3 mg every two to three months] and oral dosing [150 mg monthly]) [52,53]. However, there is no direct fracture efficacy data for IV ibandronate. In the absence of this data, zoledronic acid is our first choice for IV bisphosphonate therapy in patients who cannot tolerate oral therapy. (See "Zoledronic acid" below).

ZOLEDRONIC ACID — Zoledronic acid (ZA) is another intravenous bisphosphonate, which is administered once yearly (as a 15 minute infusion) rather than quarterly. It increases BMD and reduces fracture risk. It is approved in many countries, including the United States, for the treatment of osteoporosis.

The efficacy of ZA for the treatment of osteoporosis is demonstrated in the following studies:

In a study of five regimens of intravenous ZA infused over five minutes (1 to 4 mg administered as one to four doses over one year), lumbar spine bone density increased similarly in all five groups (4.3 to 5.1 percent) [54].

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, 7765 postmenopausal women with osteoporosis were randomly assigned to 5 mg of ZA or placebo, administered intravenously once yearly for three consecutive years [55]. Bone mineral density increased at the spine, total hip, and femoral neck and markers of bone turnover decreased in the ZA group compared with placebo.

In addition, there was a significant reduction in fracture. The three-year incidence of vertebral fracture was 10.9 percent in the placebo group versus 3.3 percent in the ZA group, a reduction of 70 percent (RR 0.30, 95% CI 0.24-0.38). The incidence of hip fracture was 2.5 and 1.4 percent in the placebo and ZA groups, respectively, a 41 percent reduction (hazard ratio 0.59, 95%CI 0.42-0.83).

In the HORIZON Recurrent Fracture Trial, 2127 men and women with hip fracture were randomly assigned to receive yearly ZA (5 mg) or placebo within three months of surgical repair [56]. Subjects also received vitamin D (50,000 to 125,000 IU 14 days prior to infusion, if 25OHD concentration was <15 mg/dl or unknown, and 800 to 1200 IU daily thereafter) and calcium. After a median follow-up of 1.9 years, new fractures occurred in 8.6 and 13.9 percent of individuals in the ZA and placebo groups, respectively, representing a relative risk reduction of 35 percent (HR 0.65, 95% CI 0.5-0.8). All-cause mortality, a secondary safety endpoint, was lower in the ZA compared with placebo group (HR 0.72, 95% CI 0.56-0.93).

Although there were no differences in serious adverse events or discontinuation because of adverse events, ZA was associated with an expected increase in post-infusion flu-like symptoms and mild transient hypocalcemia in both HORIZON studies. In addition, in the Pivotal Fracture Trial there was an unexpected increase in atrial fibrillation, which was not seen in the Recurrent Fracture Trial. There were no long-term adverse effects on renal function. A thorough search of the safety database yielded two cases of potential osteonecrosis of the jaw, one in the ZA group and one in the placebo group. (See "Adverse effects" below).

Thus, in the HORIZON studies, yearly IV ZA was associated with an improvement in BMD, a decrease in spine and hip fractures in postmenopausal women with osteoporosis (Pivotal Fracture Trial) , and a decrease in recurrent clinical fractures in men and women with recent hip fracture (Recurrent Fracture Trial). The infusions were relatively well tolerated, given the known association between intravenous bisphosphonates and flu-like symptoms.

Despite the availability of effective oral bisphosphonates, such as alendronate and risedronate, poor adherence to oral drug regimens is common. IV ZA offers an alternative option for individuals who cannot tolerate oral bisphosphonates or who find the dosing regimen more convenient. Ideal durations of therapy and long-term safety (>3 years) have not been established.

OTHER BISPHOSPHONATES — A number of other bisphosphonates are available but are used less often (or not at all) for osteoporosis.

Etidronate — Etidronate was the first bisphosphonate used in the treatment of osteoporosis. It increased bone mineral density and decreased vertebral but not nonvertebral fractures, and it was never approved for treating postmenopausal osteoporosis. In addition, there was concern that long term use may cause osteomalacia. Therefore, it has been superseded by other bisphosphonates.

Tiludronate — Tiludronate, an effective therapy for Paget disease of bone, has not been demonstrated to be effective for the treatment or prevention of osteoporosis. (See "Treatment of Paget disease of bone").

Pamidronate — Pamidronate, an intravenous preparation, has been used primarily for the treatment of hypercalcemia, and prevention of skeletal complications in multiple myeloma, breast cancer, and prostate cancer. (See "Treatment of hypercalcemia" and see "Bisphosphonates in breast, prostate, and other solid tumors", section on Pamidronate).

Pamidronate is also effective for osteoporosis, and has been used for patients with osteoporosis who could not tolerate oral bisphosphonates [57]. However, it has been superseded by zolendronic acid and in some cases intravenous ibandronate.

ORAL REGIMEN — Bisphosphonates are poorly absorbed orally (less than one percent of the dose) [58], and must be taken on an empty stomach for maximal absorption. The following regimen is recommended to maximize absorption and minimize the risk of esophageal adverse effects. (See "Gastrointestinal" below).

Bisphosphonates should not be given to patients with active upper gastrointestinal disease.

Bisphosphonates should be discontinued in patients who develop any symptoms of esophagitis.

Bisphosphonates should be taken alone on an empty stomach first thing in the morning with at least 240 mL (8 oz) of water while sitting or standing to minimize the risk of the tablet getting stuck in the esophagus. After administration, the patient should not have food, drink, medications, or supplements for at least one-half hour (alendronate, risedronate) or one hour (ibandronate).

Bioavailability may be seriously impaired by ingestion with liquids other than plain water, such as mineral water, coffee, or juice, or by retained gastric contents, as with insufficient fasting time or gastroparesis, or by eating or drinking too soon after taking the bisphosphonate.

Patients should remain upright for at least 30 minutes before eating, both to minimize the risk of reflux and improve absorption of the drug.
Compliance is also important for optimal fracture reduction [59,60].

Timing of dose — Administration of bisphosphonates first thing in the morning, prior to breakfast, appears to be important for bioavailability and subsequent suppression of bone turnover. This was illustrated in a randomized trial of nursing home residents who were assigned to risedronate or placebo between meals (after a two-hour fast) for 12 weeks, rather than before breakfast or the first liquid of the day [61]. Markers of bone turnover were not suppressed as they typically would be with before-breakfast administration, suggesting that this alternative schedule may not provide the desired effects on bone mineral density.

IV REGIMEN — Intravenous bisphosphonates (zoledronic acid and ibandronate) provide an alternative option for patients who cannot tolerate oral bisphosphonates, or who have difficulty with dosing requirements, including an inability to sit upright for 30 to 60 minutes and/or to swallow a pill. IV bisphosphonates may be associated with flu-like symptoms and hypocalcemia. Acetaminophen can be administered to prevent or treat flu-like symptoms.

Hypocalcemia is more likely to occur in those individuals with vitamin D deficiency, and therefore, it can be minimized by vitamin D and calcium supplementation. A serum calcidiol (25-hydroxyvitamin D) concentration should be assessed prior to IV bisphosphonate infusions. Individuals with vitamin D deficiency (25-hydroxyvitamin D <15 ng/mL [37 nmol/L]) should be treated prior to the infusion. (See "Treatment of vitamin D deficient states"). Increasing calcium supplementation (doubling of usual dose) for five to seven days, starting on the day of the infusion, may also minimize hypocalcemia. (See "Adverse effects" below).

KIDNEY DISEASE — Patients with chronic kidney disease with creatinine clearance (CCr) above 30 to 35 mL/min are usually managed similarly, with appropriate modification of bisphosphonate doses based upon level of kidney function [62-64]. However, there is little data about fracture prevention efficacy and long-term adverse effects in subjects with reduced renal function, and bisphosphonates are generally not recommended for those with CCr below 30 to 35 mL/min.

Retrospective analyses of the Fracture Intervention Trial (FIT) data and pooled data from nine risedronate studies revealed that 7 to 10 percent of subjects had severe renal impairment (defined as an eGFR <30 to 45 ml/min) and 37 to 45 percent had moderate impairment (eGFR ≥30 to 59 ml/min) as estimated by the Cockcroft-Gault formula [64,65]. Compared with placebo treated women, alendronate and risedronate increased BMD and prevented vertebral fracture regardless of degree of renal impairment.

There were no differences in the adverse event rate between subjects with normal or reduced renal function in either study. In the FIT study, there was a small increase in creatinine during the three year study, but the increase was similar in those with and without reduced renal function (mean increase in both groups 0.01 +/- 0.10) and in those taking placebo or alendronate. There was no increase in serum creatinine in the risedronate studies (mean exposure of two years).

Thus, bisphosphonates appear to be effective in individuals with moderately reduced renal function. However, women with serum creatinine >1.27 mg/dl (112 mmol/liter) or serum PTH >85 pg/ml were excluded from participation in FIT, ie, women with renal dysfunction resulting in secondary hyperparathyroidism were not treated with alendronate. Therefore, there is inadequate data with regard to fracture prevention efficacy in those with more severe kidney disease resulting in secondary hyperparathyroidism and in end-stage renal failure.

With progression of renal failure, serum PTH concentrations rise, and the bone morphologic features of renal osteodystrophy [osteitis fibrosis cystica (due to secondary hyperparathyroidism), osteomalacia, adynamic bone disease, and/or mixed osteodystrophy], rather than osteoporosis, become predominant. The principal goal with regard to bone disease in patients with significant renal dysfunction is to prevent or manage renal osteodystrophy, largely by controlling secondary hyperparathyroidism. In this setting, the diagnosis of osteoporosis should be made only after excluding renal osteodystrophy. The diagnosis and management of renal osteodystrophy and secondary hyperparathyroidism are discussed in detail elsewhere. (See "Active vitamin D analogs and calcimimetics to control hyperparathyroidism in chronic kidney disease").

MONITORING THE RESPONSE — Serial BMD measurements are performed to assess the clinical response to therapy. This topic is reviewed in detail elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women", section on Monitoring the response to therapy, and see "Overview of dual-energy x-ray absorptiometry", section on Interpretation of BMD changes, and see "Use of biochemical markers of bone turnover in osteoporosis").

ADVERSE EFFECTS

Gastrointestinal — Gastrointestinal side effects have been the primary concern for patients taking oral bisphosphonates. However, the incidence of these side effects is very low if proper administration instructions are followed. (See "Oral regimen" above).

Alendronate — In clinical trials, the incidence of upper gastrointestinal problems in women receiving alendronate daily [6,66] or once weekly [67] was not different from those receiving placebo. However, pill-induced esophagitis and esophageal ulcers can occur, and may be disabling and require hospitalization or rarely lead to esophageal stricture [68,69]. In addition, endoscopically apparent gastric ulcers have been described in patients receiving a bisphosphonate [70]. The risk may be potentiated by concomitant use of a nonsteroidal antiinflammatory drug [71].

Esophageal complications are infrequent if patients follow the recommendations outlined above [2,4-6]. (See "Oral regimen" above). There has been concern that these complications may be more frequent in ordinary practice than in clinical trials, because patients with dyspepsia were excluded from the trials [72]. However, in a study of 72 patients who discontinued alendronate because of gastrointestinal side effects and who were then randomly assigned to a rechallenge with either alendronate or placebo, 15 percent of the patients taking alendronate and 17 percent of those taking placebo stopped treatment because of gastrointestinal side effects. These data suggest that many of the gastrointestinal side effects seen reflect a high background incidence of gastrointestinal complaints, rather than an alendronate-specific effect [73-75].

Risedronate — The risk of upper gastrointestinal side effects with risedronate also appears to be low.

In clinical trials, the incidence of gastrointestinal side effects was not different from placebo [28].

In an endoscopic study of 515 postmenopausal women receiving risedronate (5 mg/day) or alendronate (10 mg/day) for two weeks, significantly fewer patients in the risedronate group had gastric ulcers (4.1 percent versus 13.2 percent for alendronate) [76]. Another endoscopic trial confirmed these findings [77]. However, a third randomized endoscopy study comparing risedronate to alendronate found no difference in ulcerations between the two agents [78].

In a pooled analysis of nine clinical trials that included 10,068 patients randomly assigned to risedronate (5 mg/day) or placebo for up to three years, upper gastrointestinal tract adverse events were no different between the two groups (29.8 and 29.6 percent, respectively) [79]. Unlike clinical trials with alendronate, patients with active gastrointestinal disease were not excluded from the studies. (See "Medication-induced esophagitis").

Thus, the risk of esophageal adverse effects appears to be low with risedronate, even in patients with a history of esophageal disease.

Flu-like symptoms — Intravenous bisphosphonates are often associated with an acute-phase reaction within 24 to 72 hours of the infusion, characterized by low grade fever, myalgias, and arthralgias. Treatment with antipyretic agents (ibuprofen or acetaminophen) generally improves the symptoms, and the recurrence of symptoms decreases with subsequent infusions.

In the HORIZON trial, the most commonly reported side effects were fever, flu-like symptoms, myalgia, headache, and arthralgia, which occurred within three days after the first infusion in 32 percent of individuals in the ZA group [55]. Post-dose symptoms decreased in frequency in the ZA group after the second and third infusion (6.6 and 2.8 percent, respectively).

Other

Hypocalcemia — Treatment with an oral bisphosphonate lowers serum calcium concentrations, but clinically important hypocalcemia has been reported only in patients with hypoparathyroidism [80]. It might also be expected in patients with vitamin D or calcium deficiency.

In the HORIZON trial, hypocalcemia (calcium < 8.3 mg/dl [2.075 mmol/L]) occurred more commonly with intravenous ZA than with placebo (1.3 versus 0.02 percent) [55]. Hypocalcemia was noted nine to eleven days post infusion and was reported to be transient and asymptomatic. However, hypocalcemia may be more severe and prolonged in individuals who are vitamin D deficient at the time of IV treatment [81,82]. (See "IV regimen" above).

Ocular side effects — Ocular side effects including pain, blurred vision, conjunctivitis, uveitis, and scleritis have been reported with most bisphosphonates. However, these complications appear to be rare [55,83-85].

Musculoskeletal pain — Although rare, some patients have experienced severe musculoskeletal pain (bone, joint, and/or muscle pain) while taking oral bisphosphonates [86-88].

Osteonecrosis of the jaw — Osteonecrosis of the jaw (ONJ, avascular necrosis of the jaw), often associated with pain, swelling, exposed bone, local infection, and pathologic fracture of the jaw, has been described in patients receiving chronic bisphosphonate therapy. Risk factors for developing ONJ include intravenous bisphosphonates, cancer and anti-cancer therapy, duration of exposure, dental extractions, dental implants, poorly fitting dentures, glucocorticoids, smoking, and pre-existing dental disease [89,90]. (See "Risks of bisphosphonate therapy in patients with malignancy", section on Osteonecrosis of the jaw).

Although most cases have been in cancer patients or in patients with a compromised immune system (particularly multiple myeloma and metastatic breast cancer), who were treated with intravenous bisphosphonates, cases have been noted in patients with postmenopausal osteoporosis taking oral bisphosphonates [91,92]. It has been estimated that the risk of ONJ is approximately 1 in 10,000 to 1 in 100,000 patient-years in patients taking oral bisphosphonates for osteoporosis [89,93,94]. There is little data on the risk of ONJ in patients using intravenous bisphosphonates at doses recommended for the treatment of osteoporosis. In two clinical trials of zoledronic acid versus placebo for the treatment of osteoporosis, there were two potential cases of ONJ (one in each group). (See "Zoledronic acid" above).

In patients initiating or receiving treatment with oral bisphosphonates for the treatment of osteoporosis, the American Society of Bone and Mineral Research recommends that clinicians discuss the risk, signs, and symptoms of ONJ, and the risk factors for developing ONJ [89]. Although good oral hygiene and regular dental visits are encouraged, a dental visit prior to beginning oral bisphosphonates is not necessary.

In patients already receiving oral bisphosphonates, there is particular concern for patients scheduled for invasive dental procedures that involve the jaw, such as extractions or implants.

The American Association of Oral and Maxillofacial Surgeons suggest performing dentoalveolar surgery, such as extractions and implants, as usual in patients who have been treated with oral bisphosphonates for less than three years. However, if a patient has been treated for more than three years, they recommend discontinuing oral bisphosphonates for three months prior to performing the dental surgery and restarting when the bone has healed [95]. These criteria were chosen on the basis of clinical experience and observational data as to which patients are at higher risk for developing ONJ.

However, there are no data to suggest that this would lower ONJ risk. In addition, bisphosphonates stay in bone for years, not months. But if a patient chooses to stop the bisphosphonate, it is unlikely that there would be adverse consequences on BMD or fracture risk.

Potential complications and recommendations for patients receiving bisphosphonates for the treatment of malignancy are described in detail elsewhere. (See "Risks of bisphosphonate therapy in patients with malignancy", section on Osteonecrosis of the jaw).

Arrhythmia — Bisphosphonates in general have not been associated with atrial arrhythmias. However, in the HORIZON Pivotal Fracture Trial, the number of patients who had arrhythmia, including serious atrial fibrillation (AF), was greater in the ZA compared with placebo group (1.3 versus 0.5 percent) [55]. In contrast, an increase in atrial arrhythmia was not seen in the HORIZON Recurrent Fracture Trial, which included older individuals and identical dosing. Hypocalcemia may be related to AF. However, most of the events occurred more than 30 days after the infusion, at which time mild, transient hypocalcemia would have resolved. Whether the acute-phase reaction contributes to the risk of AF is unclear.

This finding in the HORIZON Pivotal Fracture Trial prompted additional review, as illustrated by the following:

In a retrospective review of the Fracture Intervention Trial data, there was a trend toward an increased risk of serious AF in the alendronate compared with placebo group (relative hazard 1.5, 95% CI 0.97-2.40) [96].

In a retrospective analysis of clinical trials of risedronate versus placebo for the treatment of osteoporosis, there was no difference in the incidence of AF (reported as an adverse or serious adverse event) [97].

In a population based case-control study from Denmark, which evaluated 13,586 patients with atrial arrhythmia and 68,054 population controls, current, former, or new use of bisphosphonates (etidronate and alendronate) was not associated with an increased risk of atrial fibrillation or flutter (adjusted RR for current use compared with non-use 0.95, 95% CI 0.84-1.07) [98].

In another case-control study from the US (719 women with AF, 966 control subjects), ever use of alendronate was associated with a higher risk of AF than never use (odds ratio [OR] 1.86, 95% CI 1.09-3.15) [99]. However, the risk of AF was increased in past (OR 3.27, 95% CI 1.43-7.47), not current users (OR 1.42, 95% CI 0.78-2.59). In addition, the risk was not temporally related to the interval since first prescription or dose of alendronate.

Thus, data on the potential increased risk of atrial fibrillation with bisphosphonates are conflicting. However, the large observational study from Denmark and the absence of an association between current use and AF in the US case-control study suggest that the risk of atrial fibrillation from oral bisphosphonates is small, if it exists at all.

The observed association between intravenous zoledronic acid and atrial fibrillation may be plausible, but the studies do not prove causality. Osteoporosis and atrial fibrillation are more common in the elderly and share similar risk factors, which may explain the reported findings. In the absence of more definitive data, the benefits of fracture prevention must be weighed against the potential risk of atrial fibrillation, and some caution should be employed when considering IV bisphosphonates for patients with serious underlying heart disease and/or a history of atrial fibrillation.

Theoretical risks — Bisphosphonates inhibit bone resorption by suppressing osteoclast activity. Although clinical trial data clearly support the beneficial effect of bisphosphonates on the prevention of osteoporotic fracture, there is theoretical concern that prolonged therapy leads to oversuppression of bone turnover ("frozen bone") and increased skeletal fragility [100]. In animal studies, high-dose bisphosphonate accumulation results in microscopic damage [101]. Although similar findings do not appear to be common by histomorphometry in postmenopausal women on long-term bisphosphonates [102], individual cases of atypical fracture (particularly sub-trochanteric fractures) and severely suppressed bone turnover in the setting of prolonged bisphosphonate therapy have been reported [103,104].

The observed association in the case reports does not prove causality, and additional studies are required to determine if oversuppression of osteoclasts by prolonged bisphosphonate therapy can result in atypical fractures in selected individuals. Such data would also influence decisions on duration of therapy. Stopping bisphosphonate therapy after five years (with careful BMD and risk factor assessment follow-up) may be reasonable for some women (stable BMD, no previous vertebral fractures, and who are at low risk for fracture in the near future), but concern about oversuppression of bone turnover is not a reason to stop bisphosphonate therapy in the vast majority of women. (See "How long to treat?" aboveSee "How long to treat?" above and see "Duration of therapy" belowsee "Duration of therapy" below).

DURATION OF THERAPY — There is currently no consensus on how long to continue bisphosphonate therapy. Alendronate and risedronate have demonstrated efficacy for 10 and 7 years, respectively. Stopping therapy after five years may be reasonable for some women, as there appears to be residual BMD and fracture benefit. (See "How long to treat?" aboveSee "How long to treat?" above).

Many practitioners give a drug "holiday" after five years of therapy in an attempt to reduce the risk of ONJ, an extremely rare complication. However, there are no data to suggest that this reduces ONJ risk. (See "Risks of bisphosphonate therapy in patients with malignancy", section on Osteonecrosis of the jaw).

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Osteoporosis prevention and treatment"). We encourage you to print or e-mail this topic, or to refer patients to our public web site www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS — Bisphosphonates, one of the available therapeutic options for the management of osteoporosis, inhibit bone resorption with relatively few side effects. As a result, they are widely used for the prevention and treatment of osteoporosis. Candidates for pharmacologic therapy for prevention and treatment are discussed elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women", section on Candidates, and see "Prevention of osteoporosis").

Prevention — For most postmenopausal women, pharmacological therapy for prevention of osteoporosis is not necessary. However, it should be considered for women at high risk of fracture. (See "Prevention of osteoporosis").

For postmenopausal women who are candidates for and desire pharmacologic therapy for prevention of osteoporosis, we recommend bisphosphonates or raloxifene as first-line choices (Grade 2B). (See "Prevention of osteoporosis").

The dose for prevention for both alendronate and risedronate is 35 mg given once-weekly. (See "Alendronate" aboveSee "Alendronate" above, and see "Risedronate" abovesee "Risedronate" above).

Treatment

For postmenopausal women with established osteoporosis or fragility fracture, we recommend pharmacologic therapy (Grade 1A).
Additional information about candidates for pharmacologic therapy are found elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women").

For treatment of osteoporosis in postmenopausal women, we suggest bisphosphonates as first-line therapy (Grade 2B).

We favor bisphosphonates over raloxifene for osteoporosis treatment because they increase bone mineral density (BMD) more than raloxifene, and have documented hip fracture efficacy. (See "Overview of the management of osteoporosis in postmenopausal women", section on Recommendations).

Choice of bisphosphonate

For postmenopausal women with osteoporosis, we suggest either weekly alendronate or risedronate as the initial choice of bisphosphonate (Grade 2B). Alendronate is available in a liquid preparation for individuals who cannot swallow pills. Although oral ibandronate may be more convenient for patients, a reduction in hip fracture risk has not been established. (See "Ibandronate" above).

For women with a history of significant gastroesophageal reflux or peptic ulcer disease, we suggest initial therapy with risedronate over alendronate, to minimize adverse gastrointestinal side effects (Grade 2B). (See "Gastrointestinal" above).
We suggest an intravenous bisphosphonate formulation for patients who cannot tolerate oral bisphosphonates, or who have difficulty with dosing requirements, including an inability to sit upright for 30 to 60 minutes (Grade 2B). Zoledronic acid is the only intravenous bisphosphonate that has demonstrated efficacy for fracture prevention in clinical trials and is therefore our agent of choice. However, long-term safety data in patients with osteoporosis is lacking. (See "Zoledronic Acid" above).

Dental procedures

For patients scheduled for invasive dental procedures, we suggest not stopping bisphosphonates (Grade 2C). However, the risk of developing ONJ as a rare complication of intravenous or oral therapy should be discussed with patients.
There are no data to suggest that discontinuing bisphosphonates for dental procedures would lower ONJ risk. In addition, bisphosphonates stay in bone for years, not months. However, if a patient chooses to stop the bisphosphonate, it is unlikely that there would be short term adverse consequences on BMD or fracture risk. (See "Osteonecrosis of the jaw" above).

Duration of therapy

For patients on bisphosphonates for five years who are at high risk of fracture (previous fractures, older age, frail, high risk for fall, etc), we suggest continuing therapy (Grade 2B).

Residual benefit after stopping therapy has not been demonstrated in this population. In addition, the benefits of continued therapy likely outweigh the risk of ONJ, an extremely rare complication.

For patients taking alendronate for five years who have a stable BMD, no previous vertebral fractures, and who are at low risk for fracture in the near future, we suggest discontinuing the drug (Grade 2C). We then monitor BMD and urinary markers of resorption. The drug should then be resumed if BMD decreases or urinary markers of bone turnover increase.

Data demonstrating residual benefit after stopping risedronate after five years of use are not yet available. Until such studies are available, for patients taking risedronate for three years, we suggest continuing therapy (Grade 2C).

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REFERENCES

Androgen production and therapy in women

2008-09-30T11:02:00.000-07:00

Androgen production and therapy in women

Author
Laurence Udoff, MD
Section Editor
Robert L Barbieri, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD

Last literature review version 16.2: May 2008 | This topic last updated: May 28, 2008 (More)

INTRODUCTION — All women produce some androgens, which may contribute to maintaining normal ovarian function, bone metabolism, cognition and sexual behavior. This topic will review androgen production in pre- and postmenopausal women and the effects of androgen therapy in postmenopausal women. Female sexual dysfunction, including hypoactive sexual desire disorder, is discussed elsewhere. (See "Etiology and diagnosis of sexual dysfunction in women" and see "Treatment of sexual dysfunction in women").

ANDROGEN PRODUCTION

Premenopausal women — The major androgens in the serum of normal cycling women are dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione (A), testosterone (T), and dihydrotestosterone (DHT) in descending order of serum concentrations [1] .

Though abundant in the circulation, DHEA-S, DHEA, and A may be considered pro-hormones requiring conversion to T or DHT to express their androgenic effects. Androgens are mainly produced in the adrenal gland, the ovary and from the peripheral conversion of pro-hormones.

• DHEA-S is produced solely by the adrenal gland at a rate of 3.5 to 20 mg per day [2] . Circulating levels are in the range of 1 to 4 mcg/mL.
• DHEA is also produced in the adrenal gland (50 percent), the ovary (20 percent) and from peripheral conversion of DHEA-S (30 percent) with total production rates of 6 to 8 mg per day [3] . Circulating levels are in the range of 1 to 10 ng/mL.
• A production is split equally between the adrenal gland and the ovary. Daily rates of production are 1.4 to 6.2 mg/day and circulating levels are in the range of 0.5 to 2 ng/mL [4,5] .
• T is synthesized in the adrenal gland (25 percent), the ovary (25 percent) and from the peripheral conversion of A (50 percent). Daily production rates are in the range of 0.1 to 0.4 mg/day and circulating levels are between 0.2 and 0.7 ng/mL with the lowest levels found during the early follicular phase followed by a 20 percent increase at midcycle [3] . Nearly all (99 percent) of circulating T is protein-bound (mainly to sex-hormone binding globulin [SHBG]) [6] . Therefore, any impact on SHBG concentration (eg, oral estrogen-mediated increase in SHBG) affects the concentration of the free/active androgen.
• Lastly, DHT is mainly a peripheral product of T conversion and has very low circulating levels [7] .

All the major androgens are metabolized and excreted into the urine almost exclusively as 17-ketosteroids.

Natural history — In a report of normal women ages 18-75 years, serum androgen concentrations (total and free testosterone, DHEA-S, and androstenedione) gradually declined in women of reproductive age [8,9] , with no further decrease after clinical menopause [10] .

Putative roles for androgens — Androgens are essential precursors for estrogen synthesis. They also play an important role in follicular development. Maintenance of a precise balance of estrogens and androgens within ovarian follicles is a requirement for successful follicular maturation [11-13] . In addition, many tissues have androgen receptors, including the central nervous system [14] and bone [15] , which has led to speculation that androgens affect their function.

It has also been proposed that androgens play a role in sexual behavior. A woman's libido is dependent upon many factors, including psychological factors [16] . As an example, in a study of 341 peri- and postmenopausal women, common menopausal symptoms, including depression, sleep disturbances, and night sweats, were associated with diminished libido [17] .

A balance of estrogen and androgen also may be necessary for normal sexual desire and responsiveness, but the results of studies on the role of androgens in sexuality in normal premenopausal women are inconclusive [9,16] . As an example, a cross-sectional study of a population-based cohort of women ages 48 to 58 years suggested that most aspects of female sexual function were not affected by age, menopausal functioning, or serum sex hormone concentrations [9] . Additionally, a study comparing women with premature ovarian failure with normal premenopausal controls did not find an important role for circulating androgens in sexual functioning [18] .

The special case of adrenal insufficiency may be an exception, as data suggests that young women with this condition may show improvement in sexuality with the addition of DHEA to their replacement regimen. (See "Dehydroepiandrosterone and its sulfate", section on Adrenal insufficiency).

Androgens may also be important for the maintenance of normal affect, cognitive functioning and of skeletal homeostasis. (See "Cognitive function" below and see "Bone metabolism" below). Regarding the latter, a significant body of evidence exists implicating a role for androgens in the maintenance of bone health. Androgens may impact bone homeostasis directly (eg, all bone cells including osteoblasts, osteoclasts, and osteocytes have androgen receptors), or indirectly by conversion to estrogen, or by their effect on local and systemic factors that control the bone cells' microenvironment [15] .

Low serum androgen concentrations may be associated with lower bone density and fracture risk:

• Serum free androgen concentrations and bone mineral density have been positively correlated in several studies [19-21] .
• In another study, postmenopausal women with a history of vertebral crush fractures had lower serum free androgen concentrations (and similar serum estrogen values) when compared to women with no fractures [19] .
• Women with hypopituitarism (who are androgen deficiency) have low bone density [22] .

Postmenopausal women — The production rate and serum concentrations of androstenedione fall by 50 percent after the menopause (show figure 1) [23,24] . This change appears to result from decreased ovarian production of the hormone with the adrenal glands becoming the major site of androstenedione production. This hypothesis is based upon the following findings in postmenopausal women:

• Administration of corticotropin (ACTH), but not human chorionic gonadotropin (hCG), raises serum androstenedione concentrations.
• Serum androstenedione concentrations fall little after oophorectomy, but markedly after the administration of dexamethasone, which suppresses the release of ACTH.
• There is a diurnal variation in serum androstenedione concentrations that parallels the diurnal variation in serum cortisol concentrations.
• The ratio of androstenedione in ovarian venous blood to peripheral venous blood is decreased [24] .

The rate of testosterone production also falls in postmenopausal women (show figure 2) [25,26] , mostly because of a decline in the peripheral production of testosterone from androstenedione [27] . Ovarian testosterone production remains relatively constant, thereby increasing the relative ovarian contribution to overall testosterone production [27] . These observations are substantiated by the larger ovarian-to-peripheral serum gradient of testosterone in postmenopausal than in premenopausal women [24] , and by the 40 to 50 percent decrease in serum testosterone concentration seen after oophorectomy in postmenopausal women [28] , a change that persists over time [29] .

In addition to this decline in ovarian androgen secretion, there is an age-related decline in the adrenal androgens dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S). As an example, in women ages 40 to 50, serum DHEA concentrations are approximately 50 percent of the peak concentrations seen in younger women [30] . (See "Dehydroepiandrosterone and its sulfate").

Serum androstenedione and testosterone concentrations fall little with advancing age after the menopause, despite a progressive fall in serum DHEA concentrations [31] . This difference suggests that little androstenedione and testosterone are derived from DHEA in older women, and that ovarian androstenedione and testosterone production increases or their clearance decreases with age [32] .

The decline in ovarian androgen production in postmenopausal women is much less than the decline in estrogen production; as a result, the ovaries become primarily androgen-producing glands. The relatively high rate of androgen production is due to the increase in gonadotropin secretion, which stimulates steroidogenesis in ovarian hilar cells or luteinized stromal cells [32] . Ovarian stromal tissue has receptors for both follicle-stimulating hormone and luteinizing hormone [30,33] , and chorionic gonadotropin (hCG) stimulates androstenedione, estradiol and progesterone secretion by isolated ovarian cortical stromal and hilar cells [34,35] . In addition, postmenopausal women given hCG have a small increase in serum testosterone concentrations [36] and hyperplasia of their ovarian hilar cells [37] ; in comparison, their serum estrogen concentrations do not increase [38] .

The vast majority of evidence suggests that the postmenopausal ovary is a major androgen-producing gland [27-38] , with the exception of one study [39] . In 10 postmenopausal women with adrenal insufficiency, women with natural and surgical menopause had undetectable serum androgen concentrations. In addition, ovarian stimulation with hCG did not increase circulating levels of androgens in the women with intact ovaries. Negligible levels of T and A were found in ovarian homogenates, and ovarian immunocytochemistry did not detect the presence of enzymes for androgen synthesis. These data have not been confirmed by other investigators.

ANDROGEN DEFICIENCY — Women with low levels of circulating androgens are said to have androgen deficiency or androgen insufficiency syndrome. However, there are no clear biochemical criteria for this syndrome; measurement of serum androgen concentrations, in particular, free testosterone, is problematic because of a lack of validated assays in the female range (much lower than the male range); there are no age-based normative data; and serum androgen concentrations do not appear to be an independent predictor of sexual function in women [40-44] .

An Endocrine Society Clinical Practice Guideline recommended against making a diagnosis of androgen deficiency because of the lack of both a well-defined clinical syndrome and age-based normative data for serum testosterone and free testosterone concentrations That said, there are a number of conditions that may represent androgen deficiency syndromes:

• Bilateral oophorectomy
• Primary adrenal insufficiency
• Hypopituitarism, particularly women with both ACTH and gonadotropin deficiency [45]

Medications including oral contraceptives and glucocorticoids may cause a relative androgen deficiency due to ovarian and adrenal androgen suppression, respectively. Oral estrogens, even at low doses (menopausal replacement) reduce serum free testosterone concentrations by increasing serum SHBG levels.

Women with anorexia nervosa have lower serum concentrations of total and free testosterone, but not DHEAS concentrations when compared to normal-weight women with hypothalamic amenorrhea or healthy controls [46] . In this report, women with anorexia nervosa who were taking oral contraceptives had the lowest concentrations of free testosterone and DHEAS.

EFFECTS OF EXOGENOUS ANDROGENS — Androgen replacement therapy has been advocated by some for postmenopausal women with decreased sexual desire associated with personal distress and with no other identifiable cause [47,48] . However, given the lack of a well-defined clinical syndrome, age-based normative data for serum testosterone concentrations, and long-term safety data for testosterone preparations, we agree with the Endocrine Society guidelines and currently do not suggest the routine use of androgen therapy in women [42] .

Exceptions to this may include women with hypopituitarism (ACTH and gonadotropin deficiency), bilateral oophorectomy and premature ovarian failure (POF). However, our ability to treat these women is limited by the lack of an approved testosterone preparation. Women with primary and secondary adrenal insufficiency are candidates for DHEA therapy. (See "Dehydroepiandrosterone and its sulfate").

Sexual function — Testosterone therapy in postmenopausal women may have a beneficial effect on sexual function in select women, but data are variable.

Replacement vs. supraphysiologic therapy — Studies of androgen therapy in women with androgen deficiency (eg, hypopituitarism, bilateral oophorectomy) should be considered separately from studies in women with sexual desire disorders who are not androgen deficient, as the former would be considered to be replacement therapy, and the latter, supraphysiologic therapy. However, in almost all trials reporting a beneficial effect of testosterone, including those considered to be "replacement" trials, serum testosterone concentrations are higher than the upper limit of normal for premenopausal women.

• Studies in heterogeneous populations - Many testosterone trials have been performed in heterogeneous populations of women (natural or surgical menopause, with normal or low libido) receiving variable types, doses, and routes of administration of estrogen and testosterone. One of these trials reported no effect of testosterone on sexual arousal [49] , while others reported an improvement in sexual function in women with normal [50,51] or low [52] libido at baseline.

A trial in naturally menopausal women diagnosed with hypoactive sexual desire disorder who were taking estrogen reported improved sexual function with the transdermal testosterone patch (dose 300 mcg/day) [53] .

• Women post-oophorectomy — The main evidence that testosterone has an effect on sexual function comes from trials that have examined a transdermal testosterone preparation combined with exogenous estrogen in women who have undergone bilateral oophorectomy and subsequently developed hypoactive sexual desire disorder (HSDD). Although there is a modest improvement in sexual function with testosterone in these trials, serum testosterone concentrations are typically in the high normal or supranormal range for younger premenopausal women.

In one study, 300 mcg/day of transdermal testosterone improved sexual function and psychological well-being, but mean serum free testosterone concentration increased to approximately twice the mean of premenopausal women [54] . A dose of testosterone (150 mcg/day) that increased the mean serum testosterone to a value similar to that of the mean in premenopausal women did not increase sexual function or psychological well-being.

In a second, larger, multicenter trial, 532 women with hypoactive sexual desire who had undergone hysterectomy with bilateral oophorectomy received either testosterone (300 mcg/day) or placebo patch twice per week (in addition to estrogen) for 24 weeks [55] . Sexual desire and frequency of sexual activity increased more in the testosterone group compared to placebo, but only by one additional episode per 2.5 week interval in the testosterone group versus one additional episode per 5.5 week interval with placebo. Serum testosterone levels and androgenic side effects increased with transdermal therapy; however, the side effects were considered mild. Although promising, the results of this trial do not address the safety of long-term testosterone administration.

Additional, phase-III trials reported similar results on sexual desire and sexual activity [56,57] . In one study, no additional benefits were observed with a testosterone patch delivering 400 mcg/day when compared to 300 mcg/day [56] .

• Hypopituitarism — Women with hypopituitarism, in particular those with both ACTH and gonadotropin deficiency, may also benefit from testosterone therapy. In a trial of women with androgen deficiency due to hypopituitarism, treatment with 150 to 300 mcg of testosterone transdermally daily for one year improved overall sexual function, as judged by a questionnaire, by a small but statistically significant amount [58] .
• Use of testosterone without estrogen — Preliminary data from a trial in postmenopausal women (both natural and surgical) with hypoactive sexual desire disorder receiving transdermal testosterone 300 mcg (without estrogen) suggest that sexual function may also be improved in this group of patients [59] .
• Meta-analysis — In a systematic review of 23 clinical trials (with 1957 participants) of testosterone plus hormone therapy versus hormone therapy alone in peri- or postmenopausal women, a significant decrease in serum HDL concentrations was observed, there was insufficient evidence of a treatment effect in perimenopausal women, and there appeared to be an improvement in sexual function scores in postmenopausal women [60] . However, only three trials were included in the sexual function analysis. In addition, this review was not limited to women who would be considered to be truly androgen-deficient (ie post-oophorectomy). (See "Androgen deficiency" above).

Other effects

Vasomotor symptoms — Testosterone therapy may be effective for postmenopausal women who remain symptomatic (eg, hot flashes) despite estrogen or estrogen-progestin treatment [61-63] . Because androgen production declines after the menopause, it is reasonable to assume that some postmenopausal symptoms could at least in part be due to androgen deficiency. However, we do not consider persistent vasomotor flushes to be an indication for routine androgen replacement.

Cognitive function — Some data from uncontrolled studies in which postmenopausal women were treated with estrogen alone or with androgen have suggested that androgen may improve affect and cognitive functioning. This issue was also addressed in a randomized double-blind, placebo-controlled trial in which postmenopausal women were treated for two months with either estrogen, estrogen plus testosterone, or placebo [64] . Both hormone treatments were associated with better scores on a self-rating scale of anxiety and depression than placebo, and there was a trend towards better scores in the estrogen plus testosterone group as compared with the estrogen group.

In another study of the effect of hormone treatment on energy, well-being and appetite, estrogen plus testosterone was superior to estrogen alone [65] . Androgen therapy has also resulted in increased well-being, improved energy levels, and less dysphoric mood in oophorectomized women [66] .

A common criticism of these studies is that the testosterone given is metabolized into estrogen and therefore that the results are mainly due to an estrogen effect. However, in the last report, there was no difference in the incidence of hot flashes between the treatment and placebo groups, suggesting a mode of action for testosterone distinct from aromatization to estrogen [66] .

Bone metabolism — A direct correlation between bone density and serum androgens has been noted in postmenopausal women [20,21] . The effects of androgen therapy on bone in postmenopausal women have been examined in studies of androgen alone and androgen in combination with estrogen; numerous observations are compatible with a beneficial effect of androgen in this setting [49,67-74] :

• In a study of biochemical markers of bone resorption and formation, women receiving either estrogen or estrogen plus androgen had evidence of increased bone formation, whereas bone resorption decreased only in the women receiving estrogen alone [67] . In another report, androgen monotherapy in postmenopausal women with osteoporosis reduced markers of bone turnover (serum alkaline phosphate concentrations and urinary calcium excretion) to the same extent as estrogen [75] .
• A number of reports have shown that nandrolone increased bone mineral density at the spine and radius when compared with no treatment [68-70] .
• In studies of the effect of androgen plus estrogen, the addition of androgen to a regimen of estrogen with or without progestin had a more beneficial effect on bone density [72-74] .
• In a study of women with clear androgen deficiency due to hypopituitarism, who were taking estrogen and had normal baseline bone density, physiologic testosterone replacement (150 to 300 mcg/day transdermally) increased serum testosterone into the normal range, and increased mean hip and radius, but not spine, bone mineral density [58] .

Taken together, these results suggest that androgen alone or in combination with estrogen may protect against osteoporosis. The putative mechanisms involve a decrease in bone resorption by either direct androgenic action or conversion of androgen to estrogen, or an increase in bone formation. However, there is no strong evidence that the addition of androgen to estrogen in postmenopausal women is more beneficial than estrogen alone.

Adrenal androgen replacement — DHEA replacement therapy appears to be effective in women with adrenal androgen deficiency, including those with primary adrenal insufficiency, hypopituitarism (ACTH deficiency), and chronic glucocorticoid use (for example, women with systemic lupus erythematosus). (See "Dehydroepiandrosterone and its sulfate", section on Adrenal insufficiency and see "Overview of the therapy and prognosis of systemic lupus erythematosus in adults", section on Dehydroepiandrosterone (DHEA)).

DHEA supplementation has also been proposed as adjunctive hormone replacement therapy for aging men and women. While there is a well-known decline in serum DHEA and DHEA-S concentrations with age, the role of adrenal androgen replacement in peri- and postmenopausal women is unclear. However, DHEA supplementation in otherwise healthy peri- or postmenopausal women does not appear to have clinical benefits. (See "Dehydroepiandrosterone and its sulfate").

Risks and side effects — One concern regarding androgen replacement therapy in postmenopausal women is the possible adverse effect on cardiovascular disease risk, because androgens have been thought to be atherogenic. This supposition is based mainly on the higher rates of cardiovascular disease in men as compared with women and the higher risk in women with androgen excess (eg, polycystic ovary syndrome) [76,77] . (See "Postmenopausal hormone therapy and cardiovascular risk").

One proposed mechanism by which androgens may adversely affect the risk of cardiovascular disease is through a decline in serum high-density lipoprotein (HDL) cholesterol concentrations. As compared with normal women, women with hyperandrogenism have lower serum HDL cholesterol concentrations [78] . In postmenopausal women, however, the results are less clear. One report found no strong correlation between serum androgen and HDL cholesterol concentrations [79] , but another study found that serum testosterone concentrations were inversely correlated with serum HDL cholesterol concentrations [80] . Confounding variables that could explain the disparity in the results include the effects of diet, body weight, exercise, and heredity, as well as methodological differences such as problems associated with the standardization of methods to measure serum lipids.

The more androgenic progestins (eg, norethindrone, levonorgestrel), when given as the progestin component of estrogen-progestin replacement therapy in postmenopausal women, tend to blunt the estrogen-related rise or even produce a treatment-related decline in serum HDL cholesterol concentrations [81] . However, the addition of testosterone to estrogen replacement therapy has produced conflicting results: it caused a decline in serum HDL cholesterol concentrations in studies using oral estrogen [52,74,82,83] , but not in others using non-oral routes of administration [54,62,84,85] .

One study suggests that testosterone administration might decrease cardiovascular risk in postmenopausal women on hormone replacement therapy (HRT) [86] . In 33 postmenopausal women on HRT compared with 15 controls, both endothelial-dependent and -independent brachial artery vasodilatation was improved by the addition of a testosterone implant (50 mg) for six weeks. Additionally, it has been shown in a group of sixty postmenopausal women that endogenous testosterone levels are positively correlated with brachial artery vasodilation [87] .

Other potential side effects of adding androgen to estrogen in postmenopausal women are acne, hirsutism, deepening of the voice, and clitoromegaly. Among women given testosterone implants, 15 to 20 percent had slight increase in downy facial hair after several years, but acne, voice changes and clitoromegaly were very rare [88] . Women given oral methyltestosterone doses (2.5 mg daily) may become mildly hirsute [74] . Androgen replacement therapy does not affect body weight or blood pressure [63,89] .

A possible association between testosterone administration and breast cancer risk has been reported. However, data are limited. (See "Postmenopausal hormone therapy and the risk of breast cancer", section on Effect of testosterone).

In a review of available testosterone clinical trials, hirsutism and acne appeared to be the major adverse reactions (both were dose- and duration-related and generally reversible). Virilization was rare, and oral, but not parental or transdermal, testosterone was associated with a decrease in serum HDL concentrations, which could have a negative impact on cardiovascular risk. However, there were no adverse effects on blood pressure, vascular reactivity, blood viscosity, hemoglogin concentration, coagulation factors or insulin sensitivity. All available trials are limited by their short duration (≤ two years) and the co-administration of estrogen or estrogen-progestin therapy [90] .

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sexual problems in women" and see "Patient information: Postmenopausal hormone therapy" and see "Patient information: Alternatives to postmenopausal hormone therapy"). We encourage you to print or e-mail these topic reviews, or to refer patients to our public web site, www.uptodate.com/patients, which includes these and other topics.

SUMMARY — The use of androgens as an addition to estrogen or estrogen-progestin therapy for postmenopausal women is controversial.

• The clearest indication for androgen replacement therapy is in patients with symptomatic androgen insufficiency in association with hypopituitarism, adrenal insufficiency, premature ovarian failure, or in women who have undergone bilateral oophorectomy.
• Androgens may significantly improve sexual functioning in select postmenopausal women. (See "Sexual function" above).
• The data that androgens significantly improve cognitive function and affect are not compelling. (See "Cognitive function" above).
• Androgen may have a beneficial effect on bone, which may simply be due to the additional estrogen formed from the administered androgen; studies with nonaromatizable androgens could resolve this question. (See "Bone metabolism" above).
• Serum HDL cholesterol concentrations decline slightly in postmenopausal women receiving oral testosterone therapy, but it is not known if the change substantially affects overall cardiovascular risk. (See "Risks and side effects" above).
• Cosmetic side effects such as hirsutism and acne are usually mild and are well tolerated and irreversible virilizing changes are rare.

In conclusion, for highly selected postmenopausal women, especially those who have undergone bilateral oophorectomy, estrogen replacement alone may not be adequate therapy. Based upon the finding that endogenous androgen production declines after spontaneous menopause as well as oophorectomy, it may be logical to offer some women androgen therapy in conjunction with estrogen therapy. The practitioner and patient should realize, however that many questions remain to be answered regarding the efficacy and safety of this therapy. Most androgen preparations that have been used for this indication are not approved the United States Food and Drug Administration. (See "Treatment of sexual dysfunction in women").

Treatment of sexual dysfunction in women

2008-09-30T10:54:00.000-07:00

Treatment of sexual dysfunction in women

Author
Alan Altman, MD
Section Editor
Robert L Barbieri, MD
Deputy Editor
Kathryn A Martin, MD

Last literature review version 16.2: May 2008 | This topic last updated: June 11, 2007 (More)

INTRODUCTION — A number of nonpharmacologic and pharmacologic therapies are available to treat sexual dysfunction in women. Prior to initiating treatment, however, it is important to emphasize that sexual activity or frequency is not necessarily correlated with sexual satisfaction. Sexual dysfunction only becomes a problem when the patient or her partner finds it to be a problem.

The management of sexual dysfunction in women is reviewed here. The etiology and diagnosis are discussed separately. (See "Etiology and diagnosis of sexual dysfunction in women").

NONPHARMACOLOGIC THERAPY — Treatment of sexual dysfunction can begin with any of a number of nonpharmacologic measures. Blood flow increases during sexual activity; thus, sexual activity begets better sexual function. Masters and Johnson demonstrated this in their early work; sexual activity maintained vaginal pH, pO2, and mucosal health and allowed successful function to continue. The same beneficial effects could be achieved with sexual activity of any kind, partnered or unpartnered, including masturbation or sexual fantasy alone.

A number of other nonpharmacologic interventions also may be helpful.

Communication — Communicating sexual likes and dislikes, in a nonthreatening manner, can reignite novelty and intensify satisfaction. This may be difficult if techniques of communication were never the couple's forte. Sex videos or erotic literature can assist in seeking out new directions. Communication also means giving attention to a partner's presence, discussions, and ideas, which can help validate their importance and self image.

Lifestyle changes — Changes in lifestyle such as smoking cessation, strength training exercises, and aerobic training, can all have positive impacts on sexuality. Strength training, with weights or resistance machines may enhance body image and therefore, indirectly enhance libido.

Vaginal weights — Vaginal weights can be used to strengthen the pelvic floor muscles. In some women with orgasmic disorders, this can improve awareness of sexual response and also potentially correct urine leakage, which might cause a problem during sexual activity [1] .

Vaginal weights are usually available in sets of five weights. The patient inserts the lightest weight and remains upright for 15 minutes, twice a day. With the weight in place, she should feel the urge to hold it in. After a number of days, she will no longer feel the urge to hold in the weight, because an improvement in muscle tone has occurred. She then moves up to the next weight in the progression. Once she no longer feels the urge to hold in the heaviest weight, a significant increase in muscle tone has taken place. Maintenance with the fifth weight should be carried out each month for five to seven consecutive days to preserve muscle tone.

Use of vaginal lubricants — Genitourinary atrophy symptoms, in particular vaginal dryness and dyspareunia, develop in a high percentage of postmenopausal women who are not taking estrogen. Vaginal estroggen is highly effective for treating these symptoms, but water soluble vaginal lubricants are also helpful for continued sexual activity. This topic is reviewed in detail separately. (See "Diagnosis and treatment of vaginal atrophy").

Increased tactile stimulation of partner — Decreased vasocongestion during arousal can create the need for increased manual and/or oral stimulation in the male to help achieve or maintain an erection, and in the female to achieve adequate clitoral, labial, and vaginal response. Just providing an explanation of the need for more stimulation in both partners can have a positive effect, not only on sexual response, but also on the relationship.

Sexual frequency — How frequent is enough? Everyone has a different answer and that answer depends on multiple variables. Surveys are notoriously inaccurate due to their questionable ability to collect honest data. The bottom line has to remain what is comfortable for each individual pair of partners [2] .

PHARMACOLOGIC THERAPY — When education, lifestyle, communication, and behavioral changes do not achieve the desired level of success, pharmacological therapy can be utilized to treat sexual dysfunction in women. Treatment options focus on providing hormonal support and increasing genital blood flow. However, there are few randomized, placebo controlled trials of pharmacologic therapy in postmenopausal women upon which to base recommendations [3] .

Estrogen — Estrogen may positively affect sexual function in a number of ways. Estrogens rapidly restore the superficial cell layer of the vaginal epithelium, reestablish elasticity, restore the balance in vaginal pH, improve mood, and increase vaginal blood flow to enhance lubrication. (See "Postmenopausal hormone therapy: Benefits and risks"). In addition, their positive effect on neuronal growth and nerve transmission could help restore tactile perception and sensation, although treatment with estrogen alone is associated with inconsistent results with respect to sexual desire and arousal.

Short-term studies of estrogen replacement therapy (ERT) have confirmed a benefit in some postmenopausal women with sexual dysfunction:

• In a report of 93 women, 68 percent reported problems with sex, specifically vaginal dryness of at least moderate degree (58 percent); dyspareunia (39 percent); decrease in clitoral sensitivity (36 percent), decrease in orgasmic frequency (29 percent), decrease in orgasm intensity (35 percent), decrease in sexual desire (77 percent), and intercourse once a month or less (50 percent) [4] . Women reported vaginal dryness, pain with penetration, and burning sensation when the serum estradiol concentration dropped below 50 pg/mL. Symptoms decreased markedly when the estradiol concentration was above 50 pg/mL. Overall, oral estrogen therapy resulted in an improvement in clitoral sensitivity. Orgasm rates also improved. The most dramatic response was seen in the women who reported a lack of desire; after three to six months of treatment, 90 percent of these women had an increase in level of desire and increase in sexual activity with ERT.
• In a study of 242 women ages 45 to 65 requiring ERT for climacteric symptoms, women were randomly assigned to blinded treatment with transdermal estrogen or placebo for 12 weeks [5] . Answers to a questionnaire regarding satisfaction with frequency of sexual activity, sexual fantasies, degree of enjoyment, vaginal lubrication, and pain during intercourse were positively influenced by estrogen compared with placebo therapy, while the frequency of orgasm and sexual arousal were not affected.

However, not all studies have demonstrated positive results [6] , possibly because women most likely to respond are those with symptoms of hypoestrogenism. Furthermore, any short term positive effects of oral estrogen may diminish in the long term because of increasing sex hormone binding globulin (SHBG) levels, which lead to reduced estrogen and androgen bioavailability, and consequent decreased desire and activity [7] . The increase in SHBG appeared to be less significant in women who use nonoral delivery systems for ERT, suggesting improved bioavailability of estrogens and androgens [8] . (See "Etiology and diagnosis of sexual dysfunction in women", for a more complete discussion of the effects of SHBG.)

Progestins — Progestational agents down-regulate the estrogen receptor, a desired result in the endometrium, but potentially undesirable in the brain, heart, bone, and genitalia. They generally have an overall negative effect in the CNS with respect to depression and mood, and have been shown to decrease sexual desire and diminish vaginal blood flow [9,10] . Medroxyprogesterone acetate (MPA) is the most potent progestin available, therefore its ability to down-regulate the estrogen receptor and diminish estrogen effects may be particularly intense. Other available options include micronized progesterone (MP) and the 19 nortestosterone derivatives, norethindrone acetate (NA) and norgestimate (NGM). (See "Preparations for postmenopausal hormone therapy"). NA, the more androgenic progestin, has been shown to decrease SHBG and increase bone density.

A number of studies have evaluated the effect of progestins on sexual function:

• The effects of estrogen alone or with MPA on psychological functioning and sexual behavior were evaluated in a study of 48 healthy, naturally menopausal women [9] . The benefits of estrogen were diminished by MPA co-administration [9] .
• A second report comparing the use of estradiol alone or in combination with lynestrenol, a 19-norsteriod, revealed that women who used the combination therapy reported more negative mood symptoms than the estrogen only group [11] .
• In a single-arm, unblinded study, women who were intolerant of a conjugated equine estrogen (CEE)/MPA regimen were switched to CEE plus progesterone and reported better vasomotor, somatic, psychologic, cognitive, and sexual functioning [10] .

Progestins appear to produce a wide range of patient responsiveness and tolerability, suggesting that women who do not tolerate one regimen might be effectively switched to another and experience improvement. When estrogen is given with a progestin, the effect on SHBG depends upon the type of progestin used; 19-nortestosterone derived progestins, such as NA, decrease SHBG levels, a potential benefit while derivatives of C-21 progesterone, such as MPA, do not significantly influence them [12] . Newer studies in progress with more modern combinations of progestins with estrogens and androgens will provide better insight into the progestational effects on sexuality.

Androgens — Androgens play an important role in physiologic aspects of the female sexual response. (See "Etiology and diagnosis of sexual dysfunction in women"). However, the effect of androgen therapy on sexual function in women is controversial. Androgen replacement therapy for women with androgen deficiency (eg, bilateral oophorectomy) must be distinguished from pharmacologic androgen treatment of women with low libido who are not androgen deficient. (See "Androgen production and therapy in women").

Some studies have reported improvements in libido, sexual arousal, and the frequency of sexual fantasies with testosterone therapy in a variety of forms [4,13-15] , while others have been unable to detect a significant benefit from androgen therapy [6,7] . The observation that testosterone therapy may result in improvements in mood and well being [16] is felt by some researchers to be most important; the central sex steroid effect on mood may be what underlies sexual function in both women and men. (See "Androgen production and therapy in women")

Side effects — Potential adverse effects of androgens include a decline in serum high density lipoprotein (HDL) cholesterol with oral preparations, and mild cosmetic side effects such as hirsutism and acne; irreversible virilizing changes are rare. (See "Androgen production and therapy in women", section on Risks and side effects.) Hepatocellular damage is rare at the prescribed doses. The effect of testosterone on breast cancer risk is discussed separately. (See "Postmenopausal hormone therapy and the risk of breast cancer", section on Effect of testosterone).

Preparations — Most early papers demonstrating a benefit of androgens on sexual function utilized injections or pellets. Since that time, compounding pharmacists have formulated testosterone creams, gels, and tablets that can be taken orally or used sublingually, but their production is not uniform, they are not approved by the United States Food and Drug Administration (FDA), and efficacy studies are lacking. Many clinicians have tried creams used for vulvar dystrophies made up with 2 percent testosterone propionate. Others tapered down the potency using micronized testosterone 0.5 percent up to 1 percent, and rarely 2 percent.

Creams were applied first on the inside of the forearms or thighs, while later paraclitoral use became common. Mixed results were common, and the effect of rubbing the cream into the clitoris prior to intercourse may have been nothing more than masturbatory prestimulation. Anecdotally, the creams seemed to work better paraclitorally in patients with sexual arousal disorder than in those with hypoactive sexual desire disorder (HSDD).

A transdermal testosterone preparation has also been studied in clinical trials of postmenopausal women (primarily women who are post-oophorectomy). These trials are discussed in detail elsewhere. (See "Androgen production and therapy in women").

Studies on the use of dehydroepiandrosterone (DHEA), which is available over-the-counter in the United States, have shown an increase in energy level, well-being, sexual satisfaction, and sexual function only in women with primary and secondary adrenal insufficiency [17,18] . There are no receptors for DHEA; side effects occur due to conversion to testosterone and then to estrogens [18] . (See "Dehydroepiandrosterone and its sulfate").

Combination therapy with oral estrogen and methyltestosterone also improved sexual interest/desire in postmenopausal women already taking estrogen who were experiencing hypoactive sexual desire. A double-blind trial randomly assigned such women to four months of therapy with 0.625 mg esterified estrogens alone (n = 111) or with 1.25 mg methyltestosterone (n = 107). Improvements in self-reported sexual desire were seen in the combined therapy group, which correlated with changes in bioavailable testosterone concentrations [19] . However, acne was more common and significant decreases in HDL cholesterol were seen with combined treatment. (See "Androgen production and therapy in women").

Thus, the data that androgen therapy significantly improves sexual functioning are suggestive but not conclusive. Many of the positive studies have been in women who had surgical menopause or who achieved supraphysiologic levels of testosterone with therapy [20] , suggesting that the clinical application may be limited. No guidelines for androgen therapy for female sexual dysfunction are available, and no androgen preparations have been approved for the treatment of sexual desire disorders, although the combination oral estrogen/methyltestosterone preparation described above is approved for management of persistent vasomotor symptoms not relieved by estrogen alone.

Women most likely to benefit from androgen therapy are probably those who have undergone bilateral oophorectomy with hysterectomy.

For any woman considering androgen therapy, the risks and benefits should be discussed prior to initiating treatment. Women with hepatic disease, a history of breast cancer, uncontrolled hyperlipidemia, acne, or hirsutism should not be treated.

Although there are no FDA-approved testosterone products for women presently available in the US, specialists utilize the following products off-label or compounded for women with sexual dysfunction after extensive history and counseling:

• Combination estrogen/methyltestosterone (Estratest or Estratest HS)
• Testim 1 percent testosterone Gel (one to two drops/day)
• Methyltestosterone (1.22 to 2.5 mg/day)
• Micronized oral testosterone (5 mg BID)
• Testosterone injectables/pellets
• Testosterone propionate 2 percent in petroleum applied QOD
• DHEA 50 mg per day

Non-oral estrogen should be administered in conjunction with testosterone therapy to avoid increasing SHBG and to negate any potential negative effects of either on lipoproteins. Baseline free and total testosterone levels, liver function tests, and a lipid profile should be obtained prior to initiating therapy, and women should be current on cervical and breast cancer screening. The lipid profile and liver function tests should be reevaluated along with a clinical evaluation for symptoms in three to four months, and the androgen tapered to the lowest dose possible. Some authors recommend that the serum testosterone concentration remain in the normal range for premenopausal women, but this is not universal. Liver function tests and lipids should be monitored every six months during therapy [1] .

Herbal therapies — The literature on herbal therapies for the treatment of sexual dysfunction in women is sparse. In general, St John's wort, ginseng, dong quai do not appear to be more effective than placebo for sexual dysfunction. Herbal products such as yohimbine have been reported to enhance desire, arousal, and orgasm in women with sexual dysfunction secondary to SSRIs, but results are inconsistent [21,22] .

L-arginine, an amino acid, has been touted as the natural Viagra due to the claimed ability to release nitric oxide, causing increased vasocongestion in the genitalia of both sexes [21,23] . More studies are necessary before conclusions can be drawn regarding any of these products.

Future therapies — A number of products are undergoing research and development for use in women with sexual dysfunction:

Tibolone — Tibolone, currently available in Europe and Australia, has not yet gained FDA approval in the United States. Taken orally, its metabolites have estrogenic, androgenic, and progestational effects. The level of androgenic activity and its potential use for sexual dysfunction is under evaluation. A small placebo controlled trial in postmenopausal women found tibolone increased vaginal lubrication, arousability, and sexual desire, but did not change frequency of sexual intercourse or orgasm compared to placebo [24] . Tibolone is effective for the management of osteoporosis, but may be associated with an increased risk of breast and endometrial cancer. Tibolone is discussed in more detail elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women").

Sildenafil — Preliminary findings on use of sildenafil demonstrated positive effects in the areas of sexual arousal and orgasm in appropriately selected women [25-28] . However, several large scale, placebo controlled studies including about 3000 women with female sexual arousal disorder yielded inconclusive results [29] . For this reason, the manufacturer has decided not to seek regulatory approval to use the drug for female sexual arousal disorder.

Other — Now available in the United States is a clitoral suction device modeled after a pump used before the advent of penile injections and sildenafil to produce and maintain erection in males, uses suction or negative pressure to increase vasocongestion and engorge the clitoris and paraclitoral tissues for enhanced arousal and orgasm [30] .

One placebo-controlled randomized study of daily apomorphine SL administered to premenopausal women suggested this drug may improve sexual desire and function in women with hypoactive sexual desire [31] . Apomorphine SL is not FDA approved for this indication and requires further investigation.

This growing pharmacopoeia should not overshadow the psychosocial, intimacy, and relationship issues that are equally, if not more involved in problems with midlife sexuality.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sexual problems in women"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

Etiology and diagnosis of sexual dysfunction in women

2008-09-30T10:46:00.000-07:00

Etiology and diagnosis of sexual dysfunction in women

Author
Alan Altman, MD
Section Editor
Robert L Barbieri, MD
Deputy Editor
Kathryn A Martin, MD

Last literature review version 16.2: May 2008 | This topic last updated: October 24, 2007 (More)

INTRODUCTION — Female sexual dysfunction refers to persistent or recurring reduction in sex drive, aversion to sexual activity, difficulty becoming aroused, inability to achieve orgasm, or dyspareunia that causes distress. According to the National Health and Social Life Survey, a study of sexual behavior in a demographically representative cohort of American men and women, sexual dysfunction is more prevalent among women than men (43 versus 31 percent) [1] .

Sexual dysfunction can occur at any age in women, but "midlife" is a particularly common time for changes to occur. The transition to menopause impacts the lives of women in different ways. Many will notice little change, some may experience an improvement, while others will complain of diminished sexual function. These variations are understandable considering the multiple factors that may affect midlife sexuality:

• Erratic ovarian function and fluctuating hormone levels that define perimenopause and the more definite decline that follows the menopause
• Alterations in anatomical structure, neurologic function, vascular responsiveness, and psychosocial function that accompany the normal aging process
• Relationship dynamics and each individual's foundation of sexual beliefs, expectations, and prior sexual experiences

Caring for women at this stage of life presents a unique opportunity for the clinician to ask the appropriate questions, bring the problem out into the open, and offer counsel and guidance. This requires the ability to communicate comfortably with patients plus an understanding of the physiology of human sexual response, the normal effects of aging on sexuality, relationship dynamics, and the healthcare provider's own limitations.

The etiology and diagnosis of sexual dysfunction are discussed here, with a focus upon changes that occur in midlife. The treatment of sexual dysfunction in women and an overview of the approach to sexual dysfunction in both men and women are discussed separately. (See "Treatment of sexual dysfunction in women" and see "The sexual history and approach to the patient with sexual dysfunction").

MIDLIFE — The concept of "midlife" must be redefined as life expectancy grows longer. Women today experience "two midlives:" one is reproductive, the other chronological, and they do not necessarily coincide. In the past, with a life expectancy of 50 to 60 years, menopause generally appeared near the end of a woman's life, and midlife, chronologically, coincided with the reproductive changes in ovarian function beginning in the mid 30s.

Today life expectancy has increased and chronological midlife has been redefined as the 50s and 60s, while age at menopause remains unchanged. This discrepancy between a woman's reproductive midlife and her chronological midlife presents some problems. It is difficult for women in their 30s to think of themselves as entering midlife, even though decline in reproductive function begins at that age. In addition, when midlife occurs it will impact the kind of sexual changes that are experienced. The older midlife woman will tend to have more physiologic and anatomic problems compared with the younger midlife woman, in whom psychosocial problems might predominate. Women and men expect sexual interest and function to continue for decades beyond the point where women lose their natural reproductive capabilities. Fortunately, the clinician can do much to help patients in reproductive midlife maintain sexual function well into and beyond chronological midlife.

Midlife sexuality — While the host of hormonal and other changes that begin prior to the menopausal transition and continue beyond the menopause affect sexuality, the desire for an active sex life remains important for many men and women throughout midlife, as illustrated by the following surveys:

• One survey of 1879 women ages 45 to 55 (most of whom had partners) was designed to identify changes in sexual interest over the previous year [2] . Of the respondents, 62 percent noted no change, 31 percent reported a decline in interest, and 7 percent indicated an increase in interest; most of the last group had new partners.
• A 1999 survey asked responders ages 45 and older if they were more or equally satisfied with their current sex life when compared with their past levels of sexual activity [3] . Fifty-six percent of men and 51 percent of women were more or equally satisfied. In addition, 54 percent of the men and 38 percent of the women considered themselves "a better lover now than in the past."

Seventy percent of males and females with partners in this study had intercourse one or two times per week. Of those without regular partners, 6 percent of males had intercourse one or two times per week; women had considerably less. Women ages 45 to 59 years were more likely than men to approve of sex outside of marriage, oral sex, masturbation, and sex, as a normal part of aging. Age became a factor when the participants were asked, "What would improve your sex life?" Men and women age 45 to 59 cited less stress and more free time; men over 60, better health; women 60 to 74, better health for their partner; and women over 75 responded that just having a partner would improve their sex life.

Midlife can be a time of sexual freedom for many women; freedom from menstrual cycles, interruptions by small children, and unwanted pregnancy. These factors may enhance midlife sexuality, especially if sex was a positive experience earlier in life. On the other hand, some women see midlife as a loss of youth, femininity, and childbearing capacity, leading to a negative impact upon sexuality. Still others see midlife as a time when they can finally use these changes as a long anticipated excuse to avoid sex that was never enjoyable for them before. Absence of sexual activity is, in itself, not a problem; it should be viewed and treated as a problem only when a woman or her partner are bothered by it.

PHYSIOLOGY OF THE NORMAL HUMAN SEXUAL RESPONSE — Knowledge of the physiology of the normal sexual response can facilitate an understanding of what may go wrong. Two basic models have been proposed to illustrate the physiology of human sexual response: the Masters and Johnson model and the biopsychosocial model (see below). While they differ in many ways, both acknowledge that neurologic and vascular responses are essential to produce a sexual response.

The brain is the most important sex organ in the human body. Neurologic changes initiate the process as the brain reacts to an image, idea, fantasy, smell, or anything else that stimulates a response or triggers desire. This leads to changes in vascular blood flow. Sex hormones play key roles here. There are estrogen, androgen, and progesterone receptors in the brain [4,5] . Estrogen and androgen receptors are particularly dense in the hypothalamus, which controls sexual function and mood.

Testosterone is the primary precursor for estradiol biosynthesis in the brain; the testosterone concentration in the brain is 7 to 10 times higher than the estrogen concentration. Thus, the free circulating concentration of estrogen and testosterone does not necessarily correlate with what is occurring in the brain.

Estrogen increases blood flow to the brain. Estrogens also increase vibratory sensation peripherally and have a positive effect on neuronal growth and nerve transmission. Other hormones, including oxytocin and endorphins, influence sexuality in the brain as well, while prolactin may have a negative effect on sexual response.

Increased blood flow to the genitalia occurs with sexual stimulation. This marks the arousal phase, in which the additional blood flow produces peripheral responses that define the sexual response. Estrogens affect how blood flows: increased estrogen increases vaginal blood flow (VBF) while a decreased concentration diminishes VBF [6] . The mechanism by which this occurs is related to estrogen stimulation of the release of vasoactive substances such as nitric oxide by endothelial cells, which induces vasodilatation [7] .

Addition of androgens to estrogen increases VBF further. Testosterone may work directly in the artery or indirectly by increasing the availability of estrogen [8] . Progesterone, on the other hand, can diminish blood flow by down-regulating the estrogen receptor [9] . Blood flow can also be increased through any mechanism that provides the neurovascular stimulus, be it sexual activity, the use of sexual aids, masturbation, or fantasy.

Masters and Johnson — Masters and Johnson first detailed the phases of human sexual response as a linear progression from excitement to plateau to orgasm, followed by resolution [10] .

Excitement — Activation of the central nervous system (CNS) causes specific changes in blood flow. Ovarian hormones also play essential roles in this process, encouraging vasodilation and increased blood flow. Uterine and internal mammary arteries contain some of the highest density of estrogen receptors, hence their responsiveness in the excitement phase.

Genital vasocongestion occurs because of this increase in blood flow and smooth muscle relaxation. The vaginal wall becomes lubricated. The labia increase in size and spread open. The clitoris increases in size and the vagina expands while the uterus elevates. Other areas of the skin, including the face and breasts, demonstrate this increase in blood flow with the "sex flush."

Following Masters and Johnson, Kaplan replaced the excitement phase with two phases: desire, in which the neurologic stimulus occurs; followed by arousal, in which blood flow produces the peripheral response leading up to orgasm [11] .

Plateau — Masters and Johnson presented this as a separate phase, while Kaplan later blended it into the arousal phase. Actions associated with this phase include retraction of the clitoris and engorgement of the labia. Bartholin gland secretion occurs, as well as congestion of the outer third of the vagina and further expansion of the upper two thirds of the vagina. Muscle tension builds.

Orgasm — In the orgasm phase, 8 to 12 muscular contractions of the levator ani muscles occur at precise intervals. Vaginal and uterine contractions occur followed by massive release of muscle tension. Regularly orgasmic women will achieve orgasm 50 to 70 percent of the time and a satisfying prolonged plateau phase other times.

Resolution — The final phase, or culmination, is often characterized as a gradual, pleasant diminishment of sexual tension and response, differing in the time it lasts among individuals.

The biopsychosocial sexual response — An alternative model has also been proposed to describe the female sexual response. Proponents believe that a large component of women's sexual desire is responsive rather than spontaneous. They maintain the biopsychosocial nature of the female sexual response cycle is a result of the dynamic and mutable interaction of four components [12,13] :

• Biology
• Psychology
• Sociocultural influences
• Interpersonal relationships

If only the biological or physiological component is addressed, as with the use of pharmacotherapy, successful treatment will frequently not be achieved. In this model, emotional intimacy of some kind motivates the woman to seek out or become responsive to sexual stimuli, which in turn leads to arousal. Once arousal is achieved, sexual desire is then accessed, allowing continuation of the experience for sexual reasons. Hence, sexual desire can be responsive to arousal instead of preceding it. While spontaneous drive can occur, it is not essential. Thus, lack of spontaneous desire is not necessarily a dysfunction. In addition, satisfaction is the goal, which may or may not include orgasm.

SEXUAL CHANGES WITH AGING — Sexuality and sexual capacity evolve over a lifetime of development and change, based on personal experience, interest, cultural attitudes, interpersonal relationships, desires, behaviors, physiology, and other factors.

Epidemiology — Although many older adults remain sexually active, sexual problems become more common, and these problems are infrequently discussed with their health care providers. This was illustrated in a national probability sample study of 3005 men and women ages 57 to 85 years [14] . The prevalence of sexual activity decreased with age in both men and women, but women at all ages were less likely than men to be sexually active (62, 40, and 17 percent among women who were ages 57 to 64, 65 to 74, and 75 to 85 years, respectively). The most common sexual problems in women were low desire, vaginal dryness, and inability to achieve orgasm (43, 39, and 34 percent, respectively). Only 38 percent of men and 2 percent of women reported having discussed their sexual concerns with a health care provider since the age of 50.

Estrogen — Estrogen deficiency develops gradually as women near menopause. A more abrupt decline is seen with surgical menopause. This decline in estrogen can cause several changes that may affect sexual function.

Urogenital function — Estrogen sustains the structure and function of the cells of the vagina. Every woman with estrogen deficiency for a prolonged period of time will develop some degree of vaginal and genital atrophy. Epithelial changes in the vagina occur first within weeks to months of estrogen loss. This leads to a decrease in superficial cells, an increase in parabasal cells, and a progressive loss of elasticity and integrity of the epithelium. Along with this change comes an increase in vaginal pH, which promotes the growth of organisms and leads to more frequent vaginal infections [15] .

Later changes, over years, affect the deeper structures such as the underlying vascular, muscle, and connective tissue, leading to a decrease in vaginal blood flow, and both foreshortening and narrowing of the vagina. There is actual loss of blood vessels in the layers beneath the epithelium. This constellation of changes can lead to vaginal dryness, decreased or absent lubrication and, dyspareunia. (See "Clinical manifestations and diagnosis of menopause" and see "Approach to the woman with dyspareunia").

The bladder tissues also suffer from estrogen loss with mucosal changes that can lead to urinary frequency, urgency, nocturia, dysuria, and incontinence. Clitoral changes can occur, including a 50 percent decrease in perfusion and shrinkage of the structure [16] . Neurologic changes include decreased touch perception, a decline in vibratory sensation, and slowing of nerve impulses leading to a delay in reaction time [17] . Decreased androgen levels also affect some of these changes (see below).

Effect on sexual response — Changes in the vaginal and clitoral tissues due to estrogen deficiency can have a profound effect on sexual response. The decrease in genital blood flow will affect vasocongestion. Sexual arousal will be delayed or altered. More time and stimulation may be necessary to achieve lubrication, which may be significantly reduced or absent. The outer third of the vagina, including the labia and G-spot, demonstrate decreased or absent congestion, as does the clitoris. Vaginal expansion in length and transcervical width decreases. Elsewhere, there is a reduced incidence of skin flush, a lack of increase in breast and nipple size during stimulation, decreased tactile sensation, or worse, aversion to skin touch due to pain perception instead of pleasure in the clitoris, skin, and nipples, and a general decrease in muscle tension [18] .

Taken together, these changes can result in delayed arousal, delayed or absent orgasm, or diminished peak of orgasm. Fewer uterine contractions occur with orgasm and, in older women, particularly age 70 and older, painful uterine contractions can be associated with orgasm because of vasoconstriction that produces a reaction similar to ischemia [16] .

Androgens — All women produce some androgens, which may contribute to maintaining normal ovarian function, bone metabolism, cognition, and sexual behavior [19] . However, serum testosterone concentrations are not a good predictor of libido in women. Studies evaluating vaginal blood flow and vasocongestion of the clitoris and labia suggest that normal testosterone levels are necessary for arousal and orgasm to occur [20] . In women who undergo bilateral oophorectomy and subsequently develop hypoactive sexual desire disorder, exogenous testosterone therapy may be moderately effective for libido and sexual activity. (See "Androgen production and therapy in women").

Total testosterone and androstenedione (the major androgen in the serum of cycling women) gradually decline with increasing age in normal women. Androgen levels peak around age 25 and begin a gradual, age-related decline in the early to mid 30s, much earlier than the decline in estrogen levels [21] . There is also a midcycle testosterone surge that declines with age [22] . Some have argued that the sexual effects of reduced androgen levels can occur well before menopause and the onset of estrogen deprivation [23] .

Other suggested causes of androgen deficiency include:

• Oophorectomy (producing sudden 50 percent fall in levels within 24 hours of surgery)
• Premature ovarian failure
• GnRH agonist therapy
• Corticosteroid therapy suppressing ACTH secretion
• Adrenal insufficiency

Additional important causes include exogenous oral estrogens, such as oral contraceptives (OCs) and hormone replacement therapy (HRT), both of which increase sex hormone binding globulin (SHBG), resulting in reduced bioavailability of androgens as well as estrogens. Non-oral contraceptives, ie ring and patch, also increase SHBG, while non-oral postmenopausal therapy does not.

The menopausal transition (ie, perimenopause) results in a somewhat unique hormonal profile. Erratic ovarian function leads to estrogen levels that can be normal, elevated, or decreased at any given time, but in general, estrogen secretion is preserved. (See "Clinical manifestations and diagnosis of menopause"). Ultimately, lower estrogen levels predominate. The postmenopausal ovary is an androgen-producing organ. Ovaries continue to produce androgens well into the postmenopausal years [24] . (See "Androgen production and therapy in women").

Serum androgen concentrations — It has been proposed that serum androgen concentrations are an independent predictor of sexual desire and function in women. In a community-based, cross-sectional study of 1021 women aged 18 to 75 years, low serum concentrations of testosterone, free testosterone, or androstenedione were not significantly associated with a low score on the Profile of Female Sexual Dysfunction instrument [25] . Women with low sexual function were more likely to have a low DHEAS level, however, the majority of women with a low DHEAS level did not report low sexual function. This suggests that the measurement of serum androgens in women presenting with sexual dysfunction is not clinically useful.

Impact of male sexuality — One of the major factors that impacts female midlife sexuality is the spectrum of midlife sexual changes in men. It has been reported that 50 percent of men over 50, 60 percent of men over 60, and 70 percent of men over 70 have some degree of erectile dysfunction [26] . (See "Overview of male sexual dysfunction"). Other changes include a prolonged preorgasmic or plateau phase during which it can take considerably longer to achieve orgasm after arousal, and, as with women, orgasm may not always be achieved [27] . Finally, the ejaculate itself can be decreased or absent during sexual encounters.

Many couples adjust to these changes with more manual or oral stimulation to compensate for waning maintenance of erection and carry on normal sex lives. Sexual dysfunction occurs when either partner is bothered by the changes and the lack of successful activity. In men, however, these changes often lead to performance anxiety, one of the most significant psychosocial sexual problems. When the man experiences performance anxiety, he will frequently withdraw from intimacy at all levels of the relationship for fear of stimulating his partner to expect sexual activity that he believes he cannot provide. This withdrawal from other areas of intimacy has a most profound impact on the woman because of the major importance of intimacy to female desire and sexual response.

Decreased libido or sexual desire — Decreased libido or sexual desire, termed hypoactive sexual desire disorder (HSDD), has increasingly become one of the more common complaints of women in the menopausal transition and in midlife in general [28] . Sexual desire includes sexual appetite, drive, and fantasy. While sexual arousal leading to orgasm is predominantly a physiological event dependent upon neurovascular responses to stimuli within the appropriate hormonal milieu, libido or sexual desire is more psychosocial and behavioral, impacted by a multitude of factors in daily life and relationships.

The desire for sexual intimacy can be diminished in spite of normal levels of testosterone and estrogen. Many factors affect sexual drive and its expression in midlife and should be evaluated when patients present with decreased libido.

A number of instruments exist for the measurement of female sexual function, but only one has been validated for use in evaluation of treatment response (Profile of Female Sexual Function [PFSF]) in women with HSDD in international clinical trials [29] . Of note, androgen deficiency is not one of the criterion for the diagnosis of HSDD. Revised definitions of female sexual disorders have been proposed that reflect the importance of subjective sexual arousal and the concept of a circular sex-response cycle rather than a linear model (Masters and Johnson) [30] . In this model, a woman may access desire only after she becomes aroused by her partner, in which case lack of spontaneous desire is not a sexual dysfunction.

Partner availability — Women tend to live longer than men, resulting in a natural shortage of males ages 50 and older. At the same time, many men seek out younger partners, further affecting the availability of partners for women in midlife and beyond.

Personal well-being — A woman's sense of personal well-being is important to sexual interest and activity. Low perceived levels of physical and emotional satisfaction and a sense of unhappiness correlate with low sexual desire, resistance to arousal, and pain during sex [1] . Women who experience premenopausal physical or emotional problems, particularly disorders of sexual desire, sexual response, and sexual behavior, tend to experience a worsening of these conditions after menopause [16] .

Overall health and socioeconomic circumstances — Analysis of data from the National Health and Social Life Survey of 1749 women and 1410 men indicated that sexual dysfunction is highest in women with poor health, low income, and a history of infrequent sexual interest. Sexual dysfunction is also more common among women and men with poor physical and emotional health [1] .

Other — Other predictors of decreased libido have been described in women in their late reproductive years. In a four-year prospective cohort study of 326 women ages 35 to 47 (27 percent of whom reported a decreased libido), depression, vaginal dryness, and children living at home were associated with an increased risk of low libido [31] . Mean serum testosterone concentrations (measured every eight months in the early follicular phase) were not associated with libido. However, women with the greatest variability in serum testosterone concentrations reported the greatest declines in libido.

In a second report of 341 peri- and postmenopausal women, common menopausal symptoms, including depression, sleep disturbances, and night sweats, were associated with diminished libido [32] .

Medical issues — Chronological midlife may be associated with medical issues that impact sexuality in either the woman or her partner. These problems can diminish the physical ability to perform sexually, such as with coronary artery disease or arthritis (the most prevalent cause of sexual inactivity in the United States), or can affect arousal and orgasm capability as with neurologic disorders such as multiple sclerosis, Parkinson's disease, or sequelae of diabetes [1] . Alcohol and substance abuse may have a disabling affect on performance by altering erectile capability in the male and arousal in the female. Psychiatric or emotional problems can impact sexual function due to the particular disorder or to the treatment.

Medications — Both prescription and over-the-counter medications have the capability to alter desire, arousal, and orgasm. Any medication that alters blood flow (eg, antihypertensives), affects the CNS (eg, psychotropics), or dries the skin or mucous membranes (eg, antihistamines), may disrupt normal sexual function. As previously mentioned, both oral estrogens in HRT and oral asl well as non-oral contraceptives can adversely affect levels of bioavailable androgens. Non-oral estrogens, however, used peri or postmenopausally, do not diminish bioavailable androgens.

One of the major classes of medications that impacts sexuality is the selective serotonin reuptake inhibitors (SSRIs), frequently used to treat depression in the perimenopausal woman. (See "Antidepressant medication in adults: SSRIs and SNRIs"). The risk/benefit ratio with use of these agents is based on individual need and response. When depression is severe, SSRI's may allow for increase in sexual activity by treating the underlying process. However, in many patients, therapy can diminish sexual desire and alter or eliminate arousal and orgasm. Changing to a different antidepressant may help; the addition of bupropion to ongoing therapy also has been shown to improve sexual function [33] . (See "Sexual dysfunction associated with selective serotonin reuptake inhibitor (SSRI) antidepressants").

Surgery — Surgery related to cancers of the breast or female genital tract can have a profound effect on sexuality in midlife, as can prostate surgery in men. This occurs as a result of the extensive surgery affecting body image and function, as well as the psychological sequelae of the cancer diagnosis and prognosis on patient and partner. Many of these malignancies preclude the use of hormonal therapies, leading to even further problems involving genital function. Referral for counseling is critical in these patients.

Contrary to public perception, sexual function often improves with hysterectomy. Seriousness of pathology along with level of annoyance of bleeding, pain, or pressure preoperatively, affect satisfaction with sexual activity postoperatively. A two year prospective study assessed measures of sexual functioning in over 1000 women prior to hysterectomy and at 6, 12, 18, and 24 months, after the procedure [34] . The percentage of women who engaged in sexual relations increased from approximately 71 percent before hysterectomy to 77 percent at 12 and 24 months after hysterectomy; the rate of frequent dyspareunia dropped from 19 to 4 percent; the rate of experiencing orgasms increased from 92 to 95 percent; and libido increased. Overall, the frequency of sexual activity increased and problems with sexual functioning decreased postoperatively.

There remain, however, women who note a decrease or total absence of orgasm after hysterectomy. Preoperative counseling can help to prepare and assist the patient and partner by reviewing the risks of surgery, as well as the risks of not having the surgery, and potential sexual changes, better or worse, that might follow. Preservation of the ovaries and cervix, if not contraindicated and surgically possible, may help to avoid major changes in sexual response. (See "Abdominal hysterectomy", section on Outcome).

DIAGNOSIS OF SEXUAL DYSFUNCTION — The diagnosis of sexual dysfunction should begin with use of the non-threatening question, "Are you sexually active?" If the answer is affirmative, the second question can be, "Do you have any questions, problems, or concerns about your sexual activity that you would like to discuss?" If, instead, the patient indicates that she is not sexually active, the next and most important question should be, "Does that bother you or your partner?"

There are two common reasons that these questions are not asked. First, because the clinician may feel uncomfortable with the questions or with his or her level of knowledge of the subject and, second, the amount of time needed for discussion once the patient senses sincere interest and feels comfortable beginning a dialogue with the provider. After initiating the discussion, a separate consultation can be scheduled at a later date so that more uninterrupted time can be spent, and also to allow the patient to gather all her thoughts on the topic she now knows is open for discussion. Presence of the partner may also be useful later, once the patient has covered her own concerns. (See "The sexual history and approach to the patient with sexual dysfunction").

A teaching session should occur during the second consultation, in which the clinician describes normal sexual response as well as the physiological changes in sexuality that are common in midlife. Frequently little or no therapy is needed once patients realize so many of these changes are a normal part of the aging process and learn how to cope with them effectively.

The point at which the physiologic changes of aging become sexual dysfunction is best defined within the context of each individual relationship, based on the effect these changes have on the couple. The need for referral to a specialized counselor, therapist, or sexologist, should be made when more detailed consultation is necessary or when the clinician is unable to provide the service.

A detailed gynecologic examination is an important component of the evaluation. Careful assessment of the vulva, clitoris, introitus, and vagina, for atrophic changes, loss of elasticity, inflammation, scarring, infection, or genital prolapse, is paramount. Any tenderness to palpation, superficial or deep, must be evaluated. The pelvic structures, including the bladder, should be evaluated for pathology that might interfere with successful sexual activity, such as masses, endometriosis, or urinary incontinence. Routine breast and cervical cancer screening should be updated.

Laboratory testing is guided by the history and physical examination. No specific tests are universally recommended in all women. Assessment of the serum free and total testosterone concentrations are often done in women considering androgen therapy. However, many currently available methods for measurement of total and free testosterone lack the sensitivity and accuracy necessary for determining androgen deficiency in women [35] .

It is also important to note that the type and dose of androgen replacement therapy for women has not been well established. (See "Androgen production and therapy in women").

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sexual problems in women"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

Patient information: Painful bladder syndrome and interstitial cystitis

2008-09-22T23:03:00.000-07:00

Patient information: Painful bladder syndrome and interstitial cystitis

Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Leah K Moynihan, RNC, MSN
Sandy J Falk, MD

Last literature review version 16.2: May 2008 | This topic last updated: July 12, 2007 (More)

INTRODUCTION — Painful bladder syndrome/interstitial cystitis (PBS/IC) is a group of disorders with symptoms of mild to severe bladder pain and an urgent and/or frequent need to urinate. The disorder can affect women and men, but is more common in women. It can be difficult to diagnose and treat because the underlying cause is not well understood.

The symptoms and diagnosis of PBS/IC will be discussed here. Treatment of this disorder is reviewed separately. (See "Patient information: Treatment of painful bladder syndrome and interstitial cystitis").

DEFINITION — The definitions of painful bladder syndrome and interstitial cystitis have evolved over the years, and will probably continue to change as the cause is better understood.

Painful bladder syndrome — PBS is defined as a group of symptoms that include bladder pain and a frequent and/or urgent need to urinate during the day and/or night.

Interstitial cystitis — IC is the diagnosis used to describe people who have symptoms of PBS as well as changes in the bladder lining (seen during cystoscopy, see "Cystoscopy" below).

It is difficult to know for sure how many people are affected by PBS/IC; estimates range from 0.01 to 11 percent of women and 0.04 to 5 percent of men.

CAUSES — Little is known about the cause of PBS/IC. Many studies have shown that patients with IC have abnormalities in the lining of the bladder. However, it is not known if these bladder abnormalities are the cause of symptoms or develop as a result of some unknown underlying disorder that also causes painful bladder symptoms.

It is likely that the nerves in the bladder become highly sensitive to pain and pressure as PBS/IC develops. Nerves outside the bladder, including nerves of the abdomen, pelvis, and hips, and legs, may also become more sensitive.

One or more events may lead to the symptoms of PBS/IC, including:

Urinary tract infection
• An episode of vaginitis or prostatitis (eg, a yeast infection of the vagina or a bacterial infection of the prostate)
• Bladder, pelvic, back or other type of surgery
• Trauma (eg, fall onto the tailbone [coccyx] or car accident)

However, in many people, there is no clear explanation for why or how the symptoms of PBS/IC first began.

SYMPTOMS — The symptoms of PBS/IC can vary from one person to another and from time to time for each person. All patients with PBS/IC have bladder pain that is relieved at least partially by urinating. Symptoms usually include a frequent and urgent need to urinate during the day and/or night. Most, although not all, people with PBS/IC do not have urinary leakage (incontinence). Most people describe pain in the suprapubic area (in the lower abdomen, above the pubic bone) or urethral area (show figure 1). Some people describe one-sided lower abdominal pain or low back pain. The severity of pain ranges from mild burning to severe and debilitating pelvic pain.

Most people describe symptoms that begin gradually, with worsening discomfort, urgency and frequency over a period of months. A smaller subset of patients describes symptoms that are severe from the beginning. When symptoms of PBS/IC begin suddenly, some patients are able to name the exact date on which symptoms began (see "Causes" above).

Some people have chronic pelvic pain that is distinct from bladder pain, sometimes with other pain symptoms. Some people have several pain-related diagnoses, such as irritable bowel syndrome, painful menstrual periods, endometriosis, vulvar pain (vulvodynia), or fibromyalgia. PBS/IC symptoms are sometimes at their worst during times when other pain symptoms are also at their worst. (See "Patient information: Irritable bowel syndrome" and see "Patient information: Endometriosis" and see "Patient information: Fibromyalgia").

Symptoms may vary from one day to the next. Worsening of PBS/IC symptoms may occur after consuming certain foods or drinks (eg, strawberries, oranges, beer, coffee), or during the luteal phase of the menstrual cycle (14 to 28 days after the first day of the last period), during stressful times, or after activities such as exercise, sexual intercourse, or being seated for long periods of time (eg, during a plane trip).

A person with severe disease may have to urinate several times per hour, which can seriously disrupt daily activities and sleep. As a result of these symptoms, home and work life are often disrupted, interest in sex may be minimal, and difficulty coping with chronic pain and fatigue can occur. In surveys, 50 percent of patients reported being unable to work full-time, 75 percent described pain with intercourse, 70 percent reported sleep disturbance, and 90 percent reported that PBS/IC affected their daily activities [1] .

EVALUATION — The diagnosis of PBS/IC is based upon a person's symptoms and examination. A careful medical history, physical examination, and sometimes laboratory testing are needed to confirm the diagnosis and also to be sure that another condition (eg, bladder infection or kidney stone) is not the cause of symptoms. There is no single test that can definitively diagnose PBS/IC. (See "Patient information: Urinary tract infections in adolescents and adults" and see "Patient information: Kidney stones in adults").

Physical examination — The physical examination usually includes a complete pelvic examination with a brief rectal exam. Often, patients with PBS/IC have tenderness in the lower abdomen, hips, and buttocks. Women often have tenderness in the vagina and around the bladder, and men may have tenderness in the scrotum and penis. For this reason, being examined can be uncomfortable. In some individuals, it may be necessary to use ultrasound to ensure that the pelvic organs have no evidence of abnormalities.

If an examination or ultrasound is too uncomfortable, some healthcare providers will recommend that the patient begin a course of treatment for PBS/IC without further testing. If improvement is not seen, it may be necessary to perform more testing to confirm the diagnosis.

Some providers will measure the amount of urine remaining in the bladder after the patient urinates; this is called a post-void residual. This measurement can be done by inserting a small catheter into the bladder or by using ultrasound. While it is normal to have some urine in the bladder after voiding, having a large amount of urine is not normal. Urinary retention is the medical term for retaining urine in the bladder, and is not typical of PBS/IC.

Laboratory tests — Most clinicians will perform a urine test to confirm the diagnosis of PBS/IC and ensure that a person's symptoms are not related to another condition, such as a kidney stone or bladder infection. If a urinary tract infection is discovered, the person will be treated with antibiotics. If blood is detected in the urine, further urine and/or diagnostic testing (eg, cystoscopy) may be recommended. (See "Patient information: Urinary tract infections in adolescents and adults" and see "Patient information: Blood in the urine (hematuria)").

Recurrent urinary tract infection — PBS/IC is sometimes misdiagnosed as a chronic or recurrent urinary tract infection. Some people are given antibiotics to treat the pain, urgency, and frequency of PBS/IC, although there is no benefit of antibiotics unless an infection is present. The best way to determine if a urinary tract infection is present is to have a urine culture and sensitivity. (See "Patient information: Urinary tract infections in adolescents and adults").

Cystoscopy — Cystoscopy is a test that allows a doctor to examine the inside of the bladder. Cystoscopy is not required to diagnose PBS/IC, but may be recommended in certain situations. Cystoscopy can be done in the office, after a numbing gel is applied inside the urethra. It can also be done in an operating room while a patient is under anesthesia, sometimes in combination with other procedures (see "Hydrodistension" below).

To perform cystoscopy, a physician inserts a thin telescope with a camera through the urethra and into the bladder. The physician examines the inside (lining) of the bladder to determine if there are any abnormalities. A person with PBS/IC may have either a normal or abnormal-appearing bladder. If an abnormality is seen, further testing may be recommended.

Hydrodistension — Hydrodistension is a procedure that is sometimes recommended to diagnose interstitial cystitis. The procedure is done while a person is under anesthesia, after cystoscopy. The physician fills the patient's bladder with water to stretch the walls of the bladder. The water is released after a few minutes, and then filled again with a smaller amount of water. The lining of the bladder is then examined with a cystoscope to determine if there are signs of IC. Signs of IC can include glomerulations (small reddened areas) and Hunner's patches (larger red areas). Some patients with painful bladder symptoms can have a completely normal appearance during cystoscopy, however. A biopsy (small tissue sample) may be taken from any abnormal areas and later examined with a microscope.

There are conflicting opinions about the need for hydrodistension in the diagnosis of IC. Although some clinicians still perform hydrodistension, most clinicians believe is not necessary or helpful to see such evidence of IC before treating it.

TREATMENT — A topic review that discusses the treatment of painful bladder syndrome/interstitial cystitis is available separately. (See "Patient information: Treatment of painful bladder syndrome and interstitial cystitis").

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.

National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)

National Institute of Diabetes and Digestive and Kidney Diseases
(http://kidney.niddk.nih.gov/kudiseases/pubs/interstitialcystitis/)

Interstitial Cystitis Association
(www.ichelp.org)

Interstitial Cystitis Network
(www.ic-network.com)

European Society for the Study of Interstitial Cystitis
(www.essic.eu)

United States Department of Health and Human Services
(www.4woman.gov/faq/intcyst.htm)

Treatment of painful bladder syndrome/interstitial cystitis

2008-09-22T22:56:00.000-07:00

Treatment of painful bladder syndrome/interstitial cystitis

Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Sandy J Falk, MD

Last literature review version 16.2: May 2008 | This topic last updated: May 16, 2008 (More)

INTRODUCTION — Although painful bladder syndrome/interstitial cystitis (PBS/IC) can cause major deterioration in quality of life, there is no consensus surrounding the optimal approach to its treatment. This is due, in part, to our lack of a clear understanding of the etiology of the disorder, which precludes development of therapies targeted at the underlying pathophysiology. In addition, there have been few randomized, controlled treatment trials of PBS/IC, instead the great majority of therapeutic studies have been retrospective and/or uncontrolled. Lastly, varying definitions of the condition and outcome have been an impediment to interpretation of results and their application to clinical care [1] .

The symptoms of PBS/IC can be somewhat nonspecific; these patients probably suffer from one or more unrecognized disorders. Therefore, it is not surprising that clinically popular treatment algorithms for PBS/IC usually involve several treatment modalities or cycling through various therapies when initial treatments are unsuccessful. This was illustrated by the Interstitial Cystitis Data Base study, which recorded data on 581 women with a diagnosis of IC [2] . These women underwent 183 different types of therapy over several years follow-up. No one therapy was successful in a majority of patients.

In practice, physicians who treat patients with PBS/IC choose a model of the disease that seems to fit their clinical experience, and treat according to that model. Clinicians tend to favor one theory over others, and initiate treatment(s) in line with their favored theory. Therefore, treatment algorithms are highly empiric and vary considerably from site to site. Since treatments tend to have a low success rate, most patients try more than one therapy before finding relief. In this clinical setting, it cannot be determined whether the relief that patients experience is simply due to the passage of time and natural remission of symptoms, or whether the treatment was responsible for the improvement.

NONSPECIFIC THERAPIES — Common sense dictates that the following components are part of all treatment programs:

Psychosocial support — Psychosocial support is an integral part of treatment of any chronic pain disorder. Patients may benefit from identification of a support person within the clinical practice whom they may contact, as needed. They may wish to be in touch with local pain support groups, or with national support groups, such as the Interstitial Cystitis Society (www.ichelp.org) or the Interstitial Cystitis Network (www.ic-network.com). Some centers may have resources to refer patients for formal counseling by a psychologist with expertise in support of patients with chronic illness.

Depression is common in patients with chronic pain, and may impede treatment success. Referral for mental health evaluation may be useful when there is any suspicion that depression is present. (See "Depression: Clinical manifestations and diagnosis").

Referral to pain management specialists — Referral to specialists in pain management should be considered if the full range of pain management options is not available within the practice.

Treatment of comorbid conditions — Acute genitourinary disorders (eg, urinary tract infection, vulvovaginitis) can exacerbate PBS/IC symptoms, thus they should be addressed promptly. Other disorders associated with visceral pain should also be treated since sensitization of any viscera probably results in increased bladder sensitivity. Therefore, it is critically important to treat concomitant inflammatory bowel disease (Crohn's disease, ulcerative colitis, diverticulitis), irritable bowel syndrome, dysmenorrhea or endometriosis. Since PBS/IC patients often carry more than one of these diagnoses, treatment decisions can be complex, and collaboration with other medical professionals is usually necessary. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").

Avoidance of activities associated with flares — Patients frequently note that some exercises or recreational activities, sexual activities, or body positions seem to worsen bladder symptoms. Others note that some foods or beverages are troublesome. Common sense suggests that these factors be avoided until symptoms are resolved, at which time they may be reintroduced. Some practitioners strongly recommend the highly restrictive interstitial cystitis diet [3] , but its benefit has never been studied, and in practice, most patients with food sensitivities are already aware of them and have already excluded them from their diet.

Behavioral therapy — Behavioral therapy forms the cornerstone of all treatment packages. It includes avoidance of exacerbating activities, and also some form of a timed voiding protocol to expand functional bladder capacity. Such protocols are critical because frequent voiding leads to diminished functional bladder capacity (possibly due to shrinkage of smooth muscle, similar to diminished stomach capacity after fasting or after chronic intake of smaller amounts of food).

A typical bladder reeducation protocol involves teaching patients to "void by the clock" rather than voiding when they feel an urge to do so. As an example, a patient who is currently voiding every half an hour is asked to void only on the hour during the daytime (drills are not typically continued through the night), whether they feel the need to void or not, and not to void more frequently than the prescribed interval. This voiding interval is continued for a full week, and if patients are successful at that voiding interval, it is increased by an appropriate amount. This might result in the prescription of a voiding interval of 90 minutes for the second week, of two hours for the third week, 2.5 hours for the fourth week, and three hours for the fifth week. Other similar bladder retraining therapies are widely used since they are cheap, without side effects, and universally available.

The only study of timed voiding in IC patients reported 15 of 21 patients experienced a 50 percent decrease in their IC symptoms [4] .

SPECIFIC THERAPIES

Correction of uroepithelial abnormalities — Proponents of the theory that urothelial abnormalities are responsible for symptoms favor use of therapies directed at the urothelium. These include:

Pentosan polysulfate sodium — Pentosan polysulfate sodium (PPS) is the only oral medication approved by the United States Food and Drug Administration (FDA) for treatment of IC. The approved dose is 100 mg three times daily, although off-label treatment using 200 mg twice daily is clinically common. The medication is a protein that is supposed to be filtered by the kidneys and appear in the urine so that it can reconstitute the deficient glycosaminoglycan (GAG) layer over the urothelium. In fact, only a tiny proportion of the drug is absorbed by the gastrointestinal tract and excreted in the urine. Urinary levels in patients who respond to treatment are not significantly different from the levels in nonresponders [5] .

A systematic review of randomized trials assessing pharmacologic treatments of PBS/IC found that PPS was more effective than placebo in overall improvement of patient-reported symptoms (pain, urgency, frequency) (RR 1.78, 95% CI 1.34-2.35), but the magnitude of effect was modest [6] . There was considerable heterogeneity in the studies that addressed this question.

Intravesical heparin and lidocaine — Some practitioners recommend intravesical instillations of heparin and/or lidocaine, PPS, and sodium bicarbonate in various nonstandardized drug cocktails. No controlled studies of these therapies exist. As an example, use of a solution consisting of 40,000 units of heparin, 8 mL of 2 percent lidocaine, and 3 mL of 8.4 percent of sodium bicarbonate to reach a total fluid volume of 15 mL instilled into the bladder has been described as effective, with over 80 percent of patients experiencing good remissions after two weeks of three treatments per week [7] . Similar solutions have been recommended for use in patients with severe symptoms as a "rescue" intervention. Patients can be taught to perform the instillations themselves at home.

Intravesical dimethyl sulfoxide (DMSO) — Dimethyl sulfoxide (DMSO) was approved by the FDA for use in IC in 1997 on the basis of data from one uncontrolled clinical trial. Its action is thought to be nonspecific, including antiinflammatory, analgesic, smooth muscle relaxing, and mast cell inhibiting effects [8] . Treatment involves bladder catheterization with instillation of 50 mL DMSO weekly for six to eight weeks, followed by 50 mL every two weeks for 3 to 12 months. Small randomized trials initially suggested benefit [9,10] , but adverse effects, including pain and significant exacerbation of symptoms, limited its use. DMSO is currently less commonly used than in the past, as other, less painful treatments have become available.

Hydrodistension — Hydrodistension is usually used as a diagnostic aid for PBS/IC. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis" section on Hydrodistension). It has also been used as a treatment because some patients report prolonged relief of symptoms after the procedure, possibly due to disruption of sensory nerves within the bladder wall [11] . An uncontrolled study reported a positive effect in 35 of 50 patients who underwent 30 minutes of hydrodistension [8] , but others have reported lower success rates [12] . Even when there is benefit, it is usually short-lived, and many patients experience worsening of their symptoms; thus, many clinicians feel that the risk-benefit ratio of hydrodistension therapy is not appropriate for their patients. It may be appropriate to reserve use of repetitive therapeutic hydrodistension for patients who generally obtain significant and prolonged relief. Risks of hydrodistension include bleeding (from ruptured vessels) and, rarely, rupture of the bladder wall.

Neuromodulating therapies — Proponents of the theory that PBS/IC represents a neurological hypersensitivity disorder tend to favor use of neuromodulating treatments. These include:

Amitriptyline — Medications used to treat other pain syndromes are commonly utilized for IC patients, as well. Amitriptyline is commonly prescribed for relief of PBS/IC symptoms. In Germany, one trial randomly assigned 50 subjects with IC to amitriptyline or placebo (IC was defined according to National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria) (show table 1) [13] . Subjects were treated for four months with a self-titration protocol that allowed them to escalate drug dosage by 25 mg increments weekly to a maximum of 100 mg. Amitriptyline use resulted in greater improvement in symptom scores than placebo. In addition, significantly more subjects prescribed amitriptyline rated their satisfaction with treatment as being "good" or "excellent" than those given placebo, 63 and 4 percent, respectively. However, only 42 percent of patients in the amitriptyline group experienced greater than 30 percent decrease in symptom score, suggesting that benefits are modest.

An open-label study of the long-term use of amitriptyline in 94 patients followed for a mean of 19 months reported similar results [14] . Almost one-half of patients rated satisfaction with treatment as "good" or "excellent" and designated themselves as being "moderately" or "markedly" improved. However, about one-third dropped out of the study after a mean treatment period of six weeks, with nonresponse to treatment being the primary reason for dropout. Side effects of amitriptyline include sedation, dry mouth and weight gain.

A National Institutes of Health-sponsored randomized trial comparing behavioral therapy to amitriptyline-plus-behavioral therapy for treatment of PBS is ongoing [15] .

Side effects of amitriptyline include anticholinergic effects, sedation, weight gain, orthostatic hypotension, and conduction abnormalities. (See "Antidepressant medication in adults: Tricyclics and tetracyclics", section on Heterocyclic antidepressants).

Gabapentin — In an uncontrolled study, 21 patients with refractory genitourinary pain were treated with gabapentin at a dose of 300 to 1200 mg/day [16] . About one-half of the patients reported improvement in pain, including five of eight patients who had a diagnosis of IC. Anecdotal reports also suggest that pregabalin can be effective for pain relief in PBS/IC, but no formal studies support its use. (See "Antiepileptic drugs in the treatment of neuropathic pain").

Electrical stimulation therapy — Several reports support treatment of PBS/IC symptoms with implanted sacral neuromodulation (eg, InterStim device, Medtronic Inc, Minneapolis, MN). This device is FDA approved for treatment of urinary urgency and frequency, but not specifically for treatment of PBS/IC. The device consists of an implanted lead that lies along a sacral nerve root (usually at S3 level) and is attached to an implanted pulse generator. An uncontrolled study from a single center described 17 patients diagnosed with IC according to NIDDK criteria (show table 1) who received InterStim implants and were followed for an average of 14 months [17] . Mean daytime and nighttime voiding frequencies decreased from 17 and 9 to 4 and 1, respectively. Average pain rating decreased from 5.8/10 at baseline to 1.6/10 [17] . Another case series documented "moderate" or "marked" improvement in pain in 20 of 21 IC patients (NIDDK criteria) during one year of follow-up [18] .

InterStim is a costly procedure, and surgical revisions are relatively common. Adverse events include surgical site infections and pain, and reoperation for revisions at the lead or pulse generator site(s) is not uncommon.

Somatic therapy — Proponents of the theory that bladder symptoms are caused or maintained by somatic (body wall) abnormalities favor somatic therapies. At present, physical therapy is the only somatic therapy in routine use.

Physical therapy — Treatment of the somatic abnormalities in PBS/IC patients is not within the scope of training of most physical therapists, even those who are skilled in treatment of urinary incontinence. Resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues requires specialized training in pelvic soft tissue manual manipulation and rehabilitation. The therapist may also suggest that manual therapy treatments be supplemented by heat or ice treatments.

Several case series have described symptom relief from manual physical therapies. As an example, one study reported that 70 percent of IC patients who were treated with manual physical therapy to the pelvic floor tissues for 12 to 15 visits experienced moderate to marked improvement [19] . Another study of 21 women with IC and associated pelvic floor hypertonicity demonstrated decreased symptom scores after five weeks of pelvic floor massage [20] . A randomized trial of physical therapies for treatment of PBS/IC is currently ongoing [15] .

Therapies directed at mast cells — Proponents of the theory that mast cells play a critical role in the development and/or maintenance of IC symptoms favor therapies directed at mast cells and allergic phenomena. These include:

Hydroxyzine and cimetidine — Until recently, the antihistamine hydroxyzine was a mainstay of IC treatment, with initial dosing of 10 mg in the evening [21] , increasing to 50 to 100 mg daily as needed. However, a randomized controlled trial found hydroxyzine had no benefit over placebo [22] .

Two small studies suggested benefit of treatment with cimetidine, an H2-receptor blocker, but clinical experience has not generally supported these smaller studies and cimetidine is not commonly used [23,24] .

Montelukast — The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis suggest cysteinyl containing leukotrienes may have a role as proinflammatory mediators in this disease [25] . One small study of 10 women with interstitial cystitis (NIDDK criteria) and detrusor mastocytosis received a single dose of montelukast daily for three months [25] . After one month of montelukast treatment, there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the three months of treatment. After three months, 24-hour urinary frequency decreased from 17.4 to 12 voidings, nocturia decreased from 4.5 to 2.8 voidings, and pain decreased from 46.8 to 19.6 mm on a visual analog scale. No side effects were observed during treatment. Further investigation of this modality is required.

Dimethyl sulfoxide — (see "Intravesical dimethyl sulfoxide (DMSO)" above)

Immunomodulatory treatments — There is some current interest in exploration of immunomodulatory treatments for PBS/IC. In one trial, 64 patients were randomized in a 1:1 ratio to 1.5 mg/kg cyclosporine A twice daily or 100 mg PPS three times daily for six months [26] . Cyclosporine A was superior to PPS in all clinical outcome parameters measured: micturition frequency in 24 hours was significantly reduced (-6.7 +/- 4.7 versus -2.0 +/- 5.1 times) and the clinical response rate (according to global response assessment) was significantly higher for cyclosporine than PPS (75 versus 19 percent). Adverse effects of cyclosporine A include hair growth, gingival hyperplasia, paresthesias, abdominal pain, flushing and muscle pain.

Although intravesical instillation of bacillus Calmette-Guerin (BCG) triggers a variety of local immune responses and has an acceptable safety profile, it has not provided significantly greater relief of IC symptoms than placebo in randomized trials [27,28] .

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Painful bladder syndrome and interstitial cystitis" and see "Patient information: Treatment of painful bladder syndrome and interstitial cystitis"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS — Painful bladder syndrome/Interstitial cystitis (PBS/IC) causes significant deterioration in quality of life, and there is no consensus on the optimal treatment. Several etiologies have been proposed, and clinicians tend to treat according to their belief about the pathophysiology of the disorder. Significant advances in treatment success are likely to depend on major advances in our understanding of the etiology of these disorders, and refinements in diagnosis. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").

Pentosan polysulfate sodium is the only oral treatment for IC approved by the FDA. Uncontrolled studies suggest modest benefit, in a minority of patients, but a randomized controlled trial suggested no benefit over placebo. (See "Pentosan polysulfate sodium" above).

Intravesical therapy with dimethyl sulfoxide is approved by the FDA, but is not in common clinical use due to associated pain and uneven clinical benefit. Intravesical therapy with heparin, lidocaine and/or pentosan polysulfate sodium is also used clinically, without strong evidence to support its use. (See "Intravesical heparin and lidocaine" above and see "Intravesical dimethyl sulfoxide (DMSO)" above).
Hydrodistension is primarily a diagnostic test, but may be considered for patients who obtain significant relief of symptoms after the procedure. (See "Hydrodistension" above).

Amitriptyline has clinical utility, probably acting as a nonspecific neuromodulatory agent that decreases the sensitivity of bladder sensory pathways. (See "Amitriptyline" above).

Sacral neuromodulation with implanted electrodes that lie along a sacral nerve root has shown significant benefit in uncontrolled studies, but is expensive and is not approved by the FDA for this indication. (See "Electrical stimulation therapy" above).

Physical therapy is directed at resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues, but requires specialized training. (See "Physical therapy" above).

There is no good evidence showing that one treatment regimen is clearly superior to another. We suggest physical therapy for initial treatment of patients with PBS/IC (Grade 2C). We also suggest a trial of amitriptyline (Grade 2B). We start with 10 mg nightly and increase to 25 mg nightly as tolerated, in accordance with side effects and symptom relief. In our experience, it is only those women with the most severe symptoms who are willing to tolerate the side effects (eg, sedation and weight gain) that can be associated with amitriptyline use. When symptoms improve on this dual therapy, patients can usually discontinue amitriptyline while maintaining physical therapy, which is continued until their symptoms have resolved. We suggest sacral neuromodulation to patients who do not respond to physical therapy and/or amitriptyline (Grade 2C).

Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis

2008-09-22T22:51:00.000-07:00

Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis

Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Sandy J Falk, MD

Last literature review version 16.2: May 2008 | This topic last updated: June 3, 2008 (More)

INTRODUCTION — Painful bladder syndrome/interstitial cystitis (PBS/IC) is a disorder characterized by bladder pain of variable severity, lasting over a protracted period of time. It can affect women or men, but is more common in women. The diagnosis and treatment of PBS/IC are controversial, similar to other enigmatic medical conditions of unknown origin that are difficult to treat.

The diagnosis and etiology of PBS/IC will be discussed here. Treatment of this disorder is reviewed separately. (See "Treatment of painful bladder syndrome/interstitial cystitis").

DEFINITION — Definitions of IC have widely varied over the past few decades. Before 2002, IC was defined in research settings according to the criteria of the National Institute for Diabetes and Diseases of the Kidney (NIDDK), the so-called "NIDDK criteria" (show table 1) [1] . The NIDDK criteria were soon recognized as being too restrictive for general use; therefore, in 2002 the International Continence Society (ICS) published new recommendations for definition of the painful bladder disorders (show table 1) [2] . Although this definition has been recognized as having some limitations, it is widely used. The ICS defines PBS as a clinical syndrome (ie, a complex of symptoms) consisting of "suprapubic pain related to bladder filling, accompanied by other symptoms, such as increased daytime and nighttime frequency in the absence of proven infection or other obvious pathology." By comparison, the term "interstitial cystitis (IC)" is reserved for patients who have PBS symptoms, but who also demonstrate "typical cystoscopic and histological features" during bladder hydrodistension.

In 2006, the European Society for the Study of IC/BPS (ESSIC) proposed yet another system that is likely to become popular (show table 1) [3] . The diagnosis of Bladder Pain Syndrome (BPS), distinct from PBS, is based upon the presence of pain related to the urinary bladder and accompanied by at least one other urinary symptom. Diseases that cause similar symptoms need to be excluded and cystoscopy with hydrodistension and biopsy (if indicated) should be performed. The ESSIC suggest avoiding the term IC, and instead using the term BPS, followed by a grade denoting severity of cystoscopic appearance and severity of biopsy findings (if performed).

It is likely that further refinement of terminology will occur during the coming years.

PREVALENCE — Because of variable diagnostic criteria, reported prevalence rates for PBS/IC vary widely.

Population-based studies report prevalence rates of 10 to 865 cases per 100,000 women [4,5] .

A survey of participants in the United States Nurses' Health Studies suggested a prevalence of 52 to 67 cases per 100,000 women [6] .
The prevalence of physician-diagnosed PBS/IC in a managed care population was 197 cases per 100,000 women and 41 per 100,000 men [7] , but the prevalence of PBS/IC symptoms in the same population was much higher, at 11 percent of women and 5 percent of men [8] .

A Canadian survey of the diagnostic patterns of 65 urologists found that 2.8 percent of patients seen during a two-week period were diagnosed with IC (7.9 percent of female and 0.4 percent of male patients seen in the office, female:male ratio 8:1) [9] .

The estimated clinical prevalence is highest in reports by researchers who believe that many, or even most, women with chronic pelvic pain may actually have IC; as well as those who feel that many men with lower urinary tract symptoms or prostatitis also may have IC and those who use somewhat nonspecific symptom questionnaires to make the diagnosis [10-12] . The "true prevalence" of PBS/IC will only be established when agreement is reached about diagnostic criteria, and a gold standard is available for its diagnosis.

EPIDEMIOLOGY — Studies have consistently found that PBS/IC is more common in women [12] , with a female:male ratio typically reported as 4.5 to 9 females to one male [5,9,13] . The mean age of diagnosis is probably about 42 to 45 years, although symptoms have been recognized in children [4,14,15] . A greater concordance of IC among monozygotic than dizygotic twin pairs suggests a genetic susceptibility to IC [16] .

ETIOLOGY AND PATHOGENESIS — Little is known about the etiology and pathogenesis of PBS/IC. Ongoing and future research will likely demonstrate that patients currently grouped together under the umbrella diagnosis of PBS/IC actually suffer from several distinct conditions with distinct etiologies. Several pathogenetic mechanisms have been proposed to explain the clinical phenomena, and it is accepted that any of several inciting factors may lead to the clinical manifestation of PBS/IC.

Many studies have documented that patients with IC have urothelial abnormalities present in bladder biopsies. Importantly, it is not known whether these urothelial abnormalities represent primary or secondary phenomena (ie, whether the bladder abnormalities are secondary to another process that is yet unrecognized). These abnormalities include: altered bladder epithelial expression of HLA Class I and II antigens, decreased expression of uroplakin and chondroitin sulfate, altered cytokeratin profile (towards a profile more typical of squamous cells), and altered integrity of the glycosaminoglycan (GAG) layer [17-23] . In addition, the expression of interleukin-6 and P2X3 ATP receptors is increased, and activation of the NFkB gene is enhanced.

The GAG layer normally coats the urothelial surface and renders it impermeable to solutes, thus defects in this layer may allow urinary irritants to penetrate the urothelium and activate the underlying nerve and muscle tissues [24] . This process may promote further tissue damage, pain, and hypersensitivity. Bladder mast cells may also play a role in the propagation of ongoing bladder damage after an initial insult [25,26] .

Antiproliferative factor (APF) may also have a pathogenetic role in the generation of PBS/IC symptoms. APF is a sialoglygopeptide that is produced by the urothelium of IC patients, but not by controls without IC [27] . APF may affect urothelial activity through altered production of growth factors and other proteins involved in urothelial growth and function [28] .

It is likely that neurologic upregulation with central sensitization and increased activation of bladder sensory neurons during normal bladder filling plays a role in the generation and maintenance of PBS/IC symptoms [29,30] . This increased sensitivity may be present in the bladder itself, or may be due to increased activity and new pathways within the central nervous system. Animal models suggest that hypersensitivity in bowel and other pelvic organs may be responsible for sensitization of the bladder [31] . Similar alterations in neural pathways may be responsible for the tenderness that is present in PBS/IC patients [32] . It is also possible that the increase in visceral (bladder) sensitivity is secondary to a primary somatic injury that has sensitized central pathways that overlap with afferents from the bladder.

CLINICAL MANIFESTATIONS — The presentation of PBS/IC is variable, but there are many common clinical features [33,34] . All patients with PBS/IC have pain, which is associated with bladder filling and/or emptying, and usually accompanied by urinary frequency, urgency, and nocturia. The pain that is thought to be of bladder origin is usually described as being suprapubic or urethral, although patterns such as unilateral lower abdominal pain or low back pain with bladder filling are not uncommon [35,36] . The severity of pain ranges from mild burning to severe and debilitating.

Increased urinary frequency arises because the pain of bladder filling is partially or completely relieved by voiding, so patients prefer to maintain low bladder volumes. Clinically, it is useful to ask patients why they void frequently to help distinguish PBS/IC from other causes of frequency. As an example, patients with overactive bladder syndrome void frequently to avoid urinary urge incontinence, whereas in PBS/IC they void frequently to avoid discomfort.

Affected patients may also describe chronic pelvic pain that is distinct from their bladder pain, as well as other ongoing, distinct pain symptoms. These patients often carry several diagnoses, such as irritable bowel syndrome (another visceral pain syndrome), dysmenorrhea, endometriosis, vulvodynia, or fibromyalgia [37] . They may also describe exacerbation of their PBS/IC symptoms during times when other pain symptoms are at their worst (eg, "flares" of PBS/IC when irritable bowel syndrome is symptomatic).

The character of symptoms may vary from one day to the next in a single patient. Exacerbation of PBS/IC symptoms may occur after intake of certain foods or drinks (eg, strawberries, oranges, beer, coffee), or during the luteal phase of the menstrual cycle, stressful times, or after activities such as exercise, sexual intercourse, or being seated for long periods of time (eg, a plane trip).

In severe disease, urinary frequency of as many as 60 voids daily may occur, with associated disruptions of daytime activities, and of sleep. Patients may describe sitting on the toilet for hours at a time in order to let urine dribble from their bladders more or less continuously so that bladders remain as empty as possible and pain is minimized. Associated disruption of home and work life, avoidance of sexual intimacy, chronic fatigue and pain, predictably result in some degree of worsening of quality of life in all affected patients. In surveys, 50 percent of patients reported being unable to work full-time, 75 percent described dyspareunia, 70 percent reported sleep disturbance, and 90 percent reported that PBS/IC affected their daily activities [36] .

The majority of patients describe symptoms that are of gradual onset, with worsening of discomfort, urgency and frequency over a period of months. A smaller subset of patients describes symptoms that are severe from their onset. Symptoms of PBS/IC begin suddenly, with some patients able to name the exact date on which symptoms began. In other patients, symptoms begin after an apparently uncomplicated urinary tract infection or surgical procedure, episode of vaginitis or prostatitis, or after a trauma, such as a fall onto the coccyx. In hindsight, these "sentinel events" have often been empirically diagnosed and treated, and usually are themselves somewhat enigmatic.

DIAGNOSTIC EVALUATION — The diagnosis of PBS/IC is based upon the presence of characteristic symptoms, provided that no symptoms or signs of other conditions are present. Confounding conditions, such as genitourinary cancers, urinary tract stones, urinary infection, urinary retention, or pelvic masses, should be excluded by careful history, physical examination, and laboratory tests, as indicated.

Physical examination — A thorough physical examination of patients with PBS/IC is of critical importance in making a diagnosis, and also in treatment planning. On observation, many patients will be tearful and appear fatigued and/or depressed. Variable tenderness of the abdominal wall, hip girdle, soft tissues of the buttocks, pelvic floor, bladder base, and urethra is almost universally present, probably due to sensitization of afferent nerve fibers in the dermatomyotomes (thoracolumbar and sacral) to which the bladder refers. In males, scrotal and penile tenderness can be present.

In some women, adequate speculum and bimanual examination cannot be conducted due to exquisite tenderness of the pelvic tissues. Pelvic ultrasound can be helpful for assessing the pelvic organs in these patients. It is important to remember that allodynia (perception of non-noxious stimuli, such as light touch, as being noxious or painful) can be present in any patient who has been in chronic pain, and that adequate pelvic examination may be impossible in the awake patient. In this situation, clinicians may choose to begin empiric treatment for PBS/IC, and to defer full examination until either symptoms have improved to the point where examination is possible, or until symptoms have failed to respond to usual therapies and the diagnosis must be revisited.

Laboratory tests

Urinalysis with microscopy and urine culture should be performed in all patients to exclude significant hematuria and infection.

Urine cytology and cystoscopy are performed in high risk groups. (See "Epidemiology and etiology of urothelial bladder cancer").

A post-void residual urine volume should be measured, either using a catheter (usually avoided due to associated pain) or by ultrasound.

Examination of the urine for chlamydia is reserved for patients at high risk of sexually transmitted infections. Compliance with standard guidelines for screening for cervical, prostate, and colorectal cancers is important in all patients, including those with painful bladder disorders.

Cystoscopy — Cystoscopy is not mandatory and is typically performed at the discretion of the clinician. In the United States, it is usually reserved for patients with hematuria (gross or microscopic) or with symptoms that raise suspicion for other processes. As an example, synthetic mesh is frequently used for urologic and gynecologic surgery, and mesh erosion into the lower urinary tract has become an increasingly important cause of urinary symptoms. When a patient has a history of pelvic surgery that predates their symptoms, it is important to use cystoscopy to exclude the presence of foreign body in the lower urinary tract. (See "Reconstructive materials in urogynecology: Classification and host response").

Hydrodistension — Hydrodistension of the bladder is not required for diagnosis or treatment of PBS/IC, although strong opinions are voiced on both sides of this issue [38,39] . Patients are placed under anesthesia and the bladder is filled with water or saline until 70 cm of water pressure is reached, usually at a bladder volume that is far greater than the awake-capacity of the patient (eg, 1000 mL). This bladder dilation is maintained for several minutes, then the dilating fluid is released and the bladder is refilled. During this second bladder fill, the bladder epithelium is examined cystoscopically for characteristic findings of IC, which include glomerulations (petechial red areas) and reddened patches (Hunner's patches). Biopsies are taken from any suspicious areas.

Although many medical centers in the United States continue to perform hydrodistension, it has fallen from favor as glomerulations are now considered nonspecific findings (eg, one study found glomerulations in 45 percent of healthy patients [40] ), their presence does not correlate well with symptoms [41] , and the results of hydrodistension do not necessarily affect clinical management.

Bladder biopsy — Bladder biopsy is not required for a diagnosis of PBS/IC, except for exclusion of other disorders. The lack of utility of bladder biopsy was illustrated in a longitudinal study that investigated associations between bladder biopsy features and urinary symptoms in 204 patients with a clinical diagnosis of IC [41] . Only 50 percent of patients demonstrated an increase in mast cell count in the bladder lamina propria (>30 cells per mm(3)), 11 percent demonstrated complete loss of urothelium (ie, an ulcer), 14 percent demonstrated granulation tissue in the lamina propria, and submucosal hemorrhage of varying degree was seen in 67 percent. It is important to note that some of these biopsy findings may have been due to the hydrodistension procedure itself, and that chronic inflammation was present only in a minority of patients.

Findings such as these were behind the impetus to discourage routine use of the term "interstitial cystitis" to describe the clinical syndrome of urinary urgency, frequency and pain, since biopsies suggested that the process is neither "interstitial" nor "cystitis."

Potassium sensitivity test — The potassium sensitivity test (PST) has also been proposed by some researchers as useful for diagnosis of PBS/IC [42] , but is not recommended for routine use since its results are nonspecific for PBS/IC [43] . During this test, 40 mL sterile water is instilled into the bladder, and note is made of any associated pain. The bladder is drained and then filled with a 40 mL of 0.4 M potassium chloride; a finding of increased pain during this second fill is considered indicative of bladder hypersensitivity and suggestive of PBS/IC.

Symptom scales — Some centers use symptom scales to aid in diagnosis of PBS/IC, but in practice, use of these scales adds little to the ability to make a diagnosis and their use is not widespread. However, these scales can be useful in the monitoring of clinical progress after diagnosis [44,45] . Three such scales are the O'Leary-Sant IC symptom and problem index, the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale, and the University of Wisconsin Interstitial Cystitis Scale [44,46,47] .

Biomarkers — Several biomarkers are being considered as possibly useful for diagnosing PBS/IC. The most promising marker is APF (see "Etiology and pathogenesis" above). In a study in which urine from 219 patients with symptomatic IC was compared with that from 324 controls without IC, the sensitivity and specificity of APF for IC 94 and 95 percent, respectively [27] . Use of APF and other biomarkers requires further validation before they can be recommended clinically.

Urodynamic testing — Urodynamic testing is not currently considered to have a role in the diagnosis of PBS/IC.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Painful bladder syndrome and interstitial cystitis" and see "Patient information: Treatment of painful bladder syndrome and interstitial cystitis"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS

Painful bladder syndrome/interstitial cystitis (PBS/IC) refers to a chronic bladder pain syndrome. It is more common in women than men. (See "Definition" above and see "Epidemiology" above).

All patients with PBS/IC have pain, which is associated with bladder filling and/or emptying, and usually accompanied by urinary frequency, urgency, and nocturia. They may also describe chronic pelvic pain that is distinct from their bladder pain, as well as other ongoing, distinct pain symptoms, such as irritable bowel syndrome, dysmenorrhea, endometriosis, vulvodynia, or fibromyalgia. (See "Clinical manifestations" above).

The clinical diagnosis of PBS/IC is based upon the presence of characteristic symptoms, after other conditions with similar symptoms are excluded. (See "Diagnostic evaluation" above).

Physical examination is often remarkable for widespread tenderness of the abdominal wall, hip girdle, buttocks, thighs and pelvic floor, as well as tenderness of the bladder base and/or urethra. (See "Physical examination" above).

Urinalysis with microscopy and urine culture should be performed in all patients to exclude significant hematuria and infection. Cystoscopy, hydrodistension, bladder biopsy, and potassium sensitivity testing are not necessary for diagnosis of PBS/IC. (See "Diagnostic evaluation" above).

Noninvasive diagnosis of peripheral arterial disease

2008-09-04T18:14:00.000-07:00

Noninvasive diagnosis of peripheral arterial disease

Author
Emile R Mohler, III, MD
Section Editor
Denis L Clement, MD, PhD
Deputy Editor
Gordon M Saperia, MD, FACC

Last literature review version 16.2: May 2008 | This topic last updated: April 15, 2008 (More)

INTRODUCTION — In patients with suspected lower extremity peripheral arterial disease (PAD) based upon the history and physical examination (eg, symptoms of intermittent claudication) or in patients with risk factors for vascular disease (eg, older age, smoking, diabetes mellitus), noninvasive tests are performed to confirm the clinical diagnosis and to further define the level and extent of obstruction [1] . (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease").

The noninvasive tests available to the clinician to diagnose lower extremity PAD will be reviewed here. The clinical manifestations and natural history of claudication and its management by medical therapy, angioplasty, or surgery are discussed separately. (See appropriate topic reviews).

GENERAL PRINCIPLES — The location of pain in patients with claudication varies with the vessels that are involved. The usual relationship between the site of pain and site of arterial disease can be summarized as follows:

• Buttock and hip — aortoiliac disease
• Thigh — common femoral artery or aortoiliac
• Upper two-thirds of the calf — superficial femoral artery
• Lower one-third of the calf — popliteal artery
• Foot claudication — tibial or peroneal artery

Despite these general relationships, the history and physical examination are not reliable for the detection of lower extremity PAD. It has been estimated that relying solely on the classic symptoms of claudication will miss up to 90 percent of cases [2,3] . This was best illustrated in a study of 6417 patients at risk for peripheral arterial disease (either age >70 or age 50 to 60 with a history of diabetes or more than 10 pack-years of cigarette smoking) in a primary care setting [2] . PAD, identified by an ankle-brachial index ≤0.9, was present in 1865 (29 percent), only 11 percent of whom presented with classic claudication symptoms. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Atypical symptoms and section on Asymptomatic disease).

The physical examination is also unreliable. As an example, an abnormal femoral pulse has a high specificity and positive predictive value but low sensitivity for large vessel disease [4] . The best single discriminator is an abnormal posterior tibial pulse.

Patients at risk — Given these limitations, the diagnosis of lower extremity PAD often begins with noninvasive testing. The 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD and the 2007 TASC II consensus document on the management of patients with PAD identified the following groups at risk for lower extremity PAD [5,6] :

• Age ≥70 years
• Age 50 to 69 years with a history of smoking and.or diabetes
• Age 40 to 49 with diabetes and at least one other risk factor for
• atherosclerosis

• Leg symptoms suggestive of claudication with exertion or ischemic pain at rest
• Abnormal lower extremity pulse examination
• Known atherosclerosis at other sites (eg, coronary, carotid, or renal arterial disease)
• All patients with a Framingham risk score of 10 to 20 percent (see "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on Framingham risk score).

In such patients, the standard review of symptoms should include questions related to a history of walking impairment, symptoms of claudication, ischemic rest pain, or nonhealing wounds [5,6] . Measurement of the resting ankle-brachial index should be performed in patients with one or more of these findings.

NONINVASIVE TESTS — A variety of noninvasive examinations are available to assess the presence and degree of peripheral arterial disease (show algorithm 1 and show algorithm 2). They include the ankle-brachial index (ABI), exercise treadmill test, segmental limb pressures, segmental volume plethysmography, and ultrasonography. Data suggest that magnetic resonance imaging may become an important noninvasive method for assessment [7] ; however, the cost and the time necessary for the study limit its use as a routine screening modality at this time. (See "Clinical utility of cardiovascular magnetic resonance imaging").

Ankle-brachial index — A relatively simple and inexpensive method to confirm the clinical suspicion of arterial occlusive disease is to measure the resting and post-exercise systolic blood pressures in the ankle and arm. This measurement is referred to as the ankle-brachial (or ankle-arm) index or ratio, and provides a measure of the severity of peripheral arterial disease [8] .

Calculation of the ankle-brachial index (ABI) is performed by measuring the systolic blood pressure (by Doppler probe) in the brachial, posterior tibial, and dorsalis pedis arteries (show figure 1) [9,10] . The highest of the four measurements in the ankles and feet is divided by the higher of the two brachial measurements:

• The normal ABI is 1.0 to as high as 1.3, since the pressure is higher in the ankle than in the arm. Values above 1.30 suggest a noncompressible calcified vessel.
• An ABI below 0.9 has 95 percent sensitivity (and 100 percent specificity) for detecting angiogram-positive peripheral arterial disease and is associated with ≥50 percent stenosis in one or more major vessels.
• An ABI of 0.40 to 0.90 suggests a degree of arterial obstruction often associated with claudication.
• An ABI below 0.4 represents advanced ischemia.

The ABI should be measured in both legs in all new patients with suspected PAD both to confirm the diagnosis and to establish a baseline [5] .

If ABIs are normal at rest but symptoms strongly suggest claudication, ABIs and segmental pressures should be obtained before and after exercise on a treadmill (see "Exercise treadmill testing" below) or using active pedal plantarflexion, which involves repeatedly standing up on the toes [11] .

The ABI correlates with clinical measures of lower extremity function such as walking distance, velocity, balance, and overall physical activity [12] . In addition, a low ABI has been associated with a higher risk of coronary heart disease, stroke, transient ischemic attack, progressive renal insufficiency, and all-cause mortality [13-17] .

• In a prospective study among nearly 1500 women, 82 (5.5 percent) had an ABI of less than 0.9, 65 of whom had no symptoms of peripheral arterial disease. Compared to the cohort with an index greater than 0.9, this group had markedly increased relative risks of 3.1 and 3.7 for death and coronary heart disease at four years [14] .
• In a report from the Framingham study of 251 men and 423 women (mean age 80 years), 141 (21 percent) had an ABI less than 0.9 [16] . Those with a low ABI had at four years a significantly increased risk of transient ischemic attack or stroke (13 versus 5 percent; adjusted hazard ratio 2.0).

There is a general but not absolute correlation between symptoms and the site and severity of PAD. In a report described in detail elsewhere, patients with unilateral PAD as determined from the ABI often had bilateral leg pain and 14 percent of those with unilateral pain had pain in the other leg [18] . (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Correlation of ABI with symptoms and site of PAD).

High ABI — A potential source of error with the ABI is that calcified vessels may not compress normally, possibly resulting in falsely elevated Doppler signals. Thus, an ABI above 1.3 is suspicious for a calcified vessel. In some patients with arterial calcification, an accurate pressure may be obtained by measuring the toe pressure and calculating the toe-brachial index. In this setting, one must recognize that a pressure gradient of 20 to 30 mmHg normally exists between the ankle and the toe.

An abnormally high ABI (>1.4) is also associated with higher rates of leg pain [18] and of cardiovascular risk [15] . The increase in cardiovascular risk was suggested in a report of 4393 native American patients in the Strong Heart Study who had bilateral ABI measurements and were followed for a mean of eight years [15] . There were 1022 deaths (23 percent) of which 272 (27 percent of all deaths) were cardiovascular. Patients with an ABI ≤0.9 or >1.4 had an increased risk of all-cause mortality (adjusted hazard ratios 1.7 and 1.8) and cardiovascular mortality (adjusted hazard ratios 2.5 and 2.1).

Similarly, data from the National Health and Nutrition Survey (NHANES) estimated 1.4 percent of adults age >40 years in the United States have an ABI >1.4, accounting for approximately 20 percent of all adults with PAD [19] .

Exercise treadmill testing — The dynamics of blood flow across a stenotic lesion depend in part upon whether the individual is at rest or exercising and upon the severity of the obstruction. Exercise normally decreases vascular resistance and enhances blood flow to the exercising extremities. An arterial stenosis of less than 70 percent may not be of sufficient severity to significantly perturb blood flow at rest or to produce a systolic pressure gradient. Exercise in such patients can induce a systolic pressure gradient across the stenosis or, in patients with more severe disease, increase the systolic pressure gradient.

These changes may be detected clinically by a fall in the ABI followed by recovery. This pattern is detected by measurement of the ABI at one minute intervals for five minutes after exercise. As a result, exercise testing is a sensitive method for evaluating patients with typical symptoms of claudication in whom the resting ABI is normal.

Several protocols exist for treadmill testing and are generally divided into those using a fixed versus a graded routine [20] . The standard exercise test is a treadmill test for five minutes at 2 mph on a 12 percent incline. Severe claudication can be defined as an inability to complete the treadmill exercise due to leg symptoms and ankle systolic pressures below 50 mmHg.

Segmental limb pressures — Once the presence of arterial occlusive disease has been verified using ABI measurements at rest or during exercise, the level and extent of PAD is routinely assessed by segmental limb pressures. A 20 mmHg or greater reduction in pressure is considered significant if such a gradient is present either between segments along the same leg or when compared to the same level in the opposite leg.

As with ABI measurements, segmental pressure measurements may be artifactually increased or not interpretable in patients with noncompressible vessels [5] . (See "High ABI" above).

Several blood pressure cuff positions have been employed to detect the level of peripheral arterial disease [21] . As examples, a significant reduction in pressure [5] :

• Between the brachial artery and the upper thigh reflects aortoiliac disease
• Between the upper and lower thigh reflects superficial femoral artery disease
• Between the lower thigh and upper calf reflects distal superficial femoral artery or popliteal disease
• Between the upper and lower calf reflects infrapopliteal disease

In addition, a toe pressure of less than 60 percent of the ankle pressure indicates digital artery occlusive disease.

Use of two specially designed narrow blood pressure cuffs rather than one large cuff on the thigh permits the differentiation of aortoiliac and superficial femoral artery disease. This technique, which is performed in the vascular laboratory, involves placement of a narrow cuff on the upper and lower thigh. The upper (proximal) thigh cuff is inflated to a pressure above systolic and then gradually deflated to determine the systolic pressure as heard by Doppler at the foot. This process is then repeated for the lower (distal) thigh cuff.

If the upper thigh systolic pressure is reduced compared to the brachial pressure (thigh-brachial index [TBI] <1.1), then the patient has a lesion in the aortoiliac territory. If, on the other hand, the TBI is >1.1 in the upper thigh and less than 1.1 in the lower thigh, the lesion is in the superficial femoral artery. In one prospective study, the use of two narrow thigh cuffs correctly identified the location in 78 percent of extremities with peripheral arterial disease versus a rate of only 19 percent with the use of a large cuff [21] .

The localization of the lesion may also be suspected from the history in patients with intermittent claudication. Thus, one should ascertain whether the pain is in the buttock or hip (suggesting aortoiliac disease), thigh (common femoral disease), upper calf (superficial femoral disease), lower calf (popliteal disease), or foot (tibial or peroneal disease). (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease").

In the patient with possible upper extremity peripheral arterial disease, a difference of ≥10 mmHg between brachial pressures suggests innominate, subclavian, axillary, or proximal brachial arterial occlusion.

Potential disadvantages in using Doppler ultrasound for segmental limb pressures are that the technique is insensitive at extremely low blood flow rates (<3 cm per second) and a venous signal can be confused with an arterial signal (especially if pulsatile venous flow is present as can occur with congestive heart failure).

Segmental volume plethysmography — Plethysmography, or the measurement of volume change in an organ or limb, is usually used in conjunction with segmental limb pressures to assess the level of arterial disease. This technique is performed by injecting a standard volume of air into pneumatic cuffs placed at various levels along the extremity. Volume changes in the limb segment below the cuff are translated into pulsatile pressure, which is detected by a transducer and then displayed as a pressure pulse contour.

The normal pulse volume recording is composed of a systolic upstroke with a sharp systolic peak followed by a downstroke that contains a prominent dicrotic notch. A change in the pulse volume contour indicates proximal arterial obstruction and is due to the dissipated energy that occurs due to arterial narrowing [22,23] .

Variations in the contours of the pulse volume recording reflect disease severity (show figure 2). As an example, mild disease is characterized by the absence of a dicrotic notch. With progressive obstruction, the upstroke and downstroke become equal, and with severe disease, the amplitude of the waveform is blunted. Pulse volume recordings are most useful in detecting disease in calcified vessels which tend to yield falsely elevated pressures.

Since the absolute amplitude of plethysmographic recordings is influenced by cardiac output and vasomotor tone, interpretation of these measurements should be limited to the comparison of one side of an extremity to the other in the same patient and not between patients. The clinician should also recognize that a dicrotic notch may be absent from the recording of a normal artery in the presence of low resistance, as may occur after exercise.

Duplex ultrasonography — Although ultrasonography is accurate in detecting peripheral arterial disease, resting segmental pulse volumes and systolic pressures are the initial screening tests in many laboratories. Ultrasonography is currently used to depict anatomy, hemodynamics, and lesion morphology; ultrasonographic equipment used for these tasks include B-mode imaging, pulse wave Doppler, continuous wave Doppler, and color Doppler display [8] .

Lower extremity examinations using the duplex Doppler begins at the common femoral artery and proceeds distally to the popliteal artery. An area of stenosis is localized with color Doppler and assessed by measuring Doppler velocities at several arterial sites.

The normal peripheral arterial velocity waveform is triphasic and consists of [24,25] :

• A forward flow systolic peak
• Reversal of flow in early diastole
• Forward flow in late diastole

With progressive peripheral arterial disease, there is elimination of the reverse flow, a decrease in systolic peak and an increase in flow in diastole (show figure 3).

It has been suggested that the main purpose of duplex Doppler ultrasonography is to avoid diagnostic angiography before intervention in patients with arterial disease proximal to the calf [26] . A meta-analysis of 14 studies found that sensitivity and specificity of this technique for ≥50 percent stenosis or occlusion were 86 and 97 percent for aortoiliac disease and 80 and 98 percent for femoropopliteal disease [26] .

Multidetector computed tomography — The development of multidetector computed tomographic (MDCT) scanners now allows rapid acquisition of high resolution, intravenous contrast enhanced images from patients with suspected peripheral arterial disease. A number of reports of small series of patients have noted excellent correlation between MDCT and digital subtraction angiography (DSA) in the detection of aortic and lower extremity arterial disease [27-29] , but these findings have not been universal [30] . In addition the total burden of radiation is relatively high.

A meta-analysis of 12 studies in which MDCT was used to evaluate 9541 lower extremity arterial segments in 436 symptomatic patients compared test performance to DSA [31] . The sensitivity and specificity for detecting a stenosis of a least 50 percent were 92 and 93 percent, respectively, compared to DSA. In the three studies that evaluated subdivisions of the arterial system, diagnostic performance in the infrapopliteal tract was lower than, but not statistically different from, that in the aortoiliac and femoropopliteal tracts.

A separate issue is the ability of MDCT to guide therapy. In an initial series of 58 patients with claudication, the findings on MDCT were used to determine whether or not an intervention was necessary [32] . Among the 29 patients in whom conservative management was indicated by MDCT, none required revascularization at a mean follow-up of 501 days.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Claudication"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

RECOMMENDATIONS — We agree with the recommendations of the 2005 ACC/AHA guideline and the 2007 TASC II consensus document on the management of PAD with regard to the identification of asymptomatic PAD and for the evaluation of patients with intermittent claudication [5,6] .

Asymptomatic patients — The main value of identifying patients with asymptomatic lower extremity PAD is related to the association of these lesions with an increased risk of myocardial infarction, stroke, and cardiovascular mortality [5,33-35] . PAD is considered to be a coronary equivalent and such patients should be treated with risk factor reduction. (See "Medical management of claudication" and see "Secondary prevention of cardiovascular disease: Risk factor reduction").

The ACC/AHA guidelines made the following general recommendations for patients with no leg symptoms or atypical leg symptoms [5] . (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Atypical symptoms and section on Asymptomatic patients).

• In patients ≥70 years of age or ≥50 years of age with a history of smoking and/or diabetes (ie, those at increased risk for PAD), the standard review of symptoms should include questions related to a history of walking impairment, symptoms of claudication, ischemic rest pain, or nonhealing wounds. Use of the Walking Impairment questionnaire can be considered. (See "Patients at risk" above).
• The resting ABI should be measured in patients with one or more of these findings. The ABI should be measured in both legs in all new patients with PAD to confirm the diagnosis and to establish a baseline.

These recommendations are consistent with those made in the 2007 TASC II consensus document on the management of PAD [6] .

Similar recommendations were made by the American Diabetes Association for monitoring asymptomatic patients with diabetes [36] . The guideline recommended that initial screening for PAD should include a history for claudication and an assessment of the pedal pulses and that consideration should be given to obtaining an ABI.

Further evaluation is dependent upon the ABI value [5] :

• An ABI ≤0.90 is diagnostic of PAD.
• An ABI of 0.91 to 1.30 is borderline or normal. Among patients with atypical symptoms, the ABI should be measured after exercise on a treadmill. An ABI that decreases by 20 percent following exercise is diagnostic of PAD, while a normal ABI following exercise eliminates the diagnosis and suggests the need to evaluate for other causes of the leg symptoms.
• An ABI >1.30 suggests the presence of calcified vessels and the need for additional vascular studies, such as pulse volume recording or measurement of the toe-brachial index. Abnormal results confirm the presence of PAD. (See "High ABI" above).

Symptomatic patients — The evaluation is similar in patients with classic claudication (cramping, pain, or muscle fatigue that is reproducibly induced by exercise and promptly resolves with rest). The history should document the degree of walking impairment and lifestyle limitation and the peripheral pulses should be examined.

Further evaluation is dependent upon the ABI value:

• An ABI ≤0.90 is diagnostic of PAD.
• An ABI of 0.91 to 1.30 should be followed by further testing, such as measurement of the ABI after exercise, segmental limb pressures, or duplex ultrasonography. An abnormal test is diagnostic of PAD, while a normal test excludes PAD although arterial entrapment syndromes may be considered.

Although considered the "gold standard" of diagnostic evaluation for peripheral atherosclerotic disease, the use of iodinated contrast agents involves exposure to the patient of risk from iodine allergy, contrast nephropathy and the risks inherent to percutaneous intervention. With the advent of rapid 3-D imaging sequences combined with existing extracellular gadolinium contrast agents, magnetic resonance angiography (MRA) has shown promise to become a time-efficient and cost-effective tool for the complete assessment of peripheral arterial disease [1-3] . Current available gadolinium compounds are typically used "off-label" and are not approved by FDA for MRA in the United States.

One potential complication with use of gadolinium in patients with chronic kidney disease is skin sclerosis and, therefore, should be used with caution in this population. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced renal failure", section on gadolinium).

MRA is usually performed if revascularization is being considered. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease" and see "Indications for surgery in the patient with claudication").

Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease

2008-09-04T17:53:00.000-07:00

Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease

Author
Emile R Mohler, III, MD
Section Editor
Denis L Clement, MD, PhD
Deputy Editor
Gordon M Saperia, MD, FACC

Last literature review version 16.2: May 2008 | This topic last updated: January 18, 2008 (More)

INTRODUCTION — Patients with compromise of blood flow to the extremities as a consequence of peripheral arterial disease may present with typical ischemic pain of one or more muscle groups, atypical pain or no symptoms. Intermittent claudication (derived from the Latin word for limp) is defined as a reproducible discomfort of a defined group of muscles that is induced by exercise and relieved with rest. This disorder results from an imbalance between supply and demand of blood flow that fails to satisfy ongoing metabolic requirements.

The etiology, risk factors, and clinical manifestations of claudication are reviewed here, with emphasis upon the presentation of peripheral arterial disease (PAD) due to atherosclerosis. The frequency of asymptomatic disease will also be discussed. The noninvasive evaluation and management of this disorder by medical therapy, percutaneous intervention, and surgery are presented separately. (See "Noninvasive diagnosis of peripheral arterial disease" and see "Medical management of claudication" and see "Indications for surgery in the patient with claudication").

The majority of patients with PAD have atherosclerotic disease of the lower extremity. Atherosclerotic PAD of the upper extremity is much less common and is discussed elsewhere. (See "Upper extremity peripheral arterial disease").

ETIOLOGY — Although numerous diseases can cause intermittent claudication (show figure 1), the vast majority of patients with claudication suffer from peripheral atherosclerosis. The clinical history can help distinguish among some of the less common causes of this disorder. As examples, a history of limb trauma, radiation exposure, vasculitis, or ergot use for migraines represent some important clues to the etiology of claudication. In endurance athletes, especially cyclists, a common cause is kinking of the iliac artery which may result in endofibrosis [1] .

Nonarterial pathologic conditions should also be considered in the differential diagnosis of limb discomfort. These include:

• Deep venous thrombosis
• Musculoskeletal disorders
• Peripheral neuropathy
• Spinal stenosis (pseudoclaudication)

PREVALENCE — The prevalence of PAD increases progressively with age, beginning after age 40 [2-7] . As a result, PAD is growing as a clinical problem due to the increasingly aged population in the United States and other developed countries.

The relationship between PAD prevalence and age was illustrated in an analysis of 2174 participants ≥40 years of age in the 1999 to 2000 National Health and Nutrition Examination Survey (NHANES) [7] . The prevalence of PAD, defined as an ankle-brachial index (ABI) <0.90 in either leg, was 0.9 percent between the ages of 40 and 49, 2.5 percent between the ages of 50 and 59, 4.7 percent between the ages of 60 and 69, and 14.5 percent age 70 and older. (See "Noninvasive diagnosis of peripheral arterial disease", section on Ankle-brachial index).

A higher prevalence was noted in the PARTNERS program of primary care practices across the United States in which almost 7000 patients age ≥70 years or 50 to 69 years with a history of cigarette smoking (more than 10 pack-years) or diabetes were evaluated by history and by ABI (with a value ≤0.90 considered diagnostic of PAD) [8] . PAD was present in 29 percent overall: 13 percent had PAD alone (55 percent newly diagnosed) and 16 percent had PAD and cardiovascular disease (35 percent newly diagnosed). A classic history of claudication, as described below, was present in only 11 percent of patients with PAD.

The 2007 TASC II consensus document on the management of PAD made the following estimates for the prevalence of PAD in Europe and North America [9] :

• 27 million affected individuals
• 413,000 hospital discharges of paitents with chronic PAD per year with 88,000 hospitalizations involving lower extremity arteriography and 28,000 discharges for embolectomy or thrombectomy of lower limb arteries

RISK FACTORS — The risk factors that favor the development of peripheral arterial atherosclerosis are similar to those that promote the development of coronary atherosclerosis [7,8,10-14] . These include:

• Diabetes mellitus
• Hyperlipidemia
• Cigarette smoking
• Hypertension

Data from the Framingham Heart Study of 381 men and women who were followed for 38 years revealed that the odds ratio for developing intermittent claudication was 2.6 for diabetes mellitus, 1.2 for each 40 mg/dL (1 mmol/L) elevation in the serum cholesterol concentration, 1.4 for each 10 cigarettes smoked per day, and 1.5 for mild and 2.2 for moderate hypertension [11] . In addition, diabetic patients have worse arterial disease and a poorer outcome than nondiabetics [15] .

Similar findings were noted in NHANES analysis cited above of 2174 patients aged 40 and older [7] . The risk of PAD was significantly increased in current smokers (odds ratio [OR] 4.46) and for patients with diabetes (OR 2.71), hypertension (OR 1.75), or hypercholesterolemia (OR 1.68). Other significant risk factors were black race (OR 2.83) and decreased renal function (OR 2.00).

Patients with PAD are more likely to have increased levels of triglycerides and/or cholesterol, apolipoprotein B, and very low density lipoprotein [16-18] . Conversely, high density lipoprotein cholesterol and apolipoprotein A-I and A-II values, the "protective" lipoproteins, are reduced in these patients [19] . The risk of intermittent claudication may also be increased in patients with elevated plasma lipoprotein(a) and fibrinogen levels [20-22] . (See "Lipoprotein classification; metabolism; and role in atherosclerosis").

In addition to atherosclerotic risk factors being associated with an increased prevalence of PAD, these risk factors are also associated with the earlier onset of PAD. Patients who are 50 to 69 years with a history of cigarette smoking (more than 10 pack-years) or diabetes may have a similar incidence of asymptomatic PAD as patients ≥70 years of age [8] .

The importance of ethnicity in the risk for PAD was evaluated in a population-based epidemiologic survey of 2343 randomly selected participants in San Diego [23] . PAD was defined as an ankle-to-brachial index ≤0.90, an abnormal Doppler waveform, or prior revascularization for PAD. Blacks had a significantly higher prevalence of PAD than non-Hispanic whites (7.8 versus 4.9 percent, odds ratio 2.30). Although blacks had significantly higher rates of diabetes and hypertension and a significant increase in body mass index, the increase in risk for PAD was similar after adjustment for these and other variables. Hispanics and Asians had somewhat lower rates of PAD than non-Hispanic whites, but the number of affected patients was small and the difference was not significant.

Patients at risk — Based in part upon the above observations, the 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD, which were produced in collaboration with major vascular medicine, vascular surgery, and interventional radiology societies, identified the following groups at risk for lower extremity PAD [24] :

• Age ≥70 years
• Age 50 to 69 years with a history of smoking and.or diabetes
• Age 40 to 49 with diabetes and at least one other risk factor for atherosclerosis

• Leg symptoms suggestive of claudication with exertion or ischemic pain at rest
• Abnormal lower extremity pulse examination
• Known atherosclerosis at other sites (eg, coronary, carotid, or renal arterial disease)

Predictors of progression — The risk factors that predict progression of PAD were evaluated in a longitudinal study of 403 patients at baseline and at a mean follow-up of 4.6 years using a standard questionnaire, clinical examination, and noninvasive testing assessing the ankle-to-brachial index (ABI) for large vessel (LV) disease and the toe-to brachial index (TBI) for small vessel (SV) disease [25] . The following findings were noted:

• Among patients with the largest fall in ABI (the LV cohort), current cigarette smoking, the ratio of total to HDL cholesterol, hs-CRP, and Lp(a) were statistically important predictors.
• Among patients with the largest fall in the TBI (SV cohort), diabetes was the only significant predictor of progression.

CLINICAL PRESENTATION — Patients with PAD often present with symptoms of leg ischemia. However, many patients are asymptomatic, particularly those first detected by ABI screening, and, among symptomatic patients, atypical symptoms are more common than classic claudication [8,26] . The 2005 ACC/AHA guidelines on PAD suggested the following distribution of clinical presentation of PAD in patients ≥50 years of age [24] :

• Asymptomatic — 20 to 50 percent
• Atypical leg pain — 40 to 50 percent
• Classic claudication — 10 to 35 percent
• Critical limb ischemia — 1 to 2 percent

The clinical manifestations of critical limb ischemia (also called limb-threatening ischemia) are discussed separately. (See "Clinical manifestations and evaluation of chronic critical limb ischemia").

Classification — Two classification systems have been used for lower extremity PAD: the Fontaine system and the Rutherford system. Both are based upon the severity of symptoms and markers or severe disease such as ulceration and gangrene (show table 1) [9] .

Symptomatic disease — Among symptomatic patients, the perception of claudication can vary from severe debilitating discomfort at rest to a bothersome pain of seemingly little consequence. The severity of symptoms of claudication depends upon the amount of stenosis, the collateral circulation, and the vigor of exercise.

Patients with claudication can present with buttock and hip, thigh, calf, or foot claudication, either singly or in combination. The usual relationship between the site of pain and site of arterial disease can be summarized as follows:

• Buttock and hip — aortoiliac disease
• Thigh — common femoral artery or aortoiliac
• Upper two-thirds of the calf — superficial femoral artery
• Lower one-third of the calf — popliteal artery
• Foot claudication — tibial or peroneal artery

Physical examination in the patient with claudication can be normal, but commonly reveals diminished or absent pulses below the level of stenosis with occasional bruits over stenotic lesions and evidence of poor wound healing over the area of diminished perfusion [27] . Other physical findings may include a unilaterally cool extremity, a prolonged venous filling time, shiny colored skin, hair loss, skin atrophy and nail changes [27] .

Physical signs can also help determine the extent and distribution of vascular disease [27] . These include an abnormal femoral pulse, lower extremity bruits, and the Buerger test (foot pallor with elevation of the leg and, in the dependent position, a dusky red flush spreading proximally from the toes).

Buttock and hip claudication — Patients with aortoiliac occlusive disease (Leriche's syndrome) may complain of buttock, hip, and, in some cases, thigh claudication. The pain is often described as aching in nature and may be associated with weakness of the hip or thigh with walking. Bilateral aortoiliac disease that is severe enough to cause symptoms almost always causes impotence in men; another diagnosis should therefore be entertained if impotence is absent.

Physical examination reveals diminished or absent pulses beginning in the groin area are found bilaterally, with occasional bruits over the iliac and femoral arteries. Other findings include muscle atrophy and slow wound healing in the legs.

Conditions that resemble Leriche's syndrome are:

• Osteoarthritis of the hip or knee joints — Osteoarthritis can be distinguished clinically from aortoiliac disease because osteoarthritic pain may not disappear promptly after exercise, may be associated with weather changes, and may vary in intensity from day to day.

• Neurogenic claudication — Neurogenic claudication, also called pseudoclaudication, describes a pain syndrome due to lumbar neurospinal canal compression, which is usually due to osteophytic narrowing of the neurospinal canal. The clinical presentation often helps to distinguish true claudication from pseudoclaudication. Unlike true claudication which occurs with walking and is relieved by stopping, pseudoclaudication causes pain with erect posture (lumbar lordosis) and is relieved by sitting or lying down. Patients with pseudoclaudication may also find symptomatic relief by leaning forward and straightening the spine (usually done with pushing a shopping cart or leaning against a wall). (See "Lumbar spinal stenosis").

Thigh claudication — Atherosclerotic occlusion of the common femoral artery may induce claudication in the thigh, calf, or both. Patients with occlusive disease of the femoral or popliteal arteries have normal groin pulses but decreased pulses distally.

Calf claudication — Calf claudication is the most common complaint. It is usually described as a cramping pain that is consistently reproduced with exercise and relieved with rest. Cramping in the upper two-thirds of the calf is usually due to superficial femoral artery stenosis, whereas cramping in the lower third of the calf is due to popliteal disease. This type of cramping pain in the calf can be confused with two other conditions:

• Nocturnal leg cramps — Nocturnal leg cramps occur among older and infirmed patients. This complaint is thought to be neuromuscular rather than vascular in origin. (See "Nocturnal leg cramps, night starts, and nocturnal myoclonus").
• Calf pressure and tightness. — This symptom is primarily seen in athletes, and is usually associated with chronic exercise. It is thought to be due to increased compartment pressure and may persist even after rest.

Foot claudication — Claudication of the foot is usually accompanied by occlusive disease of the tibial and peroneal vessels. Isolated foot claudication is rarely seen with atherosclerotic occlusive disease but is commonly seen with thromboangiitis obliterans (Buerger's disease).

Vasospastic claudication — Vasospastic claudication refers to a condition characterized by normal pulses and no bruits at rest, but symptoms of claudication with stress. These symptoms were originally thought to be due to vasospasm. However, a subcritical atherosclerotic lesion is now felt to underlay these symptoms in most patients. Rarely, extrinsic compression can also cause this condition, as occurs with popliteal-artery entrapment syndrome.

Ischemic rest pain — A progressive decrease in limb perfusion can result in ischemic rest pain. Such discomfort typically occurs at night and involves the digits and forefoot. The pain may be more localized in patients who develop an ischemic ulcer or gangrenous toe.

The precipitating cause of ischemic rest pain may be trauma superimposed on an area of borderline perfusion or less often microembolization or local thrombus formation. Affected patients frequently find that the pain is relieved by hanging their feet over the edge of the bed or, paradoxically, by walking around the room. Chronic tissue ischemia may also result in ischemic neuropathic pain that is frequently described as throbbing or burning with a superimposed severe shooting pain up the limb.

Atypical symptoms — Some patients with PAD have atypical symptoms as a result of comorbidities, physical inactivity, and alterations in pain perception. This issue was addressed in a study of 460 men and women with known PAD [26] . Symptoms were classified as follows:

• Classic claudication — Exertional calf pain that does not begin at rest, causes the patient to stop walking, and resolves within 10 minutes of rest — 150 patients (33 percent)
• Atypical exertional leg pain type I — Pain similar to that of classic claudication, but does not cause the patient to stop walking — 41 patients (9 percent)
• Atypical exertional leg pain type II — Pain similar to that of classic claudication, but does not involve the calves or does not resolve within 10 minutes of rest — 90 patients (20 percent)
• Leg pain on both exertion and rest — 88 patients (19 percent)
• No exertional leg pain, physically active (walked more than six blocks in previous week) — 63 patients (14 percent)
• No exertional leg pain, physically inactive — 28 patients (6 percent)

Compared to patients with classic claudication, those with leg pain on both exertion and rest were more likely to have diabetes, neuropathy, or spinal stenosis in addition to PAD. Functional capacity varied among groups, being best among those with type I atypical exertional leg pain and worst among those with pain on both exertion and rest.

A much lower rate of classic claudication was noted in the report from the PARTNERS program cited above in which 6417 patients were at risk for PAD (either age ≥70 or age 50 to 69 with a history of diabetes or more than 10 pack-years of cigarette smoking) in a primary care setting [8] . PAD, identified by the ABI or by history, was present in 29 percent:

• Among the patients with a new diagnosis of PAD, approximately 47 percent had no history of leg symptoms, 47 percent had atypical leg symptoms, and only 6 percent had classic claudication.
• Among the patients with known prior PAD, approximately 25 percent had no leg symptoms, 61 percent had atypical leg symptoms, and 14 percent had classic claudication.

Popliteal aneurysm — The popliteal artery is the most common site of a peripheral artery aneurysm [28] . A popliteal aneurysm in one leg should prompt evaluation for other aneurysms as they are bilateral in approximately half of cases and are associated with an abdominal aortic aneurysm in approximately one-third of cases [29] .

The etiology is unclear, but risk factors include hypertension, diabetes, smoking, and ischemic heart disease. The pathophysiology of the aneurysm involves inflammatory infiltration with associated mediators, such as matrix metaloproteinases, that result in degradation of the medial layer of the vessel wall [30] .

The initial presentation of a popliteal aneurysm may be distal lower extremity ischemia due to embolization from the aneurysmal sac. It is estimated that 60 percent of patients are symptomatic at time of presentation and approximately 30 percent have limb-threatening ischemia [31,32] . Rupture is another mode of presentation and is thought to occur in 2 to 4 percent of patients [33] . Popliteal aneurysms can also compress the adjacent vein causing distal edema and a prominent venous pattern on the lower leg. Nerve compression may also cause symptoms.

Intervention is indicated in aneurysms greater than 2 centimeters in diameter or in aneurysms that contain mural thrombus. The standard surgical approach is open surgical ligation and bypass with saphenous vein. One surgical case series reported a five-year patency of 69 percent, a secondary patency of 87 percent, and limb salvage rate of 87 percent [34] . An adjunctive approach is use of intraoperative intra-arterial thrombolysis [35] .

An endovascular approach to repair of popliteal aneurysms involves placement of a fabric-lined metal stent within the vessel known as a "stent graft" [33] . There are more than 20 reports of endovascular repair of popliteal aneurysms, but most are small case series. In one randomized study patients received either conventional open repair or endovascular repair using a stent graft [36] . One patient had early stent graft thrombosis on the day after the procedure that was treated with thrombolysis and angioplasty. The 12 month and 48 month follow-up showed a primary patency rate for the conventional group and of the endovascular repair group to be 100 and 86.7 percent and 81.6 and 80 percent, respectively.

Asymptomatic disease — Many patients with PAD have unrecognized disease as illustrated by the following observations:

• The PARTNERS program cited above evaluated 6417 patients at risk for PAD (either age ≥70 or age 50 to 69 with a history of diabetes or more than 10 pack-years of cigarette smoking) in a primary care setting [8] . PAD, identified by the ABI or by history, was present in 29 percent. Among the patients with a new diagnosis of PAD, approximately 45 percent had no history of leg symptoms and only 5.5 percent had classic claudication.

• Another study included 239 men and women ages 55 and older with no history of PAD who were recruited from a general internal medicine practice [37] . The ABI was abnormal (<0.90) in 14 percent. Most of these patients did not report exertional leg symptoms. However, they were not able to walk as far in six minutes as a group of patients without PAD (1,362 versus 1,539 feet).

The physical examination is also unreliable. As an example, an abnormal femoral pulse has a high specificity and positive predictive value but low sensitivity for large vessel disease [38] . The best single discriminator is an abnormal posterior tibial pulse. This part of the physical examination should only be performed after the patient has warmed up after coming indoors from cold weather.

Detection of asymptomatic PAD has value because it identifies patients at increased risk of atherosclerosis at other sites. As an example, as many as 50 percent of patients with PVD have at least a 50 percent stenosis in one renal artery [39] . Thus, patients with asymptomatic PAD, most often detected by ABI, should be aggressively treated with risk factor reduction (eg, aspirin, lipid lowering, blood pressure control). In addition to protecting against coronary disease and stroke, lipid lowering may also slow progression of the PAD (as measured by angiography) [40] . (See "Medical management of claudication", section on Risk factor reduction, and see "Secondary prevention of cardiovascular disease: Risk factor reduction").

Activity level — As noted in some of the studies described above, functional capacity is diminished in some patients with PAD even in the absence of claudication [37,41] . In addition, a gradual decline in activity level may mask the symptoms and lead to an underestimation of disease severity.

This issue was addressed in a study of 417 patients with PAD and 259 without disease who underwent measurement of ABI and assessment of functional capacity at baseline and one and two years later [41] . Patients with an ABI <0.50 had a significantly greater annual decline in six-minute walk distance than those with an ABI of 0.50 to <0.90 or those with an ABI of 0.90 to 1.50 (73 versus 59 and 13 feet, respectively). In addition, patients with PAD who reported no exertional pain had a greater annual decline in six-minute walk distance than those with typical intermittent claudication (77 versus 36 feet).

These findings suggest that activity level is an important factor in the evaluation of patients with PAD. Patients with evidence of PAD who report no or few symptoms should be asked about functional capacity and decline in activity over time.

Correlation of ABI with symptoms and site of PAD — There is a general but not absolute correlation between symptoms and the site and severity of PAD, with severity being estimated from the ankle-brachial index (ABI, abnormal less than 0.90). (See "Noninvasive diagnosis of peripheral arterial disease", section on Ankle-brachial index).

This was illustrated in a study using a claudication questionnaire for exertional leg pain in 3658 subjects, 24 percent of whom had PAD (defined as an ABI ≤0.90) in one or both legs [42] . The following findings were noted:

• At ABIs of 1.00-1.09 (normal), 0.80 to 0.89 (just abnormal), and 0.40 to 0.49 (markedly reduced), the proportion of legs with any leg pain increased progressively from 18 percent to 61 percent to 83 percent. Pain was also more common in legs with ABIs ≥1.40, a presumed marker of vascular stiffness

• At the same ABIs, the proportion of legs with classic claudication increased progressively from 2 percent to 22 percent to 46 percent. In contrast, typical pain and noncalf pain did not show much correlation with the ABI. Pain occurring at rest was the most common pain symptom in patients without PAD.

• Discordance was noted in some patients between the site of PAD and the site of pain. Patients with unilateral PAD were more likely to report bilateral than unilateral pain (42 versus 29 percent). Furthermore, among 80 patients with unilateral PAD and unilateral pain, the pain was in the other leg in 11 (14 percent).

Not surprisingly, since PAD is a manifestation of systemic atherosclerosis, a low ABI is also predictive of an increased risk of all-cause and cardiovascular mortality [43,44] and of the development of coronary artery calcification [45] . (See "Diagnostic and prognostic implications of coronary artery calcification detected by computed tomography").

DIAGNOSIS — As noted above, there is a high prevalence of lower extremity PAD in patients over age 70 and in patients between the ages of 50 and 69 with atherosclerotic risk factors, particularly smoking and/or diabetes [7-9] . (See "Prevalence" above and see "Risk factors" above).

Based upon these observations, the 2005 ACC/AHA guidelines on PAD and the 2007 TASC II consensus document on the management of PAD recommended that the standard review of symptoms should include questions related to a history of walking impairment, symptoms of claudication, ischemic rest pain, or nonhealing wounds in patients ≥70 years of age, those ≥50 years of age with a history of smoking and/or diabetes, or, in TASC II, those with a Framingham risk score of 10 to 20 percent at ten years [9,24] .

Measurement of the resting ankle-brachial systolic pressure index (ABI) should be performed in patients with one or more of the above findings on the review of symptoms. An ABI of ≤0.90 has a high degree of sensitivity and specificity for the diagnosis, using arteriography as the gold standard [9] . (See "Noninvasive diagnosis of peripheral arterial disease", section on Ankle-brachial index).

DIFFERENTIAL DIAGNOSIS — Classic claudication is characterized by cramping pain that is consistently reproduced with exercise and relieved with rest. However, many patients have atypical symptoms that may be confused with a number of other disorders [8,9,26] . These include nerve root compression, spinal stenosis, and hip arthritis (show table 2). (See "Atypical symptoms" above).

NATURAL HISTORY — 2005 ACC/AHA guidelines on PAD estimated the following rates of limb and cardiovascular outcomes at five years in patients with noncritical claudication [24] :

• For limb morbidity — stable claudication in 70 to 80 percent, worsening claudication in 10 to 20 percent, and critical limb ischemia in 1 to 2 percent

• For cardiovascular morbidity and mortality — nonfatal myocardial infarction or stroke in 20 percent, and death in 15 to 30 percent (three-quarters due to cardiovascular causes); an association between cardiovascular disease and PAD has been noted in multiple studies [43,44,46] . The importance of PAD as a marker for coexistent coronary artery disease cannot be understated.

Among the 1 to 2 percent of patients with critical limb ischemia, the guidelines estimated the following outcomes at one year:

• Alive with two limbs — 50 percent
• Amputation — 25 percent
• Cardiovascular mortality — 25 percent

These general estimates do not apply equally to all patients. The risk factors for progressive PAD are described above [25] . The prognosis for both limb loss and survival is significantly worse in diabetic patients and those who continue to smoke [47] . (See "Predictors of progression" above).

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Claudication"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

Medical management of claudication

2008-09-04T17:37:00.000-07:00

Medical management of claudication

Author
Emile R Mohler, III, MD
Section Editor
Denis L Clement, MD, PhD
Deputy Editor
Gordon M Saperia, MD, FACC

Last literature review version 16.2: May 2008 | This topic last updated: March 25, 2008 (More)

INTRODUCTION — Patients with compromise of blood flow to the extremities most commonly present with pain of a muscle group. Intermittent claudication (derived from the Latin word for limp) is defined as a reproducible discomfort of a defined group of muscles which is induced by exercise and relieved with rest. The symptoms result from an imbalance between supply and demand of blood flow that fails to satisfy ongoing metabolic requirements. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease").

Once claudication is suspected clinically, the diagnosis is confirmed and the disease is localized using noninvasive tests. (See "Noninvasive diagnosis of peripheral arterial disease").

Once the diagnosis is established, the patient can be treated medically with risk factor modification, exercise, and pharmacology or with percutaneous intervention or surgery. The medical management of claudication will be reviewed here. The indications for percutaneous intervention and surgery are discussed separately. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease" and see "Indications for surgery in the patient with claudication").

RISK FACTOR MODIFICATION — The principal risk factors for the development of peripheral arterial disease (PAD) are cigarette smoking, diabetes mellitus, hypertension, and hyperlipidemia. One study of 6450 subjects estimated that 69 percent of the occurrence of PAD is attributable to these cardiovascular risk factors, with cigarette smoking being the most important factor [1] . In contrast, moderate alcohol consumption reduces the risk of PAD and intermittent claudication, as it does the risk of coronary disease. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Risk factors, and see "Cardiovascular benefits and risks of moderate alcohol consumption").

In addition to the shared risk factors, patients with peripheral arterial disease are also at high risk for coronary and cardiovascular events and mortality [2-4] . As a result, the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel [ATP] III) considered PAD as a coronary heart disease risk equivalent, thereby elevating it to the highest risk category [5] .

The overall approach to secondary prevention of cardiovascular disease is discussed separately. (See "Secondary prevention of cardiovascular disease: Risk factor reduction").

Cigarette smoking — Cessation of cigarette smoking reduces the progression of disease as shown by lower amputation rates and lower incidences of rest ischemia among those who quit [6-8] . One study of 343 patients with intermittent claudication, for example, compared the clinical outcomes among those who quit smoking (39 patients) with those who continued to smoke (304 patients) [8] . No patient who ceased smoking developed rest pain, which occurred in 16 percent of those who continued to smoke.

It is not clear whether smoking cessation reduces the severity of symptoms of claudication. In a meta-analysis that looked at pain free and total walking distance outcomes, smoking cessation was only found to be useful in nonrandomized trials [9] .

We agree with the following recommendations regarding smoking cessation made in the 2007 TASC II consensus document on the management of PAD [10] . (See "Management of smoking cessation").

• All patients should be strongly advised to stop smoking by their physicians
• All patients should be offered nicotine replacement and group counseling sessions
• Many patients may benefit from the addition of antidepressant drug therapy

Diabetes mellitus — No controlled trials have directly evaluated the effects of antidiabetic therapy upon the natural history of PAD. Aggressive control of blood sugar in both type 1 and type 2 diabetes reduces the risk of microvascular complications (eg, nephropathy, retinopathy, and neuropathy) [11,12] . However, in the Diabetes Control and Complications Trial of patients with type 1 diabetes, intensive insulin therapy had no effect upon the risk of PAD [13] . The results were similar in the United Kingdom Prospective Diabetes Study of patients with type 2 diabetes [12] . (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on Recommendations, and see "Glycemic control and vascular complications in type 2 diabetes mellitus").

We largely agree with the 2007 TASC II consensus document on the management of PAD, which recommends aggressive control of blood glucose levels with an A1C goal of <7.0 percent and as close to 6.0 percent as possible [10] . Less stringent goals may be appropriate for some patients (eg, older patients and those with comorbid conditions). (See "Glycemic control and vascular complications in type 2 diabetes mellitus").

Hypertension — Hypertension is a major risk factor for PAD. However, there are no data evaluating whether antihypertensive therapy alters the progression of claudication. Nevertheless, hypertension should be controlled in these patients to reduce morbidity from cardiovascular and cerebrovascular disease.

There has been past concern involving the use of beta blockers in the treatment of hypertension among patients with intermittent claudication, but there appears to be no adverse effect of beta-1 selective blockers on claudication symptoms [14-16] . As a result, these drugs are not contraindicated in patients with PAD [17] .

The HOPE trial suggested that the angiotensin converting enzyme (ACE) inhibitor ramipril provided added protection against cardiovascular events in patients with cardiovascular disease, including PAD [18] . Cardiovascular benefit was also seen in patients with PAD at baseline [19] . However, these benefits are likely to be a consequence of blood pressure reduction in this placebo-controlled trial, rather than a specific benefit of ACE inhibition. (See "Choice of antihypertensive drug and blood pressure goal in patients at increased risk for a cardiovascular event").

There is some evidence that ACE inhibitor therapy may increase increase walking distance in selected patients with PAD. (See "Angiotensin inhibition" below).

We agree with the 2007 American Heart Association statement on the treatment of blood pressure in ischemic heart disease and the 2007 European Society of Hypertension-European Society of Cardiology (ESH-ESC) guidelines on the management of hypertension which recommended a goal BP below 130/80 mmHg in patients with established coronary artery disease or a coronary risk equivalent (carotid artery disease, peripheral arterial disease, or abdominal aortic aneurysm) [20,21] . The 2007 TASC II consensus document set a higher goal (<140/90 mmHg) [10] . (See "Choice of antihypertensive drug and blood pressure goal in patients at increased risk for a cardiovascular event").

Hyperlipidemia — A number of cholesterol lowering trials in patients with hyperlipidemia and coronary and/or PAD have evaluated the effects on PAD. Initial studies, performed before the availability of statins, showed regression or less progression of femoral atherosclerosis with lipid-lowering therapy [22-24] and a lower incidence of intermittent claudication and limb-threatening ischemia in patients with hyperlipidemia who were treated with partial ileal bypass surgery [25] . A 2000 Cochrane meta-analysis of mostly older trials that specifically evaluated patients with lower limb atherosclerosis concluded that lipid-lowering therapy reduced disease progression (as measured by angiography) and helped alleviate symptoms [26] .

Subsequent studies confirmed these benefits in patients treated with statin therapy. Regression of femoral atherosclerosis [27] , a lower rate of new or worsening intermittent claudication [28] , and improvements in walking distance and pain-free walking time [29-31] have all described. The range of findings can be illustrated by the following observations:

• A post-hoc analysis of the Scandinavian Simvastatin Survival Study (4S), which included 4444 patients with angina or previous myocardial infarction and a baseline plasma total cholesterol between 212 and 309 mg/dL (5.5 and 8.0 mmol/L), found that treatment with 20 to 40 mg/day of simvastatin reduced the incidence of new or worsening intermittent claudication by 38 percent (2.3 versus 3.6 percent with placebo [28] .
• A randomized, double-blind trial included 354 patients with claudication attributable to PAD who were assigned to atorvastatin (10 or 80 mg/day) or placebo [30] . At 12 months, there was a significant improvement in pain-free walking time with high-dose atorvastatin (63 versus 38 percent with placebo [81 versus 39 seconds]) and in community-based physical activity with both doses of atorvastatin. There was no change in ankle-brachial index (ABI).

Statin therapy may also reduce the incidence of cardiovascular events in patients with PAD [32-34] . This was suggested by a study of 515 patients who were admitted for peripheral vascular interventional therapy (mean ABI 0.51) [32] . Statin use was recorded. At a median follow-up of 21 months, 65 patients died. Patients treated with a statin had a significant reduction in all-cause mortality (adjusted hazard ratio 0.52) and in death or nonfatal myocardial infarction (adjusted hazard ratio 0.48). A similar reduction in all-cause mortality in patients with PAD who are treated with statins (hazard ratio 0.46) was noted in a larger prospective observational cohort study [33] .

The evidence for benefit and the appropriate goals for cholesterol lowering in patients with all forms of cardiovascular disease are discussed separately. (See "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease").

We agree with the following recommendations regarding lipid control made in the 2007 TASC II consensus document on the management of PAD [10] :

• All patients with PAD should have their LDL-cholesterol lowered to <100 mg/dL (2.6 mmol/L).
• In patients with PAD and atherosclerosis in other circulatory beds it is reasonable to lower the LDL-cholesterol to <70 mg/dL (1.8 mmol/L).

Risk factor summary — The risk factors for PAD are similar to those for other forms of atherosclerotic vascular disease and PAD is associated with an increased risk of coronary, cerebrovascular, and renovascular disease. As a result, PAD is considered a coronary heart disease equivalent, thereby elevating it to the highest risk category [5] .

The 2005 American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines on PAD and the 2007 TASC II consensus document on the management of PAD recommended smoking cessation, lipid lowering with statin therapy, and treatment of diabetes and hypertension [10,17] . These secondary prevention recommendations are discussed elsewhere. (See "Secondary prevention of cardiovascular disease: Risk factor reduction").

MEDICAL VERSUS INTERVENTIONAL THERAPY — Therapy for intermittent claudication may involve medical, percutaneous, and/or surgical approaches [35] . Most patients with intermittent claudication, except for those with critical limb ischemia, are treated initially with medical therapy.

The medical management of moderate to severe intermittent claudication secondary to PAD involves two modalities in addition to risk factor modification as described above:

• Exercise training or rehabilitation
• Pharmacologic therapy

The indications for revascularization and the choice between percutaneous intervention and surgery are discussed in detail separately. Two important criteria for revascularization are severe disability that limits the patient's ability to work or to perform other activities that are important to the patient, and failure (or predicted failure) to respond to exercise rehabilitation and pharmacologic therapy. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease" and see "Indications for surgery in the patient with claudication").

EXERCISE REHABILITATION — Several studies have demonstrated the benefit of exercise rehabilitation programs in reducing symptoms of claudication [36-39] . A meta-analysis that considered only randomized, controlled trials found that exercise produced a significant increase in maximum walking time (mean difference 6.5 minutes); the benefit was greater than that seen with angioplasty at six months (mean difference 3.3 minutes) [36] .

These trials utilized leg exercise (eg, treadmill or walking). The effect of upper limb exercise was assessed in a subsequent trial in which 104 patients with stable peripheral arterial disease were randomly assigned to twice weekly aerobic exercise training with upper limb or lower limb exercise or a nonexercise training control group [40] . At six months, upper and lower limb exercise were associated with similar increases in claudication distance (51 and 57 percent), maximal walking distance (29 and 31 percent), and peak oxygen consumption.

There are several mechanisms by which exercise training may improve claudication, although the available data are insufficient to make conclusions regarding their relative importance [41] :

• Improved endothelial dysfunction via increases in nitric oxide synthase and prostacyclin [42] . (See "Endothelial dysfunction").
• Reduced local inflammation that is induced by muscle ischemia by decreasing free radicals [43] .
• Increased exercise pain tolerance [40] .
• Induction of vascular angiogenesis [44] .
• Improved muscle metabolism by favorable effects on muscle carnitine metabolism and other pathways [45] .
• Reductions in blood viscosity and red cell aggregation [46] .

Although less well studied, exercise may also improve survival. This issue was addressed in a prospective observational study of 225 men and women with PAD evaluated in whom physical activity was measured with a vertical accelerometer [47] . Patients were followed for a mean duration of 57 months at which time 75 patients (33 percent) had died. Individuals in the highest quartile of accelerometer-measured activity had a significantly lower mortality than those in lowest quartile (hazard ratio 0.29, 95% CI 0.10-0.83).

Exercise prescription — Patients should be referred to a claudication exercise rehabilitation program. These programs consist of a series of sessions lasting 45 to 60 minutes per session, involving use of either a motorized treadmill or a track to permit each patient to achieve symptom-limited claudication. The initial session usually includes 35 minutes of intermittent walking; walking is then increased by five minutes each session until 50 minutes of intermittent walking can be accomplished, surrounded by warm-up and cool down sessions of five to ten minutes each.

Ideally, the patient attends at least three sessions per week, with a program length greater than three months [17] . Each session is supervised on a one-to-one basis by an exercise physiologist, physical therapist, or nurse. The supervising provider monitors the individual patient's claudication threshold and other cardiovascular limitations for adjustment of workload. During this supervised rehabilitation program, the development of new arrhythmias, symptoms that might suggest angina, or the continued inability of the patient to progress to an adequate level of exercise may require physician review and examination of the patient.

Most patients who eventually respond to a supervised exercise protocol can expect improvement within two months. Motivated patients achieve the best results. Supervised exercise training programs are not covered by medical insurance. The benefits of exercise diminish when exercise training stops.

Despite the evidence of benefit, issues remain concerning the optimal regimen for exercise rehabilitation. In a trial cited above, for example, the improvement in claudication distance with an exercise regimen was similar with lower limb and upper limb exercise [40] . In addition, the optimal intensity of exercise is uncertain.

In an initial randomized trial addressing the issue of intensity of exercise, a regimen of low-intensity exercise for six months produced similar improvements in claudication distance and health-related quality of life as high-intensity exercise (40 versus 80 percent of maximal exercise capacity) [48] .

Another issue is the value of unsupervised exercise, which may be particularly important when access to supervised programs is limited by cost, transportation, or availability. In an observational study of 417 patients with peripheral arterial disease, those patients who reported self-directed walking for exercise ≥3 times per week walked more city blocks per week (as measured by an accelerometer) and had a significantly lower annual decline in six minute walking distance than those who walked one to two times per week or did not exercise (-48 versus -57 and -79 feet per year) [49] . Similar benefit was noted in patients who walked ≥90 minutes per week compared to a shorter duration of exercise. Benefit from exercise was also seen in the subset of patients who were asymptomatic as manifested by smaller annual declines in six minute walking performance.

The relative efficacy of supervised and unsupervised exercise in patients with intermittent claudication have been compared in eight randomized trials, which were included in a 2006 meta-analysis [50] . Walking was the dominant form of exercise training in both groups. The primary end point was maximal treadmill walking distance before and after a three month period of training. Supervised exercise led to a significantly greater improvement of approximately 150 meters (30 to 35 percent difference in improvement). However, quality of life measures (secondary end points) were not significantly different between the two groups.

PHARMACOLOGIC THERAPY — Pharmacologic therapy of claudication is aimed at symptomatic relief or slowing progression of the natural disease. A number of drugs have been evaluated but, as will be seen, the evidence of benefit is convincing only for antiplatelet agents, usually aspirin, and cilostazol [17,51] .

The benefits of drug therapy aimed to risk factor modification are discussed above. (See "Risk factor modification" above).

Antiplatelet agents — The preponderance of data on the use of currently available antiplatelet agents indicate that no or only a modest improvement in claudication symptoms can be expected and that a significant benefit may not be seen with aspirin alone. Thus, the main indication for aspirin therapy is for secondary prevention of coronary disease and stroke. (See "Benefits of aspirin in cardiovascular disease").

Aspirin — The Antithrombotic Trialists' Collaboration overview analyzed the results of randomized trials of antiplatelet therapy among more than 135,000 high-risk patients with prior evidence of cardiovascular disease, including myocardial infarction, stroke, transient ischemic attacks, unstable angina, stable angina, revascularization surgery, angioplasty, atrial fibrillation, valvular disease, and PAD [52] . Moderate dose aspirin (75 to 325 mg/day) was most commonly prescribed.

Among 26 trials of patients with intermittent claudication, 12 with peripheral grafting, and four with peripheral angioplasty, antiplatelet therapy was associated with a significant reduction in the risk of nonfatal myocardial infarction, nonfatal stroke, or vascular death (5.8 versus 7.1 percent, odds reduction 23 percent) (show table 3). The magnitude of benefit was similar in the three groups.

However, the data on aspirin alone do not suggest a statistically significant benefit in the broad PAD population, including asymptomatic patients. The overall benefit of antiplatelet therapies in the Antithrombotic Trialists' Collaboration data was driven by data from trials using ticlopidine, clopidogrel and dipyridamole [52,53] .

The Physicians Health Study, a primary prevention study, found that 325 mg of aspirin every other day decreased the need for peripheral artery surgery [54] . However, no difference was noted between the aspirin and placebo groups in the development of claudication.

Aspirin plus dipyridamole — The combination of aspirin and dipyridamole was found to increase the pain-free walking distance and resting limb blood flow in a study of 54 patients with intermittent claudication [55] . Another study in 296 patients with intermittent claudication found an improved coagulation profile and ankle/brachial index with therapy but did not report if walking distance improved with combined therapy [56] .

Ticlopidine and clopidogrel — Ticlopidine, an inhibitor of platelet aggregation. appears to modestly increase walking distance in patients with intermittent claudication [57] . However, the drug is associated with a substantial risk of leukopenia and thrombocytopenia, requiring close hematologic monitoring for at least three months. Other potential side effects include bleeding, dyspepsia, diarrhea, nausea, anorexia, rash, purpura, and dizziness. The usual dose of ticlopidine is 250 mg twice daily, with food.

Clopidogrel is a similar but safer drug. The CAPRIE trial found that clopidogrel (75 mg/day) had a modest, although significant advantage over aspirin (325 mg/day) for the prevention of stroke, myocardial infarction (MI), and PAD in 19,185 patients with a recent stroke, MI, or PAD (annual rate of 5.3 versus 5.8 percent) [58] .

Comparison of antiplatelet agents — A meta-analysis of randomized studies with antiplatelet agents found that ticlopidine had the best evidence of efficacy (ie, improvement in walking distance, reduction in occlusion and/or improvement in mortality) [59] . In addition, as noted above, the CAPRIE trial found that clopidogrel was more effective than aspirin in preventing vascular events [58] .

Nevertheless, aspirin is generally considered the antiplatelet drug of choice because of the high incidence of comorbid coronary disease, the benefits of aspirin in preventing myocardial infarction, and its lower cost.

Summary — We agree with the following recommendations for antiplatelet therapy from the TASC II consensus document for the management of PAD [10] :

• All symptomatic patients and asymptomatic patients with evidence for atherosclerosis in other circulatory beds should be prescribed an antiplatelet drug. Asymptomatic patients without evidence for atherosclerotic disease elsewhere may be considered for antiplatelet therapy.
• Aspirin is the agent of choice; clopidogrel may be used if aspirin cannot be tolerated or in the subgroup of patients with symptomatic PAD.

Warfarin — Warfarin has not been shown to improve cardiovascular outcomes in patients with PAD. (See "Secondary prevention of cardiovascular disease: Risk factor reduction", section on Warfarin).

Cilostazol — Cilostazol is a phosphodiesterase inhibitor approved by the FDA for the treatment of intermittent claudication. It suppresses platelet aggregation and is a direct arterial vasodilator [60] . The efficacy of cilostazol has been demonstrated in several studies [61-64] and in a meta-analysis of eight randomized, placebo-controlled trials that included 2702 patients with stable moderate to severe claudication [65] . In the meta-analysis, treatment with 100 mg twice daily for 12 to 24 weeks increased maximal and pain-free walking distances by 50 and 67 percent respectively [65] . Benefit may be noted as early as four weeks [63] .

Cilostazol appears to be more effective than pentoxifylline. This was illustrated in a trial of 698 patients randomly assigned to cilostazol (100 mg twice daily), pentoxifylline (400 mg three times daily), or placebo for 24 weeks [66] . The increase in mean maximal walking distance over baseline with pentoxifylline and placebo was the same (30 and 34 percent, respectively), but the increase with cilostazol was significantly greater (54 percent).

Side effects noted in clinical studies included headache, loose and soft stools, diarrhea, dizziness and palpitations [61-64] . Nonsustained ventricular tachycardia has been reported. Because other oral phosphodiesterase inhibitors used for inotropic therapy have caused increased mortality in patients with advanced heart failure, cilostazol is contraindicated in heart failure of any severity [67,68] . (See "Inotropic agents in heart failure due to systolic dysfunction", section on Phosphodiesterase inhibitors).

Based upon the evidence of benefit, a therapeutic trial (three to six months) of cilostazol (100 mg orally twice daily) is recommended (in the absence of heart failure) to improve symptoms and increase walking distance in patients with lifestyle-limiting claudication, particularly if antiplatelet agents and exercise rehabilitation are ineffective and revascularization cannot be offered or is declined by the patient [10,17,51] .

Cilostazol should be taken one-half hour before or two hours after eating, because high fat meals markedly increase absorption. Several drugs such as diltiazem and omeprazole, as well as grapefruit juice, can increase serum concentrations of cilostazol if taken concurrently [67] . Cilostazol may be taken safely with aspirin and/or clopidogrel without an additional increase in bleeding time [69] .

Pentoxifylline — Pentoxifylline (Trental) is a rheologic modifier approved by the Food and Drug Administration (FDA) for the symptomatic relief of claudication [70,71] . Its putative mechanism of action includes an increase in red blood cell deformity, and decreases in fibrinogen concentration, platelet adhesiveness, and whole-blood viscosity.

Studies investigating the efficacy of pentoxifylline have yielded conflicting results [71-74] . A meta-analysis found that pentoxifylline improved walking distance by 29 meters compared with placebo [74] . The improvement was approximately 50 percent in the placebo group, while pentoxifylline provided an additional 30 percent. The benefit was substantially less than that achieved with a supervised exercise program (123 percent increase in peak walking time in one study) [38] . In addition, pentoxifylline is less effective than cilostazol [66] .

The available data indicate that the benefit of pentoxifylline is marginal and not well established [17] . The Seventh ACCP Consensus Conference recommended against the use of pentoxifylline [18] , while the ACC/AHA guidelines concluded that pentoxifylline (400 mg three times per day) may be considered a second-line drug to cilostazol to improve walking distance [17] .

The 2007 TASC II consensus document on the management of PAD makes no recommendation on the use of pentoxifylline [10] .

Other rheologic modifiers — Hemodilution therapy for reducing the plasma viscosity involves removing blood and replacing it with a colloidal solution of hydroxyethyl starch (HES) or a low-molecular-weight dextran (LMWD) one to two times weekly for several weeks. This approach has resulted in some improvement in pain free walking distance in clinical trials [75,76] , but the relatively small benefit achieved does not warrant routine use of this therapy.

Naftidrofuryl — Naftidrofuryl is a 5-hydroxytryptamine-2-receptor antagonist that is currently available only in Europe [77-79] . The mechanisms of action of this drug are unclear but it is thought to promote glucose uptake and increase adenosine triphosphate levels. A meta-analysis of four trials showed an increase in the time to initial pain development on treadmill walking over a three to six month period [9] .

The 2007 TASC II consensus document on the management of PAD concluded that naftidrofuryl (600 mg/day orally) can be considered for the treatment of intermittent claudication [10] .

Angiotensin inhibition — As mentioned above, data from the HOPE trial suggested that ramipril therapy provided cardiovascular benefit in patients with PAD at baseline [19] . However, these benefits are likely to be a consequence of blood pressure reduction in this placebo-controlled trial, rather than a specific benefit of ACE inhibition. (See "Hypertension" above).

A separate issue is whether angiotensin inhibition might provide symptomatic benefit in patients with intermittent claudication. This was evaluated in a small randomized trial in which 40 older patients with intermittent claudication were assigned to ramipril (10 mg once daily) or placebo for 24 weeks [80] . After adjustment for baseline values, ramipril therapy was associated with a significant 227 second increase in pain-free walking time and a significant 451 second increase in maximum walking time; no changes were noted in the placebo group.

The generalizability of this initial observation is unclear since there were strict inclusion criteria, including superficial femoral artery stenosis or occlusion. Patients with diabetes, hypertension, or coronary heart disease and those with a history of ACE inhibitor therapy were excluded. Further studies are required before the use of ACE inhibitors for claudication can be recommended.

Buflomedil — Buflomedil is an alpha adrenolytic agent with vasoactive and hemorrheologic properties. It is available for use in Europe but not the United States.

The best available data in peripheral arterial disease comes from the LIMB trial, which evaluated the long-term efficacy and safety of buflomedil in 2078 patients with intermittent claudication and an ankle-brachial index between 0.30 and 0.80 who were randomly assigned to either placebo or buflomedil at 300 or 150 mg daily (adjusted to the creatinine clearance) [81] . At a median follow-up of 2.8 years, the rate of the primary outcome (composite end point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, symptomatic deterioration of PAD, or leg amputation) was significantly lower in patients who received buflomedil (9.1 versus 12.4 percent); this benefit was primarily due to a reduction in symptomatic deterioration. There were no important differences in safety outcomes.

Limitations of the trial included the use of soft end points such as self-reported symptoms and the use of statin therapy in only about 15 percent of patients [82] .

Ginkgo biloba — Ginkgo biloba has been studied in patients with intermittent claudication with modest success. The mechanism by which ginkgo may work in this disorder is unclear, but may involve a number of activities including an antioxidant effect, inhibition of vascular injury, and antithrombotic effects. (See "Clinical use of ginkgo biloba").

In a meta-analysis of eight randomized, double-blind, placebo-controlled trials, patients who received ginkgo biloba extract had a significant increase in pain free walking distance (34 meters) compared with placebo [83] . However, there were a number of problems with the studies, including lack of clarity regarding the randomization procedure. In addition, concerns about recommending herbal products in general remain since these remedies are not regulated by the United States Food and Drug Administration. (See "Overview of herbal medicine", sections on Lack of standardization and Lack of regulation).

The ACC/AHA guidelines concluded that benefit is not well established for ginkgo biloba for the treatment of intermittent claudication [17] .

Ineffective therapies

Estrogen replacement therapy — The effect of estrogen replacement therapy (ERT) on the incidence of PAD is unclear. In a population-based study of 2196 postmenopausal women, ERT for one year or more was associated with a 52 percent decreased risk of peripheral arterial disease (defined as an ankle/arm systolic blood pressure index lower than 0.9) [56] .

In contrast, the Heart and Estrogen/Progestin Replacement Study (HERS) of 2763 postmenopausal women with coronary heart disease found that hormone replacement therapy with estrogen and progesterone did not significantly reduce the incidence of peripheral arterial events (relative hazard 0.87 compared to placebo) [57] . Based upon the latter report, ERT does not appear to have a role in the management of peripheral vascular disease. (See "Postmenopausal hormone therapy and cardiovascular risk").

Chelation therapy — The use of repeated intravenous infusion of EDTA or "chelation therapy" has been advocated by some researchers in the treatment of intermittent claudication. A double-blind, randomized, controlled trial was conducted to evaluate the effectiveness of chelation therapy in patients with intermittent claudication. The main outcome measure was walking distances and ankle/brachial pulse indices. No significant difference between the chelation therapy group and the control group was observed [84] .

The ACC/AHA guidelines concluded that chelation therapy was not beneficial and may be harmful in the treatment of intermittent claudication [17] .

Vitamin E supplementation — Vitamin E has been evaluated in the treatment of coronary heart disease because of its antioxidant properties. (See "Nutritional antioxidants in coronary heart disease").

Several small trials have evaluated its efficacy in the treatment of intermittent claudication; there was no clear evidence of benefit [85] . The ACC/AHA guidelines concluded that vitamin E was not recommended for the treatment of intermittent claudication [17] .

Investigational agents — The following newer agents are currently being investigated in patients with claudication. Their clinical use is not yet recommended.

Verapamil — Vasodilators are not thought to be effective in patients with claudication because they rarely increase blood flow beyond the level produced by maximally tolerated exercise [86] . However, a randomized, double-blind, placebo-controlled crossover trial of 44 patients with stable intermittent claudication reported that treatment of verapamil (120 to 480 mg per day) for four weeks increased mean pain free walking distances by 29 percent and maximal walking distances by 49 percent compared to placebo (show figure 1) [87] . Verapamil had no effect on systolic ankle pressure, ankle/brachial pressure index, peripheral leg temperature or systolic blood pressure, suggesting that its effects are not mediated by improved hemodynamics.

Antichlamydophila therapy — It has been proposed that chronic Chlamydophila (formerly Chlamydia) pneumoniae infection may promote the development of atherosclerosis and clinical trials of antichlamydophila therapy have been performed in a variety of clinical settings. This hypothesis was tested in a randomized, placebo-controlled trial that investigated the efficacy of an antichlamydophila antibiotic, roxithromycin (300 mg/day for 30 days), to prevent progression of peripheral arterial disease (PAD) in 40 men who were seropositive for C. pneumoniae, and had established PAD and at least one carotid plaque detectable by ultrasonography [88] . During 2.7 year follow-up, patients treated with roxithromycin experienced significantly fewer invasive revascularizations (5 versus 29 interventions) compared with placebo, and had significantly less frequent limitation to 200 m walking distance (20 versus 65 percent).

These observations need to be confirmed in a larger trial of patients with PAD, particularly in view of the lack of benefit of antichlamydophila therapy in major trials of patients with coronary disease. (See "Chlamydophila (Chlamydia) pneumoniae infection as a potential etiologic factor in atherosclerosis").

Propionyl-L-carnitine — The mechanism of action of propionyl-L-carnitine in patients with claudication is thought to be via increased energy metabolism in ischemic muscle [89,90] . A double-blind placebo-controlled study of 245 patients with intermittent claudication found that active therapy resulted in a modest increase in maximal walking distance (73 versus 46 percent with placebo) and time to initial pain on treadmill walking [89,90] . In a follow-up report from this trial, propionyl-L-carnitine, but not placebo, resulted in an improvement in quality of life, emotional status, and physical function among patients with more severely limited walking capacity (<250 meters) at baseline [91] . In contrast, patients with mild functional impairment (walking distance >250 meter) had no response to the drug [92] . Other studies have also found that propionyl-L-carnitine improves exercise performance and functional status in patients with claudication [93] .

The ACC/AHA guidelines concluded that benefit is not well established for propionyl-L-carnitine for the treatment of intermittent claudication [17] .

Defibrotide — Defibrotide is a polydeoxyribonucleotide that stimulates fibrinolysis via increased release of tissue plasminogen activator and prostacyclin and reduced release of plasminogen activator inhibitor from endothelial cells. Defibrotide also decreases beta thromboglobulin and may therefore act by inhibiting platelet aggregation. The results from a placebo-controlled trial study reported an increased maximal treadmill walking distance over a six month period [94] .

Prostaglandin E1 — Prostaglandin E1 (PGE1) is a vasodilator and an inhibitor of platelet aggregation. However, it is rapidly inactivated in the lungs, and must be given intraarterially or intravenously using large doses. PGE1 is experimental and has not been approved for clinical use.

In a study of 80 patients with intermittent claudication, intravenous administration of a prostaglandin E1 prodrug produced a dose related improvement in walking distance and quality of life at four and eight weeks [95] .

A Cochrane review of five studies comparing PGE1 (eg, alprostadil, epoprostenol) with placebo found that significant increases in walking distances were attained with PGE1, which persisted even after termination of treatment [96] . Further randomized trials were recommended to confirm these results.

Prostacyclin — Beraprost is an orally-active prostaglandin I2 (prostacyclin) analog that has antiplatelet and vasodilating properties. Its efficacy was evaluated in the BERCI-2 trial of 549 patients with a pain-free walking distance of 50 to 300 meters that changed by <25 percent during a four week placebo run-in phase [97] . After six months, patients had a >50 percent increase in walking distance on a treadmill and on one or more earlier treadmill test with beraprost (40 mcg three times daily) compared to placebo (44 versus 33 percent). The pain free walking distances increased by 82 and 53 percent, respectively, and the maximum walking distances increased by 60 and 35 percent, respectively. The incidence of critical cardiovascular events (cardiac death, myocardial infarction, coronary revascularization, stroke, transient ischemic attack, or critical or subcritical leg ischemia requiring medical or surgical intervention) was the lower but not statistically significantly so (4.8 versus 8.9 for placebo).

Different results were found in another study of 897 patients, which had the same study design as BERCI-2 [98] . Patients were treated with beraprost (40 mcg three times daily) or placebo after a three week placebo run-in period. At six months, there was no difference between beraprost and placebo in the improvement of mean walking distance or pain free walking distance. There was no significant improvement in quality of life for either group. The reasons for the difference in outcome between BERCI-2 and this study may include a lower incidence of hypertension, diabetes, and lipid disorders and a higher baseline ankle/brachial index in the BERCI-2 study population.

The ACC/AHA guidelines concluded that oral vasodilation prostaglandins were not effective for the treatment of intermittent claudication [17] .

NM-702 — NM-702 is an investigational phosphodiesterase inhibitor that has been shown in phase I and II studies to be well tolerated and to improve treadmill performance. It has the additional potentially beneficial property of inhibiting human platelet thromboxane A2 synthetase.

In a study of safety and efficacy, 386 individuals with clinically stable claudication were randomly assigned to placebo or to NM-702 (4 mg or 8 mg twice daily for 24 weeks) [99] . Statistically significant improvements in treadmill claudication onset and peak walking times were noted. The drug was well tolerated and no unanticipated safety concerns were found.

Mesoglycan — Mesoglycan, a sulfated polysaccharide compound containing the thrombin inhibitors heparan and dermatan sulfate, is available in some European countries. One randomized trial of 242 patients treated for 23 weeks found that a clinical response, defined as ≥50 percent increase over baseline in absolute walking distance, was more frequently achieved with mesoglycan (50 versus 26 percent with placebo) [100] .

Glutathione — Glutathione is an antioxidant that improved pain free walking distance in a randomized, double-blind, placebo-controlled study of 40 patients with intermittent claudication [101] . However, glutathione was administered intravenously twice daily, an obvious disadvantage compared with oral therapies.

Therapeutic angiogenesis — Animal studies have suggested that angiogenic growth factors can stimulate the development of collateral arteries, an approach known as therapeutic angiogenesis [102] . The safety and efficacy of therapeutic angiogenesis in humans is under investigation with variable results in patients with peripheral arterial disease [103-106] . It is also being evaluated in other disorders such as refractory angina and limb-threatening ischemia. (See "Therapeutic angiogenesis for management of refractory angina" and see "Treatment of chronic critical limb ischemia", section on Stimulation of angiogenesis).

As an example, the TRAFFIC trial evaluated the role of recombinant fibroblast growth factor-2 (rFGF-2) in 190 patients with intermittent claudication due to infrainguinal peripheral artery disease [105] . Patients were randomly assigned to bilateral lower limb arterial infusions of placebo, single dose rFGF-2, or repeat dose rFGF-2 on days 1 and 30. At 90 days, a single infusion of rFGF-2 was associated with a significant increase in peak walking time compared with placebo (increase of 1.77 versus 0.6 minutes compared to baseline); there was no additional benefit from a second infusion. This was a phase II study that was not powered to detect functional improvements in activities of daily living or quality of life.

However, the RAVE trial found no benefit from intramuscular injection of an adenoviral vector transmitting the vascular endothelial growth factor (VEGF) gene in 105 patients with claudication [106] . Changes from baseline in peak walking time, claudication onset time, ankle/brachial index and quality of life were similar at 12 and 26 weeks with two doses of VEGF compared to placebo.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Claudication"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

RECOMMENDATIONS — The therapy of patients with claudication involves the use of antiplatelet agents, risk factor modification including an exercise program, and possibly medical therapy for improvement in symptoms (show algorithm 1). The following recommendations are generally consistent with the 2004 Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy [51] , the 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for peripheral arterial disease [17] , the TASC II consensus document on the management of PAD [10] , and the 2006 ACC/AHA guidelines on secondary prevention [107] .

Antiplatelet agents — Antiplatelet agents are warranted in all patients with claudication to reduce the risk of myocardial infarction, stroke, and cardiovascular mortality. Aspirin (75 to 162 mg/day) should be given indefinitely, particularly in patients with clinically evident coronary or cerebrovascular disease [17,51] . Aspirin may be considered in patients without symptoms [10] . (See "Benefits of aspirin in cardiovascular disease").

Clopidogrel (75 mg/day) is an alternative treatment but aspirin is preferred because the much higher cost of clopidogrel is not justified [51,53] by the possible small increase in efficacy shown in the CAPRIE trial [58] . (See "Antiplatelet agents" aboveSee "Antiplatelet agents" above).

Modification of risk factors — The risk factors for PAD are similar to those for other forms of atherosclerotic vascular disease and PAD is associated with an increased risk of coronary, cerebrovascular, and renovascular disease. As a result, PAD is considered as a coronary heart disease risk equivalent, thereby elevating it to the highest risk category [5] .

Because of this risk, secondary prevention modalities, including smoking cessation, lipid lowering with statin therapy, and treatment of diabetes and hypertension, are recommended to the goals set in current national guidelines [10,17] . (See "Risk factor modification" above and see "Secondary prevention of cardiovascular disease: Risk factor reduction" and see "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease").

Asymptomatic patients — Certain patient groups are at higher risk for PAD, such as those ≥70 years of age or ≥50 years of age with a history of smoking and/or diabetes. Such patients should be screened for PAD with measurement of the ankle-brachial index and, if necessary, other tests [17] . Patients with PAD should be treated with same secondary prevention measures as those with claudication [17] . (See "Noninvasive diagnosis of peripheral arterial disease", section on Asymptomatic patients).

Exercise — A supervised exercise program is recommended as part of the initial treatment regimen. It should be performed for a minimum of 30 to 45 minutes at least three times per week for a minimum of 12 weeks [10,17] . During each session, exercise that is of sufficient intensity to elicit claudication is recommended [10] . The value of an unsupervised exercise program is less well studied, but is generally recommended for patients who cannot participate in supervised exercise programs. (See "Exercise rehabilitation" above).

Medical therapy — Among the medical therapies that have been evaluated for the treatment of claudication. Convincing evidence of benefit is available for cilostazol [17,35,51] .

Cilostazol — A therapeutic trial of cilostazol (100 mg orally twice daily) is recommended (in the absence of heart failure) to improve symptoms and increase walking distance in patients with lifestyle-limiting claudication, particularly if the above measures are ineffective and revascularization cannot be offered or is declined by the patient [17,51] . Cilostazol is not recommended for routine use in all patients with claudication because of its cost and modest clinical benefit. (See "Cilostazol" above).

Cilostazol should be taken one-half hour before or two hours after eating, because high fat meals markedly increase absorption. Several drugs such as diltiazem and omeprazole, as well as grapefruit juice, can increase serum concentrations of cilostazol if taken concurrently [67] . Cilostazol may be taken safely with aspirin and/or clopidogrel without an additional increase in bleeding time [69] .

Because other oral phosphodiesterase inhibitors used for inotropic therapy have caused increased mortality in patients with advanced heart failure, cilostazol is contraindicated in heart failure of any severity [67,68] . (See "Inotropic agents in heart failure due to systolic dysfunction", section on Phosphodiesterase inhibitors).

Pentoxifylline — The available data indicate that the benefit of pentoxifylline is marginal and not well established [10,17] . (See "Pentoxifylline" above).
Other — The ACC/AHA guidelines concluded that benefit is not well established for ginkgo biloba, L-arginine, and propionyl-L-carnitine in patients with intermittent claudication, and that oral vasodilator prostaglandins are not effective, vitamin E is not recommended, and chelation therapy may be harmful [17] .

Overview of the management of chronic mitral regurgitation

2008-08-31T20:52:00.000-07:00

Overview of the management of chronic mitral regurgitation

Author
William H Gaasch, MD
Section Editor
Catherine M Otto, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC

Last literature review version 16.2: May 2008 | This topic last updated: April 24, 2008 (More)

INTRODUCTION — Modern management of patients with chronic mitral regurgitation (MR) requires an understanding of multiple factors: These include:

• The pathophysiology and natural history of the disease
• The severity of the valvular lesion
• The development of atrial fibrillation
• The therapeutic potential of chronic vasodilator therapy
• The indications for endocarditis prophylaxis
• The indications for mitral valve repair and mitral valve replacement

While our knowledge of these areas is not yet complete, it is possible to develop a rational plan for the management of patients with chronic MR [1,2] . These management issues will be reviewed here. The management of functional and ischemic MR are addressed elsewhere. (See "Functional mitral regurgitation" and see "Ischemic mitral regurgitation").

PATHOPHYSIOLOGY AND NATURAL HISTORY — An elusive and poorly understood aspect of the pathophysiology of MR is the nature of the transition from the chronic compensated stage to a decompensated stage. This evolution generally occurs over many years, even decades, depending upon the severity of the regurgitant lesion and the cardiovascular response to the regurgitant volume. The etiology of MR also plays a role in the natural history of this process. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet").

Stages of MR — Left ventricular (LV) chamber size and function have been used to define a compensated, transitional, and decompensated stage in patients with chronic MR (show table 1) [3-9] . (See "Pathophysiology and stages of chronic mitral regurgitation").

• The compensated stage is defined largely on the basis of natural history and other data that indicate a benign prognosis when the end-diastolic dimension is less than 60 mm and the end-systolic dimension is less than 40 mm (as measured by echocardiography).
• The natural history of the transitional stage is not precisely defined, but most published data indicate that a good clinical result can be achieved if surgery is performed at this time.
• The decompensated stage is based upon data derived from patients who have undergone valvular surgery, which indicates that patients who exhibit one or more markers of a decompensated ventricle are at risk for a poor or suboptimal clinical result after valve replacement. These markers include LV end-diastolic dimension greater than 70 mm, LV end-systolic dimension greater than 45 to 47 mm, or a left ventricular ejection fraction (LVEF) less than 50 to 55 percent. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation", section on Reduced left ventricular function).

While these considerations do not identify the optimal time for mitral valve replacement or repair, they do enable the clinician to predict a poor LV response to corrective surgery and, in this fashion, provide a picture of the options of surgical or nonsurgical treatment. In principle, corrective surgery should be performed during the transition from a compensated to decompensated stage of the disease (ie, before the decompensated stage is established). (See "Mitral valve surgery" below).

Early identification of progression avoids the development of irreversible changes in LV function that may preclude an optimal response to corrective surgery. Patients with chronic MR and severe LV dysfunction (eg, LVEF <40 percent) are at very high risk of a suboptimal postoperative result. Many of these patients exhibit characteristics of a dilated cardiomyopathy with increased LV afterload and depressed myocardial contractility. Their initial management includes aggressive medical therapy with digitalis, diuretics, and vasodilators.

Cardiac catheterization and coronary angiography should be performed in preparation for surgery. Corrective surgery (and continued medical therapy) generally provides symptomatic relief, but chamber enlargement and a low LVEF usually persist despite technically successful surgery.

Etiology of mitral regurgitation — The major causes of MR are primary diseases of the valve leaflets (eg, mitral valve prolapse and, in developing countries, rheumatic heart disease) and secondary MR due to cardiomyopathy or coronary disease. (See "Etiology, clinical features, and evaluation of chronic mitral regurgitation", section on Etiology).

The best natural history data that are currently available have come from studies of patients with mitral valve prolapse and flail mitral valve leaflet. It is generally assumed that these findings may be applied to MR of other causes. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet").

Summarized briefly, the following factors may be useful for stratifying patients into groups that can be managed medically versus those that require surgical intervention. Older age, male gender, and auscultatory evidence of severe MR are prognostic clues that identify patients with mitral valve prolapse who are at a relatively high risk of complications. Echocardiographic evidence of LV enlargement provides further evidence of high risk that requires careful follow-up.

MR due to flail leaflet — Severe MR due to a flail leaflet, an LVEF <60 percent, and presence of symptoms are predictive of excess mortality. The risk of death was reduced by mitral valve surgery (adjusted hazard ratio 0.42, 95% CI 0.21-0.84) in a series of 394 patients of varying baseline symptom status (36 percent with severe symptoms). For asymptomatic patients with flail leaflet and severe MR (as for other asymptomatic patients with severe MR), surgical correction should be considered early in the course of the disease if valve repair is feasible with a >90 percent likelihood of success. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet" and see "Mitral valve surgery" below).

Effect of pregnancy — Chronic MR is usually well tolerated during pregnancy. The normal fall in systemic vascular resistance tends to reduce the degree of regurgitation. Issues related to the management of mitral regurgitation during pregnancy are discussed separately. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet", section on Effect of pregnancy).

SEVERITY OF MR — In addition to the stage of MR (show table 1), decisions regarding the timing of surgery depend upon the severity of MR. This can be assessed by both clinical and echocardiographic criteria. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation")

Symptoms — Patients with severe chronic MR often experience exercise intolerance, dyspnea, or fatigue during the transition from a compensated to a decompensated stage. Because of the importance of identifying such a transition, a careful history is important to establish an estimate of baseline exercise tolerance [1] . (See "Etiology, clinical features, and evaluation of chronic mitral regurgitation", section on Clinical manifestations).

Most experts and the ACC/AHA guidelines recommend that patients with chronic MR who become symptomatic are candidates for corrective mitral surgery, even if the symptoms improve with medical therapy or the left ventricle appears to be compensated (show table 2) [1,2] . If there is uncertainty about the presence or absence of symptoms, exercise testing may provide objective information that may not be available from the medical history alone. (See "Indications" below).

There has traditionally been reluctance to treat asymptomatic patients with chronic MR surgery. With nothing to gain in the way of symptomatic improvement, early surgery exposes the patient to perioperative morbidity and mortality as well as the long-term complications of a prosthetic valve if a valve repair procedure cannot be performed. (See "Complications of prosthetic heart valves").

On the other hand, there may be benefit from surgery prior to the onset of symptoms. As an example, left ventricular decompensation may develop in the setting of severe MR despite the absence of symptoms. Thus, waiting for the patient to experience dyspnea or exercise intolerance may allow time for the development of irreversible depression of LV function. For this reason, it is important to have an objective measure of LV function in patients with asymptomatic MR.

Echocardiography — The severity of MR can be assessed semiquantitatively by Doppler echocardiography; the results of these two methods correlate highly in grading MR [1,10] . Transthoracic echocardiography usually provides the desired information and is preferred to routine transesophageal echocardiography because it is noninvasive (show table 3 and show table 4).

Based upon the 2003 American Society of Echocardiography guidelines [11] , the following findings, in order or priority, are consistent with severe MR (show table 5):

• A vena contracta width ≥7 mm
• A regurgitant orifice area ≥0.40 cm2
• A regurgitant volume ≥60 mL
• A regurgitant fraction ≥50 percent
• A jet area >40 percent of left atrial area, but this is not so reproducible and less often used

These values are based on an average adult size and may need to be adjusted for body size in small or large patients; however, there is no specific formula for making this adjustment. (See "Etiology, clinical features, and evaluation of chronic mitral regurgitation", section on Severity of MR).

Regardless of echo-Doppler grading, severe chronic MR does NOT exist (with rare exceptions) without clear evidence of left atrial or left ventricular enlargement. If the left ventricular end-diastolic dimension (by echocardiography) is less than 60 mm (approximately 35 mm/m2), the diagnosis of severe chronic MR should be seriously questioned. Left atrial size may reflect the "history" (severity and duration) of chronic MR [12] .

Cardiac catheterization is primarily indicated when echocardiography does not provide diagnostic information or the echocardiographic findings are discrepant from the clinical features (show table 6) [1] .

Serial monitoring — In addition to the initial evaluation, serial monitoring is warranted in patients with chronic MR. The goals of monitoring are to assess changes in clinical status by history and physical examination and to assess changes in left ventricular function, which can occur in the absence of symptoms, by echocardiography.

The 2006 ACC/AHA guidelines included recommendations for clinical and transthoracic echocardiographic monitoring in asymptomatic patients with chronic MR (show table 3) [1] . Echocardiography is performed to assess the left ventricular ejection fraction and end-systolic dimension.

The recommendations varied with the severity of MR:

• Patients with mild MR and no evidence of left ventricular enlargement, left ventricular dysfunction, or pulmonary hypertension should be seen yearly for history and physical examination with instructions to contact the physician if symptoms occur. Repeat echocardiography at these visits is not necessary in the absence of clinical evidence of worsening MR.
• Patients with moderate MR should be seen yearly or sooner if symptoms occur. Repeat transthoracic echocardiography should be obtained at these visits.
• Patients with severe MR should be seen every 6 to 12 months or sooner if symptoms occur. Repeat transthoracic echocardiography should be obtained at these visits. The six month interval is preferred if stability has not been documented, there is evidence of progression, or measurements are close to the echocardiographic cutoff values for mitral valve surgery (show table 2). (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation").

Exercise stress testing may add objective evidence about symptoms and a change in exercise tolerance; it may be particularly useful if a good history of exercise capacity is difficult to obtain. Measurement of MR severity and pulmonary artery pressure during exercise also may be helpful.

Transesophageal echocardiography is NOT ndicated for routine follow-up (show table 4). It does, however, have a role in preoperative and intraoperative evaluation when mitral valve surgery is being considered.

A separate issue, the indications for repeat echocardiography in patients with mitral valve prolapse independent of MR, is discussed elsewhere. (See "Natural history of chronic mitral regurgitation in mitral valve prolapse and flail mitral leaflet", section on Monitoring).

PHYSICAL ACTIVITY AND EXERCISE — Exercise has a variable effect on the regurgitant fraction in patients with chronic MR [13] . The reduction in systemic vascular resistance may result in no change or a mild reduction in the regurgitant fraction. On the other hand, an elevation in blood pressure, as occurs with static exercise, can lead to marked increases in regurgitant volume and pulmonary capillary pressure.

The 2006 ACC/AHA guidelines concluded that there are no exercise restrictions in asymptomatic patients who are in sinus rhythm and have normal left ventricular and left atrial dimensions and a normal pulmonary artery pressure [1] . Specific recommendations for participation in competitive sports in patients with MR were made by the 36th Bethesda Conference [13] , which also included a classification of sports (show table 7) [14] :

• Patients with mild to moderate MR who are in sinus rhythm, have normal left ventricular size and function, and normal pulmonary artery pressures can participate in all competitive sports.
• Patients with mild to moderate MR who are in sinus rhythm, have normal left ventricular systolic function at rest, and mild left ventricular enlargement can participate in low and moderate static and all dynamic competitive sports (class IA, IB, IIA, IIB, and IIC) (show table 7).
• Patients with severe MR and definite left ventricular enlargement, pulmonary hypertension, or any reduction in left ventricular systolic function at rest should not participate in any competitive sports.
• Patients with atrial fibrillation or a history of atrial fibrillation who are treated with long-term anticoagulation therapy should not engage in sports with any for bodily contact or risk of trauma (show table 7).

Recommendations for exercise after mitral repair for chronic MR are described below. (See "Exercise after valve repair" below).

ATRIAL ENLARGEMENT AND FIBRILLATION — Chronic MR is often complicated by the development of left atrial enlargement and atrial fibrillation (AF), both of which can have an impact on patient outcome.

Atrial fibrillation — If the ventricle is compensated and the heart rate is not excessive, the patient with AF merely notices palpitations. There is little or no disability in these cases except for an increased risk of stroke or other sign of systemic embolization. These patients are candidates for direct current cardioversion and antiarrhythmic drug therapy to maintain sinus rhythm. (See "Restoration of sinus rhythm in atrial fibrillation: Recommendations" and see "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations").

It can be argued, however, that mitral valve surgery should be performed before AF is persistent or resistant to cardioversion. This notion is based upon the observation that persistent AF after surgery places the patient at particularly high risk for atrial thrombus and arterial embolism.

Preoperative variables that are associated with the persistence of AF after surgery are a prolonged duration of the arrhythmia (exceeding one year) and moderate to severe left atrial enlargement [12,15,16] . When the preoperative left atrial size exceeds 50 mm (by echocardiography), fewer than one-half of the patients return to normal sinus rhythm after surgery; in contrast, when left atrial dimension is normal, 85 percent of patients return to normal sinus rhythm [15] .

These data and anecdotal clinical experience support the concept that, if postoperative AF and its complications are to be minimized, corrective surgery should be considered within months of the development of AF or before substantial left atrial enlargement is present. The 2006 ACC/AHA guidelines concluded that the weight of evidence was in favor of the efficacy of mitral valve surgery in asymptomatic patients with severe chronic MR and preserved left ventricular function who have new onset AF (show table 2) [1] . The 2007 ESC guidelines thought that this was a debatable point [2] .

Although AF is not necessarily an indication for surgery in an asymptomatic patient with preserved left ventricular function, the burden of this arrhythmia in a patient with borderline left ventricular function (LVEF 55 to 60 percent) might be used as an indication for surgery, especially if the risk of surgery is low and the valve appears to be amenable to repair. (See "Mitral valve replacement versus repair" below).

The use of the maze procedure or radiofrequency or cryoablation as an adjunct to mitral valve repair or replacement is an effective approach to reduce the incidence of postoperative AF. (See "Surgical approaches to prevent recurrent atrial fibrillation").

Left atrial enlargement — Left atrial enlargement itself, in the absence of AF, may be a risk factor for an adverse outcome following mitral valve surgery. In one study, for example, measures of left ventricular systolic function and left atrial size were equally important in predicting postoperative cardiac-related mortality in patients with symptomatic chronic MR [12] . The authors concluded that left atrial size may reflect the "history" (severity and duration) of MR. This observation again supports the notion that surgery should be considered prior to the development of significant left atrial enlargement.

USE OF VASODILATORS — The indications for vasodilator therapy in patients with chronic MR depend upon the presence or absence of symptoms and the functional state of the left ventricle. These issues are discussed in detail elsewhere and will be briefly reviewed here. (See "Vasodilator therapy in chronic mitral regurgitation").

Asymptomatic patients — There are no published studies that support the hypothesis that vasodilator therapy is beneficial in asymptomatic patients with chronic MR. In addition, the administration of vasodilators in patients with normal LV function might limit the development of symptoms due to increasing LV dysfunction, thereby masking an indication for surgery. Thus, with some exceptions (eg, the hypertensive patient), vasodilators are not recommended for use in asymptomatic patients with chronic MR due to primary valve disease [1,2] .

Symptomatic patients — Several studies confirm a beneficial effect of acute vasodilator therapy in patients with chronic MR. Intravenous nitroprusside, for example, decreases left ventricular end-diastolic pressure and volume while increasing forward stroke volume and cardiac index. Hydralazine has similar salutary effects. In contrast, the acute effect of angiotensin converting enzyme (ACE) inhibitors or nitrates is usually a decrease or no change in the cardiac index.

Data regarding the chronic effect of vasodilators are less impressive. Chronic therapy provides the most benefit for patients with the largest hearts, the poorest systolic function, and the most disabling symptoms. When combined with digitalis and diuretics, for example, hydralazine can produce substantial symptomatic and hemodynamic improvement in patients who are in NYHA functional class II-IV [17] . ACE inhibitors may also be beneficial in this setting [18] . However, because of the substantial improvement in outcome associated with surgery in patients with symptomatic MR, chronic vasodilator therapy is only indicated in those who are not surgical candidates.

In patients for whom chronic vasodilator therapy is warranted, the following recommendations can be made based upon the etiology of MR and whether or not the patient is a candidate for surgery. (See "Vasodilator therapy in chronic mitral regurgitation").

• In symptomatic patients with primary MR (eg, myxomatous or rheumatic), there is little potential to induce a change in the regurgitant orifice area via preload reduction and the therapeutic goal should be a reduction in systolic pressure. Thus, a beta blocker, diuretic, hydralazine, or calcium channel blocker should be used. However, medical therapy is not a substitute for surgical intervention in patients with chronic symptomatic MR.
• Chronic vasodilator therapy is indicated in symptomatic patients who are not candidates for surgery. The evidence of benefit is best in patients with secondary (functional) MR due to left ventricular dysfunction. Treatment of such patients should consist of optimal medical therapy of heart failure and, in appropriate patients, cardiac resynchronization therapy. With respect to ACE inhibitors and/or angiotensin II receptor blockers, the dose titration and monitoring schedules are the same as for heart failure due to left ventricular systolic dysfunction in the absence of moderate to severe MR. (See "Functional mitral regurgitation" and see "Overview of the therapy of heart failure due to systolic dysfunction" and see "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use").

CARDIAC RESYNCHRONIZATION — In selected patients with functional MR, cardiac resynchronization therapy (CRT) with biventricular pacing may be helpful. At this time, however, standard indications for CRT in patients with heart failure are based upon left ventricular (LV) function, functional class, and measures of LV dyssynchrony. (See "Functional mitral regurgitation", section on Cardiac resynchronization therapy, and see "Cardiac resynchronization therapy (biventricular pacing) in heart failure")

ANTICOAGULATION — The risk of an embolic event is increased in patients with rheumatic or nonrheumatic MR, particularly when atrial fibrillation is also present. The presence of mitral annular calcification, which if often associated with MR, also increases the risk of embolism, even in the absence of atrial fibrillation. It was estimated by the Framingham Heart Study that the risk of stroke associated with mitral annular calcification was 2.1-fold greater compared to the absence of mitral valve calcification [19] . (See "Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation" and see "Echocardiography in detection of intracardiac sources of embolism", section on Mitral annular calcification).

The Seventh ACCP Consensus Conference on Antithrombotic Therapy published in 2004 included the following recommendations for anticoagulation in patients with chronic MR [20] . These recommendations are essentially the same as for patients without mitral valve disease who have atrial fibrillation and/or systemic embolic events:

Rheumatic MR — Anticoagulation with warfarin (target INR 2.5, range 2.0 to 3.0) is indicated in patients with rheumatic MR who have a history of systemic embolism, intermittent (paroxysmal) or persistent (chronic) atrial fibrillation, or sinus rhythm with a left atrial diameter greater than 5.5 cm. Since the risk of embolism may be increased in other patients with MR who are in sinus rhythm, a decision about the use of warfarin should also be based on comorbid risk factors, including age and the hemodynamic severity of the lesion.

If recurrent systemic embolism occurs despite adequate anticoagulation, aspirin (75 to 100 mg/day) should be added. For patients unable to take aspirin, alternative therapies are dipyridamole (400 mg/day) or clopidogrel (75 mg per day).

Nonrheumatic MR/mitral annular calcification — Long-term anticoagulation with warfarin (target INR 2.5, range 2.0 to 3.0) is recommended in patients with nonrheumatic MR who have atrial fibrillation or a history of systemic embolism and in patients with mitral annular calcification complicated by systemic embolism.

Mitral valve prolapse — The 2006 ACC/AHA guidelines on the management of valvular heart disease included recommendations for aspirin and warfarin therapy in patients with mitral valve prolapse (show table 8) [1] . When warfarin is given, the target INR is usually 2.5 (range 2.0 to 3.0). (See "Nonarrhythmic complications of mitral valve prolapse").

ENDOCARDITIS PROPHYLAXIS — The 2007 American Heart Association guidelines on infective endocarditis revised prior recommendations for patients with acquired valvular disease, including those with chronic MR [21] . As a result, antibiotic prophylaxis is no longer recommended when such patients undergo dental or other invasive procedures that produce significant bacteremia with organisms associated with endocarditis. (See "Antimicrobial prophylaxis for bacterial endocarditis").

MITRAL VALVE SURGERY — Two issues must be addressed when considering mitral valve surgery in patients with chronic MR: the indications for intervention; and the choice of procedure. These issues are discussed in detail separately but will be briefly reviewed here. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation").

This discussion will be limited to chronic MR due to primary valve disease. The management of functional and ischemic MR are reviewed elsewhere. (See "Functional mitral regurgitation" and see "Ischemic mitral regurgitation").

Indications — Among patients with severe chronic MR, surgery is indicated in patients with symptoms and in asymptomatic patients with abnormalities in LV size or function, pulmonary hypertension, or new onset atrial fibrillation (show figure 1A-1B and show table 9) [1] . Surgery may also be reasonable in asymptomatic patients with preserved left ventricular function if mitral valve repair is performed in experienced centers and it is estimated that the likelihood of successful repair without residual MR is greater than 90 percent.

Asymptomatic patients with severe chronic MR who do not meet criteria for intervention can be safely treated with watchful waiting as long as the patient is carefully monitored [22] . Such patients should be seen every 6 to 12 months or sooner if symptoms occur. Repeat transthoracic echocardiography should be obtained at these visits. The six month interval is preferred if stability has not been documented, there is evidence of progression, or measurements are close to the echocardiographic cutoff values for mitral valve surgery (show table 3). (See "Serial monitoring" above).

Surgery may be offered early in patients with borderline values for LV size or function in whom access to such monitoring is limited. On the other hand, a somewhat higher threshold for surgery is used if valve replacement is required. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation", section on Outcomes with watchful waiting).

Mitral valve replacement versus repair — Two surgical procedures confined to the mitral valve itself are available for the treatment of chronic MR: valve repair and valve replacement. The choice of procedure depends, at least in part, upon the cause of the MR, the anatomy of the mitral valve, and the degree of left ventricular dysfunction.

In most patients, mitral valve repair at experienced surgical centers is the preferred approach because of both functional and survival benefits compared to valve replacement (show figure 2). (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation", section on Valve repair versus valve replacement).

When required, mitral valve replacement can be performed with a mechanical or bioprosthetic valve. Mechanical valves have the disadvantage of requiring lifelong warfarin therapy, while bioprosthetic valves have the disadvantage of limited durability due to valve degeneration, particularly in patients under age 65. (See "Complications of prosthetic heart valves").

When valve replacement is necessary, the following recommendations for the selection of a bioprosthetic or mechanical mitral valve were made by the 2006 ACC/AHA guidelines when valve replacement (show table 10) [1] :

• Bioprosthetic valves are recommended in patients who cannot or will not take warfarin or have a clear contraindication to warfarin therapy.
• Among patients who can take warfarin, the weight of evidence supports the following approach:

- A mechanical valve in patients under age 65 who have long-standing AF.

- A bioprosthetic valve in patients ≥65 years of age.

Among patients under age 65 who are in sinus rhythm, patient preference plays a central role in the choice of valve. The guidelines suggested that a bioprosthetic valve should only be considered after a detailed discussion with the patient of the risks of warfarin therapy compared to the likelihood of repeat valve replacement in the future.

Concurrent coronary disease — Many patients with nonischemic chronic MR requiring surgery also have significant coronary artery disease. Obstructive coronary lesions are usually revascularized at the time of mitral valve surgery, since concurrent bypass surgery typically adds little morbidity or mortality to the procedure [1] . A separate issue, which is discussed elsewhere, is the management of ischemic mitral regurgitation. (See "Ischemic mitral regurgitation").

Assuming that the patient is not severely hemodynamically unstable, coronary angiography was recommended by the ACC/AHA guidelines in patients who have or are suspected to have coronary disease (and who may have ischemic MR) and in those at risk for coronary disease (show table 11) [1] . At risk was defined as men ≥35 years of age, women ≥35 years of age with coronary risk factors, and postmenopausal women. A higher age threshold of ≥45 years was recommended in patients without ischemic symptoms or coronary risk factors in whom MR is due to mitral valve prolapse because of a very low rate of significant coronary disease in younger patients with mitral valve prolapse. (See "Indications for and types of corrective surgery in severe chronic mitral regurgitation", section on Predicting coronary disease).

Exercise after valve repair — The effect of exercise in patients with repaired mitral valves has not been well studied. The 36th Bethesda conference cited above recommended that such patients should not participate in sports that are associated with a risk of bodily contact or trauma that might disrupt the repair [13] . They can participate in low-intensity competitive sports (class IA) and selected patients can participate in low and moderate static and low and moderate dynamic competitive sports (class IA, IB, and IIA) (show table 7).

Antimicrobial therapy of prosthetic valve endocarditis

2008-08-31T20:39:00.000-07:00

Antimicrobial therapy of prosthetic valve endocarditis

Author
Adolf W Karchmer, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Elinor L Baron, MD, DTMH

Last literature review version 16.2: May 2008 | This topic last updated: May 12, 2008 (More)

INTRODUCTION — Infection of a prosthetic heart valve can be difficult to diagnose and manage. Optimal treatment of prosthetic valve endocarditis (PVE) requires:

• Identification of the causative microorganism.
• Selection of a bactericidal antimicrobial regimen of proven efficacy.
• A clear understanding of the intracardiac pathology and attendant complications of PVE.
• Surgical intervention, especially when infection has extended beyond the valve to contiguous cardiac tissue.

The antimicrobial therapy of prosthetic valve endocarditis will be reviewed here. The pathogenesis, microbiology, pathology, clinical features, diagnosis, prevention, and surgical management of PVE are discussed separately. (See "Presentation and diagnosis of prosthetic valve endocarditis" and see "Surgery for prosthetic valve endocarditis").

GENERAL PRINCIPLES — Treatment of PVE with antimicrobial agents alone frequently fails, and invasive infection with subsequent valve dysfunction often arises before or during therapy. Thus, all treatment for PVE should be initiated in the hospital, preferably in an institution where cardiac surgery is available. Patients should remain hospitalized until fever resolves and it is clear that surgery can be safely avoided.

It is essential to isolate the causative organism in patients with suspected PVE. For patients who are hemodynamically stable with an indolent clinical course, antibiotic therapy should be delayed pending the blood culture results. This delay allows additional blood cultures to be obtained without the confounding effect of antibiotics, which is particularly important for patients who have received recent antimicrobial agents and whose initial blood cultures may be negative.

However, patients presenting with hemodynamic instability or acute disease should receive empiric antibiotics promptly after three sets of blood cultures have been obtained. Empiric antibiotic therapy with three agents should be initiated: vancomycin, gentamicin, and either cefepime or a carbapenem. Subsequent therapy should be adjusted based on culture results; if cultures remain negative, therapy as outlined for culture negative PVE should be used (See "Culture-negative" below).

Antimicrobial treatment regimens for PVE are based upon clinical experience. The antimicrobials used to treat a specific pathogen causing PVE are generally the treatment used for that organism when it causes native valve endocarditis (NVE). Staphylococci, which commonly cause PVE, are an exception to this dictum. (See "Antimicrobial therapy of native valve endocarditis").

No randomized controlled studies have evaluated the optimal duration of therapy for PVE. Treatment guidelines from the American Heart Association (AHA) and the European Society for Cardiology (ESC) recommend that PVE should be treated with an agent(s) that is bactericidal for the isolated microorganism for at least six weeks [1-3] . We generally agree with these guidelines and recommend a minimum of six weeks of treatment.

There are small differences, described under each specific microorganism below, in recommended guidelines between the AHA and the ESC [1-3] . We are in general agreement with these guidelines.

STAPHYLOCOCCI — Treatment choices for staphylococcal PVE are not contingent on whether the pathogen is coagulase-negative or S. aureus, unlike most other types of staphylococcal infections [4,5] (show table 1). The primary consideration in choosing therapy hinges upon whether or not the organism is sensitive to methicillin and other beta-lactam antibiotics. In addition, PVE caused by S. aureus frequently requires prompt surgical intervention. (See "Surgery for prosthetic valve endocarditis" section on "Microorganisms usually requiring surgery").

Antimicrobial treatment of staphylococcal PVE requires combination therapy. We agree with the AHA and ESC who recommend a triple drug regimen, as described below.

Evidence to support a triple-drug regimen (with one drug being rifampin) comes from animal models of prosthetic device infection and retrospective clinical series [6-10] . A retrospective study of valve cultures from 61 patients with staphylococcal PVE treated surgically found that valves from patients receiving combination therapy were 5.9 times more likely to be culture-negative than those receiving monotherapy when results were adjusted for duration of therapy before surgery [6] . Although the numbers are too small to analyze, all six patients who received a triple-drug regimen that included rifampin, had negative valve cultures at surgery.

Methicillin susceptibility — Vancomycin is the critical drug for isolates resistant to methicillin, while a semisynthetic penicillinase-resistant penicillin (nafcillin, oxacillin) is the mainstay of therapy for isolates susceptible to methicillin. In patients with penicillin allergy that does not involve anaphylaxis, swelling, or hives, the AHA recommends that a first generation cephalosporin can substitute for nafcillin or oxacillin. We agree with this recommendation.

If the organism is susceptible to gentamicin by routine testing, this should be the second agent, with rifampin as the third agent. (See "Rifampin" below). The aminoglycoside should be administered for the initial two weeks of treatment, after which it can be discontinued and the other two agents continued for at least four additional weeks. If the organism is resistant to gentamicin, an alternative aminoglycoside should be sought based upon antibiotic susceptibilities.

If the isolate is resistant to all available aminoglycosides, a fluoroquinolone to which the strain is highly susceptible should be used [11-13] . If a fluoroquinolone is used in lieu of an aminoglycoside, we prefer to continue the three-drug regimen for the entire course of treatment. When the isolate is resistant to all aminoglycosides and fluoroquinolones, daptomycin [14] , linezolid [15] , or trimethoprim-sulfamethoxazole could be considered as a third drug for the initial two weeks of therapy. If breakthrough bacteremia or microbiologic failure occurs in patients receiving daptomycin, the isolate recovered from the breakthrough bacteremia should be tested for the development of daptomycin resistance [16] .

Optimal therapy of PVE caused by methicillin-resistant S. aureus with reduced vancomycin susceptibility, has not been established. Although linezolid and daptomycin are often active against these organisms, clinical experience in the treatment of PVE is limited [14,17] .

Rifampin — Rifampin appears to have the unique ability to kill staphylococci that are adherent to foreign material, based upon in vitro data, evidence from animal model experiments, and clinical observations [4,8-13,18] . This drug is an essential component of regimens used to treat staphylococcal PVE. However, bacterial cells have a relatively high intrinsic mutation rate for the gene controlling the rifampin site of action. These mutations allow the selection of a rifampin-resistant subpopulation when large numbers of staphylococci are exposed to ineffective rifampin-containing regimens [4,11] .

To protect against the emergence of resistance, the recommended regimens for staphylococcal PVE (see "Staphylococci" above) ideally contain two additional antimicrobials, which should be identified prior to the initiation of rifampin, if at all possible. Thus, a regimen with two other drugs to which the staphylococci are susceptible should be in place at the time rifampin is begun. If the isolate is not sensitive to two additional antimicrobials, therapy with a single antistaphylococcal agent should be administered for three to five days before beginning rifampin. This strategy may reduce the total number of staphylococci at the site of infection and thus diminish the probability that a rifampin-resistant subpopulation will emerge. Nevertheless, susceptibility to rifampin should be reassessed when regimens containing rifampin fail [8] .

STREPTOCOCCI — Combination therapy with a beta-lactam antibiotic and an aminoglycoside (if the isolate is susceptible) is the preferred regimen for streptococcal endocarditis due to synergistic killing of the organism when two antibiotics are used in combination [19] .

Based on in vitro studies, clinical series, and experience of experts, penicillin plus gentamicin is recommended for the therapy of PVE caused by penicillin-susceptible streptococci (minimum inhibitory concentration [MIC] <0.12 mcg/mL) (show table 2) [5,20] . Gentamicin, if the isolate does not exhibit high level resistance (see "Enterococci" below), should be given only during the initial two weeks of treatment. Streptomycin, if the isolate does not possess high level resistance, may be given in lieu of gentamicin to achieve the same effect, but gentamicin is more commonly used in clinical practice due to the wider availability of gentamicin serum levels, and because dosing regimens for gentamicin are more familiar to most clinicians than for streptomycin [21,22] . For these reasons, we recommend gentamicin if the isolate is susceptible. Penicillin, a cephalosporin, or vancomycin can be used alone if aminoglycoside therapy is relatively contraindicated [4] .

If the streptococcus is relatively resistant to penicillin (MIC ≥0.12 mcg/mL), the AHA recommends that the aminoglycoside should be continued for the entire four to six weeks of therapy, if not precluded by nephrotoxicity (show table 3). We agree with the AHA that the aminoglycoside be continued for the duration of treatment. In contrast, the ESC recommends that the aminoglycoside only be given during the initial two weeks of treatment even when the isolate is relatively resistant to penicillin. Although the AHA recommends that gentamicin be dosed once daily, we, as well as the ESC, advocate three equally divided doses.

Among patients who are allergic to penicillin, vancomycin is advised for those with immediate type reactions (urticaria or anaphylaxis). Cefotaxime or ceftriaxone may be used in non-immediate allergies. (See "Penicillin and related antibiotic allergy; skin testing; and desensitization" section on "Cephalosporins").

ENTEROCOCCI — To achieve bactericidal activity against enterococci requires the synergistic interaction of a cell wall active agent (penicillin, ampicillin, or vancomycin) and an aminoglycoside (gentamicin or streptomycin) [19] . (See "Antimicrobial therapy of native valve endocarditis"). To achieve this interaction the organism must not be resistant to the cell wall active agent at achievable serum concentrations and must not be resistant to gentamicin at 500 mcg/mL or streptomycin at 1000 mcg/mL in broth or at 2000 mcg/mL when using cultures on agar. Growth in the presence of the aminoglycoside at these concentrations indicates high-level resistance and precludes synergy when the aminoglycoside is used. Resistance to gentamicin at this concentration also indicates that synergy cannot be achieved with netilmicin, tobramycin, amikacin, or kanamycin. High-level resistance to gentamicin and streptomycin are mediated by two independently acquired genes; hence, organisms should be tested for high-level resistance to each of these drugs.

Based on in vitro studies, animal models, and clinical series [23] , we, along with the AHA and ESC recommend combination therapy with a cell wall active agent (penicillin, ampicillin, or vancomycin) plus an aminoglycoside (usually gentamicin or streptomycin) for treatment of PVE caused by enterococci (as long as the strain is confirmed to be susceptible).

Cephalosporins are not usually active against enterococci and also do not interact with aminoglycosides to result in bactericidal synergy. The cephalosporins should not be used alone as the cell wall active agent in the treatment of enterococcal PVE. In past years, the regimens outlined for treatment of enterococcal PVE in the following tables had been predictably bactericidal (show table 4 and show table 5) [23] . However, antibiotic resistance among enterococci has become significantly more common, necessitating that each strain causing endocarditis be carefully tested in order to select a synergistic regimen [24,25] .

Penicillin/ampicillin resistance will most commonly be due to alterations in penicillin-binding proteins. In that situation, vancomycin is the cell-active agent of choice. Occasionally, E. faecalis may be resistant to penicillin and ampicillin by virtue of beta-lactamase production. In this instance vancomycin or ampicillin-sulbactam could be used. (See "Mechanisms of antibiotic resistance in enterococci").

If the enterococcus has high-level resistance to both streptomycin and gentamicin, synergy is not feasible and an aminoglycoside should not be administered. When resistance precludes bactericidal therapy, a prolonged course of 8 to 12 weeks of one of the cell wall active agents should be administered instead, but therapy in patients with native valve endocarditis has only a 40 percent chance of being successful [26] .

Although the data are limited, in the setting of progressive nephrotoxicity, the duration of aminoglycoside administration may be reduced to less than six weeks with no decrease in cure rates. This was illustrated in a prospective study from Sweden of 93 episodes of enterococcal endocarditis that included 27 cases of prosthetic valve endocarditis [27] . Clinical cure was achieved in 75 of 93 episodes (81 percent) overall, and in 21 of 27 (78 percent) with PVE. In patients who achieved clinical cure, a cell wall-active antimicrobial therapy was given for a median of 42 days, and a synergistic aminoglycoside was added for a median of 15 days.

Optimal therapy of PVE caused by vancomycin-resistant E. faecium (VRE) organisms, which often are also resistant to penicillin and ampicillin, and highly resistant to gentamicin and streptomycin, has not been established. VRE are occasionally susceptible to penicillin and ampicillin and may not have high-level resistance to streptomycin and gentamicin. A full evaluation of the isolates resistance profile is required to select optimal therapy.

Although quinupristin-dalfopristin (E. faecium only) and linezolid (E. faecium and E. faecalis) are often active against these organisms, their effectiveness in the treatment of PVE caused by VRE is not known [28] . The following table outlines possible regimens for PVE caused by VRE (show table 6). Surgical intervention during suppressive bacteriostatic therapy should be strongly considered when PVE is caused by highly resistant enterococci. (See "Treatment options for infections caused by vancomycin-resistant enterococci — Human studies").

HACEK — Because some of these organisms are ampicillin-resistant due to the production of beta-lactamase, and all are highly susceptible to third generation cephalosporins, we, along with the AHA recommend therapy for HACEK PVE with one of the following antibiotics: ceftriaxone, cefotaxime, or a comparable third generation cephalosporin; ampicillin-sulbactam; or ciprofloxacin (recommended only for patients unable to tolerate cephalosporin or ampicillin therapy), administered for six weeks (show table 7). The ESC recommends ampicillin (if the organism is susceptible) or a third generation cephalosporin. Patients with HACEK PVE, who do not have valvular dysfunction, generally can be cured with antibiotics alone [29] .

CORYNEBACTERIA (DIPHTHEROIDS) — If the strain is susceptible to gentamicin (MIC <4.0 mcg/mL), penicillin plus gentamicin will result in synergistic bactericidal activity and is recommended as therapy. Gentamicin resistance precludes bactericidal synergy [30] . Vancomycin is bactericidal against diphtheroids and is recommended for therapy when strains are resistant to gentamicin or when patients are allergic to penicillin.

GRAM-NEGATIVE BACILLI — We recommend treatment of PVE caused by gram-negative bacilli be based upon the susceptibility of the causative organism. Where possible, a synergistic bactericidal regimen should be used. Treatment for Pseudomonas aeruginosa is based upon experience in patients with NVE. If the organism is susceptible, high dose tobramycin (8 mg/kg per day in three equally divided doses IV or IM to achieve peak concentrations approaching 15 mcg/mL) plus ticarcillin, piperacillin, cefepime, or ceftazidime is recommended. (See "Antimicrobial therapy of native valve endocarditis").

Surgery to excise the infected valve is often required in gram-negative bacillus endocarditis, especially that caused by P. aeruginosa or when infection involves the left-sided heart valves. (See "Surgery for prosthetic valve endocarditis").

FUNGI — No randomized, controlled studies have evaluated the optimal therapy for fungal PVE. We, along with most infectious disease specialists, recommend a combined approach that utilizes both antifungal agents and valve replacement [31] . Amphotericin B (daily doses ranging from 0.7 to 1.0 mg/kg per day) is the antimicrobial of choice for treatment of fungal PVE as the greatest clinical experience in treating fungal PVE is with this agent.

For the treatment of endocarditis caused by mycelial fungi, such as Aspergillus or Mucor species, somewhat larger doses are used (1.0 to 1.5 mg/kg per day). We recommend for the treatment of fungal endocarditis, amphotericin B be combined with flucytosine (150 mg/kg per day divided into four doses with adjustments for renal dysfunction) in an attempt to achieve a synergistic effect. This initial phase of treatment is usually given for at least six weeks. (See "Clinical use of flucytosine").

The use of a lipid formulation of amphotericin B in lieu of amphotericin B desoxycholate for the treatment of fungal endocarditis has not been evaluated. Nevertheless, if renal dysfunction complicates amphotericin B treatment, substitution of a lipid formulation is justified.

Early surgical intervention is considered by most experts to be a standard element of treatment for fungal PVE. (See "Surgery for prosthetic valve endocarditis" section on "Microorganisms usually requiring surgery").

Since the potential for relapse is high in Candida PVE, even with surgical intervention, we along with most infectious disease specialists recommend a suppressive second phase of oral therapy with fluconazole (200 to 400 mg daily or another triazole) for prolonged periods, if not indefinitely [32-34] . (See "Candida endocarditis").

Successful treatment of Candida PVE without surgery has been reported in a few case reports using a combination regimen of fluconazole and caspofungin or fluconazole and amphotericin B [35,36] .

CULTURE-NEGATIVE — Many native and prosthetic valve endocarditis patients with negative blood cultures have been rendered culture-negative by virtue of prior antibiotic therapy. The therapy to which they have been exposed is a clue and consideration in selecting empiric treatment. (See "Culture-negative endocarditis").

In the absence of clinical clues to a specific etiology, we along with the AHA recommend that treatment for culture-negative PVE, with onset within the first year following valve surgery, should include vancomycin, gentamicin, cefepime, and rifampin [1] . For patients with the onset of disease 12 months or more after valve implantation, the AHA and we recommend treatment with ceftriaxone, gentamicin, and doxycycline [1] . Aggressive efforts must be made to identify a causative agent. (See "Diagnostic approach to infective endocarditis" section on "Culture-negative IE"). Epidemiologic considerations should be weighed carefully. As an example, in some regions of the world Coxiella burnetii is a common cause of culture-negative PVE. The possibility of fungal endocarditis should be considered, especially in patients with a complex perioperative course. If unexplained fever persists in the face of empiric therapy, surgery to obtain a vegetation for microbiologic evaluation should be considered [4,20] . (See "Q fever endocarditis").

SUMMARY AND RECOMMENDATIONS

• Treatment of prosthetic valve endocarditis is more difficult than treatment of native valve endocarditis and may require surgical replacement of the prostheses in addition to antibiotic therapy. (See "Introduction" above).
• The antimicrobial regimens used are targeted to a specific pathogen, thus identification of the causative organism is critical. (See "Introduction" above and see "Diagnostic approach to infective endocarditis").
• We recommend the same treatment regimens for a specific pathogen causing PVE as is used for that organism when it causes native valve endocarditis (Grade 1B). An exception is staphylococcal endocarditis; we recommend treatment with three agents for this microorganism. (Grade 1B). (See "General principles" above and see "Staphylococci" above).
• We recommend treatment of PVE with an agent(s) that is bactericidal for the isolated microorganism for at least six weeks (Grade 1C). (See "General principles" above).
• Treatment choices for staphylococcal PVE are the same regardless of whether the pathogen is coagulase-negative staphylococci or S. aureus. The primary consideration in choosing therapy hinges upon whether or not the organism is sensitive to methicillin and other beta-lactam antibiotics. (See "Staphylococci" above).
• We recommend a treatment regimen for enterococcal PVE that includes the synergistic interaction of a cell wall active agent (penicillin, ampicillin, or vancomycin) and an aminoglycoside (gentamicin or streptomycin). (Grade 1B). (See "Enterococci" above).

Complications and outcome of infective endocarditis

2008-08-31T20:25:00.000-07:00

http://www.uptodateonline.com/online/content/topic.do?topicKey=endocard/5997&selectedTitle=36~150&source=search_result

Complications and outcome of infective endocarditis

Author
Denis Spelman, MBBS, FRACP, FRCPA, MPH
Daniel J Sexton, MD
Section Editor
Stephen B Calderwood, MD
Gabriel S Aldea, MD
Scott E Kasner, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Susan B Yeon, MD, JD, FACC

Last literature review version 16.2: May 2008 | This topic last updated: May 19, 2008 (More)

INTRODUCTION — Infective endocarditis (IE) is associated with a myriad of complications, one or more of which occur in the majority of patients. This was illustrated in a review of 223 episodes of IE in which 57 percent of patients had one complication, 26 percent two, 8 percent three or more, and 6 percent six or more complications [1] . Complications such as heart failure and stroke are relatively common and feared outcomes of IE, while other complications such as blindness and septic arthritis are, fortunately, rare in modern practice.

The frequency and type of complications due to IE has changed with advances in diagnosis and therapy. Renal failure and uncontrolled intracardiac or metastatic infection, for example, which were previously common complications of IE, are infrequent in the antibiotic era. The frequency of specific complications depends upon variables such as the infecting pathogen, duration of illness prior to therapy, and the type of treatment facility (eg, referral versus community hospital). It is often difficult to assess the true incidence of complications despite extensive literature on the subject because different reviews and case series were generally based upon retrospective chart reviews and used different diagnostic criteria to define cases of IE. (See "Infective endocarditis: Historical and Duke criteria").

The major complications of IE will be reviewed here but will only attempt to describe the frequency of these complications as relatively common, rare, or very rare because accurate numbers are not available. Complications can occur before, during and, rarely, even after the end of therapy (eg, ruptured mycotic aneurysm).

DEFINITIONS — Complications of IE can be broadly categorized as:

• Cardiac
• Septic
• Embolic
• Neurologic
• Musculoskeletal
• Renal
• Associated with medical treatment

While these categories are broad and organize the complications in an understandable fashion, they do not take into account significant overlapping features. As an example, patients with neurologic involvement can simultaneously have embolic and septic processes.

One can also consider complications in terms of their pathogenesis, which leads to different groupings:

• Embolic (eg, cerebral infarct)
• Local spread of infection (eg, heart valve destruction)
• Metastatic infection (eg, vertebral osteomyelitis)
• Immune-mediated damage (eg, glomerulonephritis)

CARDIAC COMPLICATIONS — Cardiac complications are the most common complications seen in IE, occurring in one-third to one-half of patients in most recent case series [2] .

Heart failure — Heart failure (HF) remains the most common cause of death due to IE in the modern era and is the most frequent reason for cardiac surgery in patients with IE. (See "Surgery for native valve endocarditis").

The usual cause of HF in patients with IE is valvular insufficiency resulting from infection-induced valvular damage. Rarely, embolism of fragments of valvular vegetations or vegetation-induced stenosis of the coronary ostia can cause acute myocardial infarction and subsequent HF [2] .

Perivalvular abscesses — Among patients with IE, the reported incidence of perivalvular abscess at surgery or autopsy has ranged from about 30 to 40 percent [3-5] . The aortic valve and its adjacent annulus are more susceptible to abscess formation and the complications of perivalvular extension of infection than are the mitral valve and ring [3-5] . This was illustrated in an autopsy study of patients with native valve endocarditis: annular extension of infection was far more common in patients with aortic valve compared to mitral valve endocarditis (41 versus 6 percent) [3] .

Injection drug use may be another risk factor for perivalvular abscess [4] . In contrast, although large vegetation size had been implicated as a risk factor in some series, subsequent studies have shown no correlation between the presence or size of the vegetation and the development of periannular extension [4,6] .

Paravalvular abscesses can extend into adjacent cardiac conduction tissues, possibly leading to various forms of heart block. Involvement of the conducting system is most common with infection of the aortic valve, especially when there is involvement of the valve ring between the right and non-coronary cusp (this anatomic site overlies the intraventricular septum that contains the proximal ventricular conduction system).

Paravalvular abscess should be suspected when fever persists despite appropriate antimicrobial therapy and/or when conduction abnormalities appear on the ECG [7] . Transesophageal echocardiography (TEE) has a much greater likelihood of detecting a myocardial abscess than transthoracic echocardiography (TTE). One study, for example, evaluated 118 patients with IE, 37 percent of whom had an abscess documented at surgery or autopsy [5] . The sensitivity, specificity, and positive and negative predictive values of TEE imaging were 87, 95, 91, and 92 percent, respectively; the sensitivity of TTE was much lower (28 versus 87 percent) although the specificity was 99 percent. However, some perivalvular abscesses may be missed by TEE. (See "Role of echocardiography in infective endocarditis", section on Perivalvular abscess or fistula).

Patients with perivalvular abscesses appear to have higher rates of systemic embolization and fatal outcomes. In one study comparing outcomes of patients with and without perivalvular abscesses, the rate of embolization was approximately twice as high (64 versus 30 percent) [4] . These patients also have a higher mortality rate (23 versus 14 percent in those without abscesses in a report of 118 patients, 44 of whom had a perivalvular abscess) [5] . Mortality may be particularly high in patients with at least moderate valvular regurgitation [8] .

Other extravalvular complications — Other rare extravalvular cardiac complications of IE include:

• Pericarditis, which may be suppurative or nonsuppurative, can rarely cause pain or even cardiac tamponade [9,10] . (See "Purulent pericarditis" and see "Evaluation and management of acute pericarditis").
• Fistulous intracardiac connections (eg, aorta-atrial or aorta-ventricular) due to extension of infection from the valve to adjacent myocardium may rarely result in large aneurysms, a pseudoaneurysm if the aortic wall is involved [11] , or even myocardial perforation.

The incidence of fistulous intracardiac complications was 1.6 percent in a retrospective, multicenter study of 4681 episodes of IE [12] . Surgery was performed in 66 of the 76 patients with a mortality of 41 percent. Multivariate analysis identified heart failure (odds ratio [OR] 4.3), prosthetic IE (OR 4.6), and urgent or emergent surgical treatment (OR 4.3) as being significantly associated with an increased risk of death.

• Aortic valve dissection [13] .
• Descending thoracic aorta intraluminal infectious masses [14] .

EMBOLIZATION — Embolization remains a distressingly common complication of IE and can occur even after appropriate therapy is well underway. This section will provide a general discussion of embolization in patients with IE. Issues related to embolization in patients with IE who undergo surgery are discussed separately (See "Surgery for native valve endocarditis" section on Embolization, and see "Surgery for prosthetic valve endocarditis" section on Embolization).

Systemic emboli most commonly complicate left-sided IE, but rarely can occur in tricuspid valve endocarditis via a patent foramen ovale [15] . However, emboli to the lung with subsequent abscess formation occur frequently in patients with tricuspid endocarditis. Small, clinically inapparent embolization probably occurs in most, if not all, patients with IE, but clinically recognized embolism has been reported in 13 to 44 percent of patients in published reports [16,17] .

Emboli consisting of vegetation fragments can occlude or damage virtually any blood vessel, large or small, in the systemic or pulmonary arterial circulation. As a result, emboli can produce:

• Stroke
• Blindness
• Painful ischemic or frankly gangrenous extremities
• Unusual pain syndromes (eg, due to splenic or renal infarction)
• Hypoxia (due to pulmonary emboli in right-sided endocarditis)
• Paralysis (due to embolic infarction of either the brain or spinal cord)

Emboli can occasionally cause symptoms or signs that mimic other common conditions such as kidney stones, Bell's palsy, dizziness, or pleurisy.

Endocarditis should be considered as a possible etiology in virtually all patients who present with signs or symptoms of systemic arterial embolization. In one study, cerebral infarction was the presenting sign of IE in 4 to 14 percent of all cases of IE [15] . The vast majority of patients with an acute stroke do not have endocarditis although the occurrence of a stroke in a younger patient or evidence of simultaneous or sequential cerebral and systemic arterial embolization, increase the probability of IE. As an example, in one report of 60 patients with IE and cerebral complications, 28 (47 percent) also had clinically identifiable systemic emboli [18] compared to only 2 percent of all stroke patients in a different large series [19] .

Symptomatic embolization appears to be more common with IE due to fungal pathogens. Whenever emboli to large systemic arterial vessels occur in a patient with IE, the possibility of a fungal etiology should be entertained. In a literature review of 270 patients with fungal endocarditis, peripheral arterial embolization occurred in 45 percent. The most common sites were the cerebral circulation (17 percent) and femoral artery (16 percent) [20] .

Histopathologic or microbiologic examination of occluding embolic material in such large vessels may lead to a diagnosis of an underlying fungal IE. Haemophilus species and other slow growing fastidious gram-negative organisms also seem to predispose to embolization with some frequency. (See "Candida endocarditis").

Effect of antibiotic therapy on embolic risk — The risk of embolization tends to decline after the institution of effective antimicrobial therapy, and serious embolic events rarely occur several weeks after such therapy is instituted [16,21,22] . The relationship between the initiation of antibiotic therapy and the risk of embolism is illustrated by the following observations:

In a series of 629 patients with left sided endocarditis, 131 patients (21 percent) had one or more embolic events [21] . The event occurred before the initiation of antimicrobial therapy in 42 percent, on the day therapy commenced in 14 percent, and within 15 days of initiating therapy in 82 percent.
In a study that used TTE to detect vegetations, the rate of embolization fell from 13 per 1000 patient days during the first week of therapy to less than 1.2 per 1000 patient days after two weeks of therapy [16] .
These findings suggest that surgery may not be necessary for prevention of embolic stroke in the early weeks following initiation of appropriate antibiotic therapy, if there are no other indications for surgery (such as a large mobile vegetation or congestive heart failure due to valvular leak) [22] .

Predictors of embolization — The size of a vegetation as determined by echocardiography has been assessed as a risk factor for embolization in IE. Although some data are conflicting, vegetation size is generally a risk factor for embolization. (See "Role of echocardiography in infective endocarditis", section on Echocardiographic estimation of outcome).

However, the presence or absence of vegetations, the location of the vegetations, the characteristics of vegetations by TEE, the specific etiologic microorganism, or antiphospholipid antibodies may have predictive value [23-29] :

• A multicenter prospective European study of 384 patients with definite IE by Duke criteria found that emboli were more frequently observed in cases due to Streptococcus bovis and S. aureus by multivariate analysis [29] . Multivariate analysis identified vegetation size >10 mm and severe vegetation mobility as additional risk factors for embolic events that occurred in 28 patients after the initiation of antibiotic therapy.
• Embolization occurs more frequently with left-sided than right-sided vegetations [24] . In a review of 281 patients with clinically suspected IE, the incidence of embolic events was greater with mitral than aortic valve vegetations (25 versus 10 percent) [25] . The risk was highest with vegetations on the anterior mitral leaflet (37 percent), suggesting that the mechanical effects of broad and abrupt leaflet excursion may contribute to the risk of embolization [24] .
• A prospective study of patients with IE due to S. aureus suggested that the risk of embolization was significantly greater in patients who had visible vegetations by both TTE and TEE compared to patients who had vegetations visualized only by TEE [26] .
• The absence of valvular abnormalities on TTE may be associated with a decreased incidence of complications [27] .
• The presence of antiphospholipid antibodies were correlated with an increased risk of embolization (62 versus 23 percent) in a series of 91 patients with IE, perhaps due to increased endothelial cell activation, generation of thrombin, and defective fibrinolysis [28] .

Effect of prior antiplatelet therapy — The possible protective effect of prior antiplatelet therapy (one or more of aspirin, dipyridamole, clopidogrel, or ticlopidine) on embolism in IE was evaluated in a retrospective cohort of 600 patients with IE, 147 of whom (25 percent) had a symptomatic embolic event [30] . The patients who had received continuous daily antiplatelet therapy for at least six months prior to hospitalization for IE had a significantly lower rate of a symptomatic embolic event (12 versus 28 percent without such therapy, adjusted odds ratio 0.36, 95% CI 0.19-0.68). The presumed mechanism is that platelet aggregation plays a role in vegetation formation.

In contrast to prior therapy, the initiation of aspirin after the diagnosis of IE is of no benefit and may be harmful. This was illustrated in randomized trial in which 115 patients with IE were assigned to aspirin (325 mg/day) or placebo for four weeks [31] . Aspirin did not reduce the incidence of embolic events, was associated with a trend toward an increased incidence of bleeding (odds ratio 1.92, 95% CI 0.76-4.86), and had no effect on vegetation resolution or valve function.

NEUROLOGIC COMPLICATIONS — Neurologic complications rank second to cardiac in importance, occurring in approximately 25 to 35 percent of patients [15,32-36] , although a lower rate of 10 percent was noted in one series [37] . In a review of 260 nondrug addicts with IE due to Staphylococcus aureus, 91 patients (35 percent) developed neurologic manifestations including 61 (23 percent) who presented with these symptoms [34] . (See "Complications of Staphylococcus aureus bacteremia").

Manifestations — The mechanism for and types of neurologic complications are diverse and include:

• Embolic stroke
• Acute encephalopathy
• Meningoencephalitis
• Purulent or aseptic meningitis
• Cerebral hemorrhage (due to stroke or a ruptured mycotic aneurysm)
• Brain abscess or cerebritis
• Seizures (secondary to abscess or embolic infarction)

Neurologic complications may be the presenting symptom in patients with IE. In a series of 68 patients with stroke and endocarditis, for example, two-thirds presented to the hospital with stroke, before the diagnosis of endocarditis was made [37] . Thus, the possibility of IE should be considered in all patients who present with strokes, meningitis, or a brain abscess. Unexplained fever accompanying a stroke in a patient with valvular disease is an important clue in some patients. (See "Diagnostic approach to infective endocarditis").

Outcomes — Reported patient outcomes after a neurologic complication are variable. The following findings have been noted in different series:

• Among survivors of cardiac surgery for IE, 70 percent of patients with a preoperative stroke experienced a full neurologic recovery [36] . Outcomes were worse in patients with stroke complicated by meningitis, abscess, or intracerebral hemorrhage.
• Patient mortality in more contemporary series has varied from approximately 20 to 50 percent at one year [36,37] to as high as 74 percent (time of follow-up not given) in patients with Staphylococcus aureus endocarditis [34] .

One of the dilemmas that often arises is whether neurologic complications of IE are a contraindication to valve replacement. This important issue is discussed elsewhere. (See "Surgery for native valve endocarditis", section on Effect of recent cerebral embolization).

MYCOTIC ANEURYSMS — Mycotic aneurysms can occur in the cerebral or systemic circulation of patients with IE, usually at points of vessel bifurcation. (See "Mycotic aneurysms").

RENAL DISEASE — Renal infarction (due to emboli), drug-induced acute interstitial nephritis, glomerulonephritis (due to deposition of immunoglobulins and complement in the glomerular membrane) and, rarely, renal abscess can occur in patients with IE. (See "Renal disease in infective endocarditis").

Acute renal failure, defined as a serum creatinine of 2 mg/dL (177 µmol/L) or greater, has been reported in up to one-third of patients [38] . By contrast, chronic renal failure due to immune-complex mediated glomerulonephritis, which was a common contributing cause of death in patients who presented with classic IE in the preantibiotic era, is now rare. Immune complex-mediated renal disease is also uncommon in the antibiotic era, especially in patients whose infection is detected and treated early.

METASTATIC ABSCESSES — Rarely, metastatic abscesses develop in the kidneys, spleen, brain or soft tissues (eg, the psoas muscle) in the setting of IE. There is a strong association between IE and splenic abscess, even though otherwise splenic abscesses are less frequently observed than other types intraabdominal abscesses.

Patients with splenic abscesses usually do not have marked abdominal pain or splenomegaly; persistent fever during or after treatment for IE and occasionally recurrent bacteremia after cure of the valvular infection may be the only clue to the presence of this complication [39] . Splenic abscesses are often diagnosed only at autopsy and generally require splenectomy for cure. In one study of 27 patients with splenic abscesses, mortality was 100 percent in the patients who did not have a splenectomy compared to 18 percent in the patients who had the procedure [40] .

Discrete microabscesses or larger solitary brain abscesses can rarely occur in patients with IE. Abscess formation occurs as a sequela of septic embolization. Some patients with IE and brain abscesses also have purulent meningitis. In fact, the presence of meningitis due to S. aureus should suggest the possibility of concomitant S. aureus endocarditis. In one case series of 33 patients with S. aureus meningitis, seven (21 percent) also had endocarditis [41] .

Appropriate treatment, including drainage of such abscesses, is needed not only to control the local infection but also to prevent ongoing bacteremia, which is of particular concern among patients who may require surgical treatment of endocarditis with implantation of a prosthetic valve.

MUSCULOSKELETAL COMPLICATIONS — Vertebral osteomyelitis is a well known but relatively rare complication of IE. Although the majority of patients with IE and back pain do not have vertebral osteomyelitis, protracted, severe back pain in any patient with IE should alert the clinician to this possibility. Plain films are insensitive for diagnosing vertebral osteomyelitis, especially if taken early in the course of illness [42] . (See "Vertebral osteomyelitis"). Osteomyelitis more frequently complicates S. aureus endocarditis than IE due to other microorganisms [42] .

Acute septic arthritis, involving one or more joints, may be the first clue to the presence of IE in a small percentage of patients. IE should be strongly considered in selected cases of septic arthritis:

• When infections spontaneously arise in joints of the axial skeleton (eg, sacroiliac, pubic, or manubriosternal joints).
• When organisms with a known propensity to cause IE (eg, S. aureus, viridans streptococci or non-group A beta-hemolytic streptococci) grow from a joint aspirate, particularly in patients without a history of recent surgery, joint infection, or trauma.
• When multiple joints are infected.

COMPLICATIONS OF MEDICAL OR SURGICAL THERAPY — Patients with IE can develop a number of the complications associated with prolonged parenteral antimicrobial therapy or surgery:

• Aminoglycoside-induced ototoxicity or nephrotoxicity (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity")
• Secondary bacteremia due to central vascular lines (See "Pathogenesis of and risk factors for central venous catheter-related infections")
• Mediastinitis or early postoperative prosthetic valve endocarditis (See "Postoperative mediastinitis after cardiac surgery")
• Intravenous catheter-associated phlebitis
• Drug fever (See "Drug fever")
• Allergic or idiosyncratic reactions to various antimicrobial agents
• Bleeding due to disturbances in coagulation caused by anticoagulants (in prosthetic valve endocarditis)

MORTALITY — Multiple studies have evaluated death rates in patients with both native and prosthetic valve endocarditis [43-47] :

• The in-hospital mortality rate is between 18 and 23 percent
• The six month mortality rate is between 22 and 27 percent

The outcomes in patients with neurologic complications are described above. (See "Outcomes" above).

Predictors of death — Several studies have attempted to identify predictors of death in patients with IE. Each patient may have one or more of the following:

• Infection with S. aureus [44,46,48] , while mortality is lower with streptococcal infection (8 versus 33 percent with S. aureus in one series) [46]
• Heart failure [45,47]
• Diabetes mellitus [44]
• Embolic events [44,48]
• Perivalvular abscess [5,8,47]
• Vegetation size [29,48]
• Female gender [29]
• Contraindication to surgery [46]
• Low serum albumin [43]
• Persistent bacteremia [47]
• Abnormal mental status [46]
• Poor surgical candidacy [46]

All but two of the preceding studies [44,46] were retrospective. Because the clinical and echocardiographic features of patients with endocarditis change during the course of illness, some of the above findings should be interpreted with caution. In one of the reports using a prospective study design, neither heart failure as defined by the Framingham criteria nor cardiac surgery was independently associated with in-hospital mortality [44] . However, among patients with moderate to severe heart failure, cardiac surgery in other studies has been associated with a lower rate of long-term mortality compared to medical therapy alone. The data supporting this conclusion are presented separately. (See "Surgery for native valve endocarditis", section on Efficacy).

In view of the wide disparity in the methods used in the preceding studies, one should be cautious about making prognostic predictions in individual patients with IE.

Surgery for prosthetic valve endocarditis

2008-08-31T20:16:00.000-07:00

Surgery for prosthetic valve endocarditis

Author
Adolf W Karchmer, MD
Section Editor
Catherine M Otto, MD
Scott E Kasner, MD
Gabriel S Aldea, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Susan B Yeon, MD, JD, FACC

Last literature review version 16.2: May 2008 | This topic last updated: April 29, 2008 (More)

INTRODUCTION — Infection of a prosthetic heart valve can be difficult to diagnose and manage. Optimal treatment of prosthetic valve endocarditis (PVE) requires:

• Identification of the causative microorganism.
• Selection of a bactericidal antimicrobial regimen of proven efficacy.
• A clear understanding of the intracardiac pathology and attendant complications of PVE. (See "Presentation and diagnosis of prosthetic valve endocarditis").
• Surgical intervention in nearly all cases, especially that in which infection has extended beyond the valve to contiguous cardiac tissue.

The surgical management of prosthetic valve endocarditis will be reviewed here. The antimicrobial treatment of prosthetic valve endocarditis and the role of surgery in native valve endocarditis are discussed separately. (See "Antimicrobial therapy of prosthetic valve endocarditis" and see "Surgery for native valve endocarditis").

GENERAL PRINCIPLES — Cardiac surgery plays a major role in the effective therapy of many patients with PVE. Heart failure, persistent fever for 10 or more days despite appropriate antibiotic therapy, systemic embolization, and new onset electrocardiographic conduction abnormalities are associated with high mortality rates in patients with PVE and are clinical indications of invasive infection [1-4] . (See "Presentation and diagnosis of prosthetic valve endocarditis" and see "Surgery for native valve endocarditis").

Invasive infection is demonstrated far more predictably by transesophageal echocardiography than by a transthoracic evaluation. (See "Role of echocardiography in infective endocarditis").

Invasive infection is common in PVE, especially when infection arises within 12 months of surgery or involves an aortic prosthesis [2] . For patients with complicated PVE, the survival rates are higher among surgically than medically treated patients, and relapses, rehospitalization for valve surgery, and delayed mortality due to endocarditis are less common among those treated surgically [2,3,5-7] .

INDICATIONS — Indications for cardiac surgery in patients with PVE have been developed based upon the intracardiac pathology of PVE and the risk of recrudescent infection on the new prosthesis. The 2006 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the management of valvular heart disease included recommendations for surgery in patients with prosthetic and native valve endocarditis (show table 1A-1B) [8] .

Some of the indications for surgical treatment are absolute, while others are relative and require careful risk benefit analysis. Persistent bacteremia despite optimal antimicrobial treatment requires surgical intervention.

A multicenter prospective study of 104 patients with PVE examined the influence of medical versus surgical therapy on outcome in order to identify patients for whom surgery may be beneficial [9] . Multivariate analysis identified the following independent predictors of in-hospital mortality:

• Severe heart failure (odds ratio [OR] 5.5; 95% CI, 1.9-16.1)
• S. aureus infection (OR 6.1; 95% CI, 1.9-19.2)

Independent predictors of long-term mortality (32 month follow-up) included:

• Comorbidity (risk ratio [RR] 3; 95% CI, 1.4-6.6)
• Early PVE (<60 days post-surgery, RR 2.1; 95% CI, 1.1-4.3)
• Severe heart failure (RR 4.2; 95% CI, 2.2-8.0)
• Staphylococcus infection (RR 2.0; 95% CI, 1.0-4.0)
• New prosthetic dehiscence (RR 2.4; 95% CI, 1.3-4.7)

Mortality was not significantly different between surgical and nonsurgical patients overall (17 versus 25 percent), however, in-hospital mortality was reduced by a surgical approach in patients with staphylococcal (27 versus 73 percent) or complicated PVE (18 versus 48 percent).

An international multi-center prospective study of 355 patients with prosthetic valve endocarditis found the following variables independently associated with surgical therapy: intracardiac abscess, heart failure, younger age, coagulase negative staphylococci, and S. aureus. Unadjusted in-hospital mortality rates in this study were similar for surgical and medical treatment, 25 and 23 percent, respectively. When a propensity analysis was performed to compare surgically treated patients with a population of medically treated patients selected to have similar clinical features, there was a trend toward reduced in-hospital mortality with surgical treatment (OR 0.51; 95% CI 0.23-1.36). A similar trend was noted when all patients with high propensity score for cardiac surgery were examined [10] .

In contrast, antibiotic therapy alone is often successful in patients with PVE who have no evidence of heart failure, significant prosthetic valve dysfunction, or invasive infection, and who are infected by less virulent organisms. These patients are characterized by later onset of infection (more than 12 months after prosthesis implantation), and infection by viridans streptococci, HACEK, or enterococci (that can be treated with bactericidal therapy) [9,11,12] .

Valve dysfunction — The outcome of PVE in patients who experience moderate to severe heart failure due to prosthesis dysfunction is improved if patients are treated surgically. Few survive beyond six months if treated with antibiotics alone, whereas 44 to 64 percent survive with timely surgical intervention [1,3,11,13,14] .

An unstable hypermobile prosthesis due to dehiscence of anchoring sutures is a surgical emergency, requiring urgent intervention, because the valve is likely to become increasingly unstable with acute severe valve regurgitation.

As with NVE, surgical intervention to correct valve dysfunction and heart failure must be performed before it becomes severe and intractable. There is no evidence that delaying surgery in this setting improves outcome or reduces the frequency of recurrent endocarditis [15-17] . In fact, the operative mortality of these patients is proportional to the severity of hemodynamic disability at the time of surgery [15,18] .

Patients with PVE complicated by perivalvular invasion experience high mortality rates and are rarely curable with medical treatment alone. By contrast, complex reconstructive procedures have been associated with survival rates of 80 percent [6,19] . Echocardiographic findings are enhanced with transesophageal (versus transthoracic) but can still be limited by "shadowing" from prosthetic valve sewing rings. Echocardiographic findings of perivalvular invasion include [1,2] :

• Valve dehiscence
• Paravalvular abscess
• Aortic aneurysm or pseudoaneurysm
• Fistula formation

Relapse after optimal medical therapy — If PVE relapses after appropriate antimicrobial therapy, surgical intervention should usually be performed since relapses often reflect unrecognized perivalvular infection [1,2] .

Microorganisms usually requiring surgery — Retrospective studies suggest that S. aureus PVE is associated with significant mortality, up to 70 percent in patients treated with antibiotics alone [20-24] . While mortality outcomes in patients who had surgery in these studies have varied, intracardiac complications in patients with S. aureus PVE are consistently associated with an increased mortality and surgical intervention reduces mortality in this group. In one study, for example, mortality was reduced 20-fold by surgical intervention during antimicrobial therapy (odds ratio [OR] 0.5, 95% CI 0.005-0.42) [23] . Multiple studies have concluded that PVE caused by S. aureus is most effectively treated by antibiotics and prompt surgical intervention [3,9,20,21,25] .

Another study, while not finding an improvement in overall mortality with surgical treatment of S. aureus PVE, noted that patients who developed cardiac complications defined as heart failure and/or intracardiac abscess (a group that would be considered at high risk for endocarditis related death) and underwent early valve replacement had the lowest mortality rate (28.6 percent) [24] .

Early surgical intervention is considered by most experts to be a standard element of treatment for fungal PVE [26] . Among 15 patients with fungal PVE treated with antifungal agents and with surgery, 10 (67 percent) survived with an average follow-up of 4.5 years [27] . One review of 17 patients suggested that survival rates for Candida PVE were comparable with and without surgery (46 versus 50 percent) [28] . However, only patients with uncomplicated PVE survived in this review, and many remained on long term suppressive oral therapy. Patients who have fungal PVE have significant co-morbidities (such as end-stage renal disease on hemodialysis or immunosuppressed states from chemotherapy or HIV for example). Timing and duration of medical therapy and surgical intervention are frequently complex.

Some other pathogens, such as P. aeruginosa and probably multi-resistant enterococci for which there is no synergistic bactericidal regimen, are also less amenable to medical therapy. Surgery is generally advised for PVE caused by these microorganisms.

Embolization — The frequency of embolic complications is higher in patients with NVE who have vegetations exceeding 10 mm in diameter compared to those with smaller vegetations. Comparable data are not available for patients with PVE. However, the overall rate of embolic complications is similar for patients with PVE and NVE, and emboli decrease rapidly with effective therapy in both [29] . While prevention of emboli that cause highly morbid, irreversible end-organ damage (eg, central nervous system and myocardial infarction) is a laudable goal, it has not been established that surgical intervention achieves this aim in patients with PVE, large vegetations, and no other complications. The risk of emboli in this setting, rather than constituting an indication for surgery, should be weighed with other findings that might benefit from surgical intervention and then factored into the overall management plan. Recurrent emboli despite appropriate antibiotic therapy are an indication for surgical intervention.

OUTCOME — Complex reconstruction of the aortic or mitral valve apparatus and the supporting structures is often required to achieve an optimal outcome of PVE [19,30-32] . In the hands of experienced cardiac surgeons, operative mortality rates for patients with invasive PVE, treated with valve replacement and surgical reconstruction of paravalvular tissue, range from 10 to 30 percent; in contrast the projected mortality would approach 100 percent without surgery [6,19,30-33] . These data suggest that surgical intervention for PVE complicated by extensive invasion and tissue disruption should be performed in centers with extensive experience, when possible. Earlier surgical reintervention in patients with invasive organisms may also significantly limit morbidity by avoiding the need for complex reconstructions (such as root replacement for annular abscess or atrial-ventricular reconstructions for mitral valve prosthetic valve endocarditis).

The rate of recrudescent PVE after surgery is six to 15 percent; repeat surgery is required for recurrent PVE or for dysfunction of the newly implanted prosthesis in 18 to 26 percent [2,6,15,19,30,33] . While these figures are not insignificant, they are relatively small compared with the anticipated mortality with antibiotic therapy alone. Five-year survival rates ranging from 54 to 82 percent have been reported for patients undergoing surgery for PVE [15,19,30,32,34] .

ANTIBIOTIC TREATMENT FOLLOWING SURGERY — Following valve replacement for active bacterial endocarditis, the Task Force on Infective Endocarditis of the European Society of Cardiology (ESC) recommends another full course (six weeks) of antimicrobial treatment if the intraoperative valve culture is positive [35] . If the culture is negative, the ESC recommends that the full treatment course be completed (counting the duration of preoperative antibiotics).

ANTICOAGULANT THERAPY — Among patients with prosthetic valve IE, the potential benefit of preventing embolization with anticoagulation must be weighed against the increased risk of intracerebral hemorrhage. This issue is discussed in detail separately. (See "Anticoagulant and antiplatelet therapy in patients with infective endocarditis").

SUMMARY AND RECOMMENDATIONS

• Treatment of prosthetic valve endocarditis is more difficult than treatment of native valve endocarditis and often requires surgical replacement of the prostheses in addition to antibiotic therapy. (See "Introduction" above).
• Invasive infection is common in PVE, especially when infection arises within 12 months of surgery or involves an aortic prosthesis. (See "General principles" above).
• Some of the indications for surgical treatment are absolute, while others are relative and require careful risk benefit analysis (show table 1A). (See "General principles" above).
• The outcome of PVE in patients who experience moderate to severe heart failure due to prosthesis dysfunction or who have evidence of valve dehiscence, paravalvular abscess, or fistula formation is improved if patients are treated surgically. There is no evidence that delaying surgery in this setting improves outcome or reduces the frequency of recurrent endocarditis. (See "Valve dysfunction" above).
• Surgery is generally advised for PVE caused by S. aureus when accompanied by intracardiac complications, and also for fungi, gram-negative (nonHACEK) microorganisms (particularly P. aeruginosa), and multi-drug resistant enterococci. (See "Microorganisms usually requiring surgery" above).
• In the hands of experienced cardiac surgeons, operative mortality rates for patients with invasive PVE, treated with valve replacement and surgical reconstruction of paravalvular tissue, range from 10 to 30 percent; in contrast the projected mortality approaches 100 percent without surgery. (See "Outcome" above).
• The rate of recurrent PVE after surgery is six to 15 percent. (See "Outcome" above).

Diagnostic approach to infective endocarditis

2008-08-31T19:12:00.000-07:00

http://www.uptodateonline.com/online/content/topic.do?topicKey=endocard/6293&selectedTitle=10~150&source=search_result

Diagnostic approach to infective endocarditis

Author
Daniel J Sexton, MD
Section Editor
Catherine M Otto, MD
Deputy Editor
Elinor L Baron, MD, DTMH

Last literature review version 16.2: May 2008 | This topic last updated: March 21, 2008 (More)

INTRODUCTION — The diagnosis of infective endocarditis (IE) is usually based upon a constellation of clinical findings rather than a single definitive test result. The diagnosis is usually obvious when a patient has the characteristic findings of IE:

• Numerous positive blood cultures in the presence of a well recognized predisposing cardiac lesion
• Evidence of endocardial involvement

However, some patients with IE do not have positive blood cultures (ie, culture-negative endocarditis), and approximately one-third to one-fourth of patients have no identifiable predisposing cardiac lesion at disease onset. The presence of atypical features may result in misdiagnosis or a correct diagnosis that is greatly delayed. (See "Culture-negative endocarditis" below).

The general approach to the diagnosis of IE will be reviewed here. Risk factors for IE and antibiotic prophylaxis and treatment of IE are discussed separately. (See "Infective endocarditis: Epidemiology and risk factors" and see "Antimicrobial prophylaxis for bacterial endocarditis" and see "Antimicrobial therapy of native valve endocarditis" and see "Antimicrobial therapy of prosthetic valve endocarditis").

DIAGNOSTIC CRITERIA — The diagnosis of IE is based upon a careful history and physical examination, blood culture and laboratory results, an electrocardiogram (ECG), a chest radiograph, and an echocardiogram.

Debate persists as to the optimal case definition for IE. Practical and logical case definitions are important since underdiagnosis can lead to clinical catastrophe and death, while overdiagnosis can result in weeks of unnecessary antimicrobial therapy with excessive costs and potentially avoidable drug-related side effects. It can, for example, be difficult to distinguish between IE and an alternate source of infection in a bacteremic patient with underlying heart disease.

Several sets of criteria for IE have been described. The most commonly accepted are the Duke criteria (show table 1 and show table 2 and show Calculator). (See "Infective endocarditis: Historical and Duke criteria", section on Duke criteria).

HISTORY — During the initial assessment of patients with suspected endocarditis, a careful history should be performed with special attention given to a history of prior cardiac lesions and historical clues pointing toward a recent source of bacteremia, such as indwelling intravascular catheters or intravenous drug use.

PHYSICAL EXAMINATION — The physical examination should include a careful cardiac examination for signs of new regurgitant murmurs or heart failure (see "Auscultation of cardiac murmurs").

A vigorous search should be undertaken for the classic clinical stigmata of endocarditis, including evidence of small and large emboli with special attention to the fundi, conjunctivae, skin, and digits. A neurologic evaluation may reveal evidence of focal neurologic impairment; it can also be used as a baseline examination should such abnormalities appear later. (See "Complications and outcome of infective endocarditis").

Associated peripheral cutaneous or mucocutaneous lesions of IE include petechiae, splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth spots. Petechiae are not specific for IE but are its most common skin manifestation. They may be present on the skin, usually on the extremities, or on mucous membranes such as the palate or conjunctivae, the latter usually as hemorrhages best seen with eversion of either upper or lower eyelids. Splinter hemorrhages, also nonspecific for endocarditis, are nonblanching, linear reddish-brown lesions found under the nail bed (show picture 1).

Janeway lesions, Osler's nodes, and Roth spots are more specific (but still not diagnostic) for IE. They are also less common, and Roth spots are rare.

• Janeway lesions are macular, blanching, nonpainful, erythematous lesions on the palms and soles (show picture 2).
• Osler's nodes are painful, violaceous nodules found in the pulp of fingers and toes and are seen more often in subacute than acute cases of IE (show picture 3).
• Roth spots are exudative, edematous hemorrhagic lesions of the retina.

In addition to these physical findings, patients with IE may have involvement of other organs due to embolic events (eg, focal neurologic deficits, renal and splenic infarcts) or a systemic immune reaction (eg, glomerulonephritis, arthritis). In right-sided endocarditis, septic pulmonary infarcts may be seen (show picture 4). (See "Complications and outcome of infective endocarditis" and see "Renal disease in infective endocarditis").

LABORATORY STUDIES

Blood cultures

Collection — Blood cultures should be obtained prior to antibiotic therapy. This was illustrated in a prospective study of 348 patients with suspected culture-negative endocarditis; among the 73 patients without an identifiable etiologic agent, 58 (79 percent) received antibiotics before blood cultures were obtained [9] .

A minimum of three blood cultures should be obtained over a time period based upon the severity of the illness. If the tempo of illness is subacute and the patient is not critically ill, it is reasonable and often preferable to delay therapy for one to three days while awaiting the results of blood cultures and other diagnostic tests. However, if the patient is acutely ill, three blood cultures should be obtained over a one hour time span before beginning empiric therapy. Almost all cases of bacterial IE are due to aerobic organisms; thus, culturing for anaerobes is rarely useful. (See "Blood cultures for the detection of bacteremia").

The additional diagnostic yield of more than three cultures is minimal in patients who have not recently received antimicrobial therapy. In a series of 206 cases of endocarditis, for example, the initial blood culture in patients with streptococcal endocarditis was positive in 96 percent and one of the first two blood cultures was positive in 98 percent; in patients with IE caused by bacteria other than streptococci, the first blood culture was positive in 82 percent and one of the first two cultures was positive in 100 percent [1] . Additional blood cultures are occasionally useful in patients who have been treated recently with antibiotics.

The bacteriologic diagnosis of IE is facilitated by the relative constancy, rather than random, release of bacteria from the cardiac vegetations [2] . However, since many patients with bacterial endocarditis have low grade bacteremia (eg, 1 to 10 CFU/mL of blood) [1] , a minimum of 10 mL (and preferably 20 mL) of blood should be obtained from adults and 0.5 to 5 mL from infants and children. In one study, blood cultures inoculated with at least 5 mL of blood had a significantly higher detection rate for bacteremia than bottles inoculated with less than 5 mL of blood (92 versus 69 percent) [3] . The estimated yield of blood cultures in bacteremic adults increased approximately 3 percent per mL of blood cultured.

Each set of cultures should be obtained from separate venipuncture sites. Blood cultures can be taken at any time; they do not need to be obtained with the appearance of chills or fever since patients with IE typically have a continuous bacteremia. (See "Blood cultures for the detection of bacteremia").

Organism — Not all microorganisms have the same propensity to cause endocarditis. As an example, organisms such as viridans streptococci and Staphylococcus aureus are more likely to cause endocarditis than are gram-negative rods such as Escherichia coli and Proteus spp. This distinction is important. The Duke Criteria for the diagnosis of endocarditis define the following organisms as "typical causes" of IE (show table 1 and show table 2) [4] :

• Staphylococcus aureus
• Viridans streptococci and Streptococcus bovis
• Enterococci
• HACEK group organisms (show table 2)

It was previously thought that patients who present with community-acquired enterococcal bacteremia are significantly more likely to have endocarditis than patients who develop enterococcal bacteremia while hospitalized for another cause [5] . However, this conclusion has been questioned as a result of a case-control study that compared the clinical and demographic characteristics of all patients with enterococcal endocarditis seen at a single center over eight years with controls randomly chosen from 455 patients with enterococcal bacteremia without endocarditis [6] . Community acquisition of bacteremia was not a risk factor for IE.

The probability of endocarditis varies by species of bacteria. As examples:

• S. sanguis bacteremia is more often indicative of endocarditis than is bacteremia due to S. milleri (also known as S. anginosus).
• Bacteremia with groups A or C streptococci are seldom associated with IE whereas group G streptococcal infection is often indicative of endocarditis [7] . (See "Group C and group G streptococcal infection").
• In a study of enterococcal bacteremia cited above, infection with E. faecalis, compared to other enterococcal species, was associated with IE by both univariate and multivariate analysis [6] .

The risk of endocarditis in patients with S. aureus bacteremia (regardless of source or residence at the time of onset) is particularly high. As a result, all patients with S. aureus recovered from the blood should be clinically evaluated for IE. (See "Complications of Staphylococcus aureus bacteremia").

Positive cultures — The interpretation of positive blood cultures in patients with suspected endocarditis is confounded by the fact that false-positive results occasionally occur despite use of the most exacting techniques for collection and processing. When organisms such as Propionibacterium spp., Corynebacterium spp., Bacillus spp., and coagulase-negative staphylococci are recovered from a single blood culture or a minority of blood culture bottles, the result is probably falsely positive. However, since all of these organisms are capable of causing endocarditis, it is important to determine if the bacteremia is persistent. (See "Endocarditis due to coagulase-negative staphylococci").

The definition of persistent bacteremia varies with the likelihood that the organism is a cause of endocarditis [4] :

• For an organism likely to cause endocarditis (eg, S. aureus, viridans streptococci), two positive samples collected more than 12 hours apart
• For an organism that is more commonly a skin contaminant, three or a majority of four or more separate blood cultures are positive and the first and last samples are collected at least one hour apart

Additional tests — The utility of other laboratory tests in the diagnosis of endocarditis is limited, other than the finding of an antiphase I IgG titer >1:800 for Coxiella burnetii [8] .

The following findings may be identified among patients with IE but are relatively nonspecific:

• An elevated erythrocyte sedimentation rate and/or an elevated level of C-reactive protein.
• A normochromic normocytic anemia.
• The white blood cell count may be normal or elevated in patients with subacute presentations of endocarditis; however, most patients with staphylococcal endocarditis have leukocytosis and some may have thrombocytopenia.
• Hyperglobulinemia, cryoglobulins, circulating immune complexes, hypocomplementemia, elevated rheumatoid factor titers, and false positive serologic tests for syphilis all occur in some patients.

An elevated rheumatoid factor titer in patients without a known prior rheumatologic disorder is one of six minor criteria in the Duke diagnostic scheme (show table 2) [4] . (See "Origin and utility of measurement of rheumatoid factors").

Most patients with endocarditis have an abnormal urinalysis, as manifested by microscopic or gross hematuria, proteinuria, and/or pyuria. Each of these findings lacks specificity. However, the presence of red blood cell casts on urinalysis is generally indicative of glomerulonephritis (often in association with hypocomplementemia) and is a minor diagnostic criterion for IE (show table 2) [4] . (See "Renal disease in infective endocarditis").

Electrocardiogram — We recommend that a baseline electrocardiogram be performed as part of the initial evaluation of all patients with suspected endocarditis even though this test rarely shows diagnostic findings. The presence or subsequent appearance of changes suggestive of ischemia or infarction on the electrocardiogram may provide useful clues to the presence of emboli to the coronary circulation. In addition, the initial presence or new appearance of heart block or conduction delay may provide an important clue to extension of infection to the valve annulus and adjacent septum. (See "Complications and outcome of infective endocarditis").

Chest radiograph — Chest radiographs occasionally reveal important diagnostic clues. As an example, patients with tricuspid valve endocarditis often present with radiographic evidence of septic pulmonary emboli. In such cases, there may be a few or multiple focal lung infiltrates, which may reveal central cavitation. Rarely, chest radiographs show calcification in a cardiac valve, which may raise suspicions of endocarditis in a febrile patient.

Echocardiography — The 2006 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the management of patients with valvular heart disease included recommendations for the use of transthoracic and transesophageal echocardiography in patients with suspected or proven native or prosthetic valve endocarditis (show table 3) [10] . These recommendations are generally consistent with the 2005 AHA guidelines on infective endocarditis, which were endorsed by the Infectious Diseases Society of America [11] .

The information that can be obtained by echocardiography includes:

• Evaluation of patients in settings in which endocarditis is suspected (such as persistent bacteremia without a known source or high clinical suspicion with negative cultures)
• Detection and characterization of vegetations on valves and in other sites (as in patients with congenital heart disease)
• Detection of valvular dysfunction and assessment of hemodynamic severity
• Detection of associated abnormalities such as shunts or abscesses
• Re-evaluation of patients in complex settings (such as those with virulent organisms, severe hemodynamic effects, persistent or recurrent fever or bacteremia, or clinical deterioration)

An echocardiogram should be performed in all patients with a moderate or high suspicion of endocarditis (show table 1 and show table 2). In comparison, among patients with a low clinical probability of endocarditis, the diagnostic yield of both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) is very low, and neither should be performed [12] . (See "Infective endocarditis: Historical and Duke criteria", section on Case definitions).

Role of TTE — Transthoracic echocardiography may provide confirmation of the diagnosis of endocarditis. Detection of a vegetation is a positive test show echocardiogram 1 show echocardiogram 2 show echocardiogram 3. (See "Role of echocardiography in infective endocarditis").

However, TTE has relatively low sensitivity for vegetation in IE (29 to 63 percent in different series) [13-15] . Thus, the absence of vegetation does not preclude the diagnosis and, as described in the next section, TEE is usually warranted. However, the finding of normal valves (both morphology and function) substantially reduces the probability of IE. In one study, 96 percent of patients with normal valves and no vegetation on TTE also had a negative TEE [16] .

In contrast to the variable sensitivity, TTE has a specificity (the likelihood of a negative result in a patient without disease) approaching 100 percent, indicating very few false positive studies [13] .

Role of TEE — Transesophageal echocardiography has a higher spatial resolution than TTE and is much more sensitive for the detection of endocarditis show echocardiogram 4 show echocardiogram 5. TEE is especially useful for the detection of vegetations, diagnosis of prosthetic valve endocarditis, detection of a valve abscess, and assessment of embolic risk.

• Detection of vegetations — Two series with a total of 162 episodes of suspected IE demonstrated the greater sensitivity of TEE compared to TTE (100 versus 63 percent and 94 versus 44 percent, respectively) [13,14] . In a third report of 103 patients with S. aureus bacteremia, TTE revealed valvular abnormalities in 33 patients and vegetations in seven; in contrast, TEE identified vegetations in 22 patients and abscesses in two [15] .
• Diagnosis of IE on prosthetic valves — TEE is especially important for prosthetic valves in the mitral or aortic position, because acoustic shadowing frequently makes the transthoracic approach suboptimal. TEE has superior spatial resolution, and bacteremic patients with these prostheses are at increased risk for endocarditis show echocardiogram 6. Few data are available regarding the superiority of TEE for suspected endocarditis of tricuspid and pulmonic prostheses, but presumably it would be similar. (See "Role of echocardiography in infective endocarditis", section on Prosthetic valve endocarditis).

The greater value of TEE in patients with prosthetic heart valves was demonstrated in a prospective study that compared TTE and TEE in 114 episodes of IE suspected on clinical grounds (80 on native valves and 34 on prosthetic valves) [17] . The results of the two tests were concordant in 55 percent of cases; TEE led to a reclassification in 11 percent of patients with native valves and 34 percent with prosthetic valves.

The negative predictive value of TEE is nearly 100 percent for patients with native valves, but IE can be missed in patients with prosthetic valves. In the latter patients, clinical assessment is especially important.

• Detection of a valve abscess — TEE is much more sensitive than TTE for the detection of valve abscess. This was illustrated in a series of 44 patients with IE complicated by abscess formation (sensitivity 87 versus 28 percent with TTE) [18] .

While TEE is generally much more sensitive than TTE for detection of abscess, even TEE may miss a significant number of abscesses in some populations. This was illustrated in a report of 44 patients with endocarditis by Duke criteria who had valvular abscesses identified intraoperatively. Endocarditis was detected by TEE in only 48 percent of cases; prosthetic heart valves were present in 32 percent of patients. Indications for surgery included severe valvular dysfunction (with or without heart failure), embolization during antibiotic therapy, or concommitant pacemaker infection [19] . Abscesses not visualized by TEE were located at the posterior mitral annulus in 61 percent of cases; the majority of these were associated with a large calcification, which may have interfered with detection.

• Assessment of embolic risk — In general, larger vegetation size is associated with increased risk of embolization. This issue is discussed separately. (See "Role of echocardiography in infective endocarditis" section on Echocardiographic estimation of outcome).

Recommended use — We generally perform a TTE as the first diagnostic test in most patients with suspected IE. However, it is reasonable to begin with TEE in selected settings:

• Limited transthoracic windows (eg, due to obesity, chest wall deformity, or mechanical ventilation)
• Prosthetic valves, especially prosthetic aortic or mitral valves in which shadowing may make visualization difficult by TTE
• A prior valvular abnormality (including previous endocarditis)
• S. aureus bacteremia [15]
• Bacteremia due to an organism known to be a common cause of IE such as viridans streptococci

For patients with a normal TTE (both morphology and function), the likelihood of IE is very low [16] . A subsequent TEE is not necessary unless one or more of the following is present:

• A high clinical suspicion of IE (persistently positive blood cultures and/or multiple minor criteria for endocarditis) (show table 1 and show table 2)
• A technically limited TTE study

Some patients with abnormal on findings on TTE may require further evaluation by TEE. These include patients with significant valvular regurgitation in whom surgery is contemplated and patients who have one or more of the following risk factors for paravalvular abscess:

• Conduction delay by ECG that is not known to be old
• Persistent fever despite appropriate antimicrobial therapy
• Aortic valve endocarditis

(See "Complications and outcome of infective endocarditis", section on Paravalvular abscesses).

Controversies — There are a number of unresolved controversies related to the use of echocardiography in the diagnosis and management of patients with IE:

• Some experts recommend that all patients with suspected IE, especially those with staphylococcal bacteremia should have a TEE as the initial study [20] . However, we regard the steps outlined above as sufficient to exclude IE without TEE in many cases, and do not require that all patients undergo this invasive procedure.
• Some experts believe that patients with staphylococcal bacteremia associated with a condition (such as vertebral osteomyelitis) that will require a protracted course of antimicrobial therapy do not require echocardiography to rule out associated IE, especially if there are no hemodynamic signs or symptoms of IE. However, we recommend that echocardiography be performed in such patients, since a positive result will influence the type and intensity of follow-up examinations. (See "Complications and outcome of infective endocarditis").
• On theoretical grounds, some physicians delay echocardiography for several days after the onset of bacteremia, because both TTE and TEE can be falsely negative if vegetations are small (and, occasionally, if previously present vegetations have embolized). In addition, even TEE can miss a paravalvular abscess, especially if the study is done in the first few days of illness [21] .

The 2005 AHA guidelines on the diagnosis and management of IE, which were endorsed by the Infectious Diseases Society of America, recommend that echocardiography be performed as soon as possible after the diagnosis of IE is suspected [11] .

Histologic examination — Histologic demonstration of microorganisms, vegetations, or active endocarditis in cardiac valve tissue obtained at surgery is included in the Duke criteria and is considered to be a criterion of confirmed infective endocarditis (show table 1). The histologic features that characterize endocarditis were defined in a retrospective pathologic analysis of tissue adjoining mechanical cardiac valves in 90 patients who underwent surgical removal of a mechanical valve for suspected IE (21 patients) or noninfectious dysfunction (69 patients) [22] .

IE was characterized by microorganisms, vegetations, and significant neutrophil-rich inflammatory infiltrates with extensive neovascularization. In contrast, tissue adjoining valves from noninfectious complications showed extensive fibrosis and, when present, inflammatory infiltrates that were mainly composed of macrophages and lymphocytes.

Thus, when no microorganisms are detected and vegetations are lacking in tissue adjacent to a mechanical valve, neutrophil-rich inflammation and extensive neovascularization may allow differentiation between IE and inflammatory noninfectious valve processes in patients with mechanical cardiac valves who undergo surgery.

CULTURE-NEGATIVE ENDOCARDITIS — Culture-negative endocarditis should be considered in patients with negative blood cultures and persistent fever with one or more clinical findings consistent with IE (eg, stroke or other manifestations of emboli). Culture-negative IE should also be considered in patients with a vegetation on echocardiogram with no clear microbiologic diagnosis. Issues related to culture-negative IE are discussed separately. (See "Culture-negative endocarditis").

TREATMENT — Standard antimicrobial therapy for infective endocarditis is generally administered to patients characterized as definite or probable by the Duke criteria. Patients in whom the diagnosis is "rejected" by these criteria are not usually treated with prolonged antimicrobial therapy. (See "Antimicrobial therapy of native valve endocarditis").

SUMMARY

• The diagnosis of infective endocarditis (IE) is usually based upon a constellation of history, clinical findings, laboratory studies (particularly blood cultures), and echocardiography. (See "Introduction" above).
• Physical examination findings supporting a diagnosis of IE include new regurgitant murmurs or heart failure, evidence of embolic events (eg, focal neurologic impairment, glomerulonephritis, renal and splenic infarcts, and septic pulmonary infarcts), and peripheral cutaneous or mucocutaneous lesions (eg, petechiae, conjunctival or splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth spots). (See "Physical examination" above).

As part of the initial evaluation of all patients with suspected endocarditis the following studies should be performed:

- At least three blood cultures from separate sites over a time period ranging from a few hours to one to two days depending upon the severity of illness and urgency of the need for treatment. (See "Blood cultures" above).

- An electrocardiogram to evaluate for the presence of changes suggestive of ischemia or infarction or the presence or new appearance of heart block or conduction delay. (See "Electrocardiogram" above).

- Echocardiography. (See "Echocardiography" above).

Cultures remain negative in 2 to 5 percent of patients with endocarditis, which is referred to as culture-negative endocarditis. (See "Culture-negative endocarditis").

Presentation and diagnosis of prosthetic valve endocarditis

2008-08-31T17:47:00.000-07:00

http://www.uptodateonline.com/online/content/topic.do?topicKey=endocard/4909&selectedTitle=37~150&source=search_result

Presentation and diagnosis of prosthetic valve endocarditis

Author
Adolf W Karchmer, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Elinor L Baron, MD, DTMH

Last literature review version 16.2: May 2008 | This topic last updated: May 16, 2007 (More)

INTRODUCTION — Prosthetic valve endocarditis is a serious problem with potentially fatal consequences [1] . (See "Complications and outcome of infective endocarditis", section on Mortality).

The pathogenesis, microbiology, pathology, clinical features and diagnosis of prosthetic valve endocarditis (PVE) will be reviewed here. The antimicrobial and possible surgical treatment and prevention of PVE are discussed separately. (See "Antimicrobial therapy of prosthetic valve endocarditis" and see "Surgery for prosthetic valve endocarditis").

PATHOGENESIS — PVE can arise early or late after surgery. The timing of the infection reflects different pathogenic mechanisms that, in turn, influence the epidemiology, microbiology, pathology and clinical manifestations of the infection.

Early infection — Microorganisms can reach the valve prosthesis by direct contamination intraoperatively or via hematogenous spread during the initial days and weeks after surgery. These pathogens have direct access to the prosthesis-annulus interface and to perivalvular tissue along suture pathways because the valve sewing ring, cardiac annulus, and anchoring sutures are not endothelialized early after valve implantation. These structures are coated with host proteins, such as fibronectin and fibrinogen, to which some organisms can adhere and initiate infection.

Late infection — As the sewing ring, sutures, and adjacent tissues become endothelialized over the months after valve replacement, sites for adherence of microorganisms and access to host tissues adjacent to the prosthesis are altered. The pathogenesis of late PVE has been postulated to resemble native valve endocarditis (NVE). (See "Pathogenesis of vegetation formation in infective endocarditis").

Platelet-fibrin thrombi probably form on the prosthesis and serve as sites for the organisms to adhere and cause infection. Thus, the pathogens producing PVE tend to be bacteremic isolates with the ability to adhere to these thrombi and are similar to organisms inducing NVE. Unless the infecting organism is Staphylococcus aureus or another highly virulent or invasive pathogen, the perivalvular tissues are less likely to be affected in late PVE since endothelialization limits access to these tissues. Later onset infections tend to be less invasive, are less often complicated by perivalvular abscess formation and valve dehiscence, and are more commonly restricted to the sewing ring or the bioprosthetic leaflet.

However, the leaflets of porcine bioprosthetic valves experience age-related alterations in their surface characteristics. These aging leaflets become sites for platelet-fibrin thrombus deposition and subsequent infection. As a result, the infection rates on bioprostheses increase during this later period when compared to mechanical valves [2-4] .

EPIDEMIOLOGY — The risk of developing PVE, typically expressed as a hazard function or the likelihood of infection at a given point in time, is not uniform after valve replacement. The risk is greatest during the initial three months after surgery, remains high through the sixth month, and then falls gradually with an annual rate of approximately 0.4 percent from 12 months postoperatively onward for the life of the valve recipient [3,5-8] . The percentage of patients developing PVE during the initial year after valve replacement ranges from one to three percent in studies with active follow-up; by five years, the cumulative percentage ranges from three to six percent (show table 1).

Although conclusions vary among studies, infection generally occurs with equal frequency at aortic and mitral sites and on mechanical and bioprosthetic devices during the first postoperative year [3-6,9,10] . As noted above, bioprosthetic valves carry a greater risk for infection than mechanical after the first 18 months [2-4] . When a valve is replaced in a patient with endocarditis, whether the infection was active or healed at the time of surgery, there is an increased risk for both early (some of which is recrudescence of active endocarditis) and late PVE [2,4,6,8] .

Healthcare associated infection — Some cases of prosthetic valve endocarditis result from infection acquired in healthcare settings, both inpatient (nosocomial) and outpatient (non-nosocomial). The relative frequency of health care-associated PVE was evaluated in a prospective, observational cohort multinational study of 556 patients with PVE [1] . Non-nosocomial health care-associated infection was defined as PVE diagnosed within 48 hours of admission in an outpatient with extensive healthcare contact, as defined by:

• Intravenous therapy, wound care, or specialized nursing care at home, or intravenous chemotherapy within the prior 30 days
• Residence in a nursing home or other long-term care facility
• Hospitalization in an acute care hospital for two or more days within the prior 90 days
• Attendance at a hospital or hemodialysis clinic within the prior 30 days

Healthcare-associated infection was present in 37 percent of cases: 70 percent were labeled as nosocomial and 30 percent as outpatient acquired. Approximately 70 percent of the health care-associated infections were diagnosed within the first year after valve implantation, with the majority occurring within the first sixty days. S. aureus was the most common organism, being identified as the pathogen in 34 percent of cases.

Nosocomial bacteremia occurring in patients with prosthetic valves carries a significant risk for seeding the prosthesis. Among 115 prosthetic valve recipients experiencing nosocomial bacteremia that was judged not to be the sentinel event of endocarditis, 18 (16 percent) developed PVE with the bacteremic organism between seven and 170 days thereafter (median interval 28 days) [11] . Similarly, among 37 prosthetic valve patients with postoperative candidemia without evidence of endocarditis, fungal endocarditis developed in four (11 percent) between 26 and 690 days later [12] . The patients who developed candida PVE had persistent fungemia (8.1 mean days fungemia) without evidence of endocarditis during the month after cardiac surgery. (See "Candida endocarditis").

MICROBIOLOGY — While many different organisms have caused sporadic cases of PVE, the microbiology is relatively predictable when PVE is categorized by time after implantation. The largest reported contemporary experience comes from the multinational study of 556 patients cited above [1] :

• The most frequently encountered pathogens in early PVE (within two months of implantation) were S. aureus (36 percent) and coagulase-negative staphylococci (17 percent); next in frequency were culture-negative (17 percent) and fungal infection (9 percent) (show table 2).

• When PVE presented after two months, the culture results in decreasing order of frequency were coagulase-negative staphylococci and S. aureus (18 to 20 percent each); next in frequency were no organism identified, enterococci, and viridans streptococci (10 to 13 percent each) (show table 2).

Cases occurring more than 12 months after valve surgery are usually caused by the same pathogens that produce NVE in patients who are not injection drug users, since late PVE, like NVE, usually results from transient bacteremia occurring among ambulatory patients. (See "Infective endocarditis: Epidemiology and risk factors", section on Microbiology).

The coagulase-negative staphylococci causing PVE during the initial year after surgery are almost exclusively S. epidermidis. Between 84 and 87 percent of these organisms are methicillin-resistant and thus resistant to all of the beta-lactam antibiotics [3,13] . By contrast, almost half of the coagulase-negative staphylococci causing PVE one year or more after surgery are non-epidermidis species, and only 22 to 30 percent are methicillin-resistant. (See "Microbiology, pathogenesis, and epidemiology of coagulase-negative staphylococci").

The mechanisms leading to methicillin-resistance are the same among coagulase-negative staphylococci as for methicillin-resistant S. aureus (MRSA). (See "Coagulase-negative staphylococci: antimicrobial therapy and resistance" and see "Microbiology of methicillin-resistant Staphylococcus aureus").

However, methicillin-resistant coagulase-negative staphylococci, while uniformly possessing the resistant genotype, do not always express the phenotype, a phenomenon called heteroresistance. This makes detection of methicillin-resistance among coagulase-negative staphylococci more difficult. As a result, before embarking upon therapy with a beta-lactam antibiotic, the microbiology laboratory must be asked to thoroughly exclude possible methicillin-resistance. If this cannot be done, methicillin-resistance should be assumed. (See "Overview of antibacterial susceptibility testing", section on Heteroresistance).

PATHOLOGY — The intracardiac pathology of infection involving mechanical valves, particularly when PVE presents during the early months after surgery or when it is caused by invasive organisms, shapes the requirement for therapy. Perivalvular invasion, commonly with associated dehiscence of the prosthesis and paravalvular regurgitant flow, occurs in approximately 40 percent of patients and frank extension into tissue causing myocardial abscess is seen in 15 percent [14,15] . In one series, invasion of perivalvular tissue was noted in more than 80 percent of cases [16] .

In some patients, infection of an aortic valve prosthesis extends through the annulus to cause pericarditis or, more commonly, into the membranous portion of the interventricular septum where it disrupts the conduction system, resulting in various degrees of heart block [17-19] . Large vegetations may prevent closure of the prosthesis producing incompetence or encroach upon the valve orifice causing functional stenosis.

Bioprosthetic valve endocarditis also causes invasive infection. As an example, annular and myocardial invasion was noted in 38 of 85 patients (45 percent) in one study and was more frequent among bioprosthetic PVE occurring in the first year after valve replacement than cases presenting later (59 versus 25 percent) [20] . In another series, invasive disease was more common in patients with early compared with later bioprosthetic PVE (79 versus 31 percent) [21] .

The histologic features that characterize PVE in bioprosthetic valves are not well defined. As bioprosthetic valves degenerate, they may form noninfective, calcific, vegetative-like lesions and inflammatory infiltrates thus potentially causing a noninfectious process to be misdiagnosed as PVE. A retrospective pathologic analysis of inflamed bioprosthetic valve tissue from 88 patients who underwent surgical removal of a bioprosthetic valve (21 for suspected endocarditis and 67 for noninfective dysfunction) was conducted to better define the histologic criteria for PVE [22] . Histologically, PVE was characterized by microorganisms, vegetations, and neutrophil-rich, inflammatory infiltrates. In contrast, inflammatory infiltrates in valve tissue samples from the noninfective control group consisted mainly of macrophages and lymphocytes. A neutrophil surface area with a cutoff value of >1.5 percent of total valve tissue surface was highly specific for PVE (94 percent).

CLINICAL MANIFESTATIONS — Patients with PVE present with symptoms and signs similar to those encountered in NVE. (See "Infective endocarditis: Historical and Duke criteria").

However, when PVE develops prior to discharge from the hospital, findings related to surgery or to perioperative complications may predominate over the subtle features of endocarditis.

Signs and symptoms of invasive infection — The high frequency of invasive infection results in higher rates of new or changing murmurs, heart failure, and new electrocardiographic conduction disturbances in patients with PVE than in those with NVE. The incidence of clinically overt arterial emboli is 40 percent; central nervous system complications, primarily embolic infarcts or hemorrhages, occur in 20 to 40 percent of cases [16,23-25] . (See "Complications and outcome of infective endocarditis").

Valvular dysfunction, fever which persists for nine days or more despite appropriate antibiotic therapy, new electrocardiographic conduction disturbances, and echocardiographic evidence of abscess formation are clinical manifestations of invasive infection [26,27] . These findings were noted in 64 percent of 116 patients with PVE in one study and occurred significantly more frequently when infection involved an aortic valve prosthesis and when it arose within the first year after valve replacement [27] .

DIAGNOSIS — Laboratory findings in patients with PVE are similar to those noted in patients with NVE of comparable duration. (See "Diagnostic approach to infective endocarditis").

Blood cultures — In the absence of prior antibiotic therapy, blood cultures will be positive in 90 percent or more of patients with PVE. Because bacteremia is continuous, cultures will be positive regardless of whether or not blood cultures are obtained in proximity to the fever. When blood cultures are drawn over a period of hours to days in a patient with a prosthetic valve and all or most are positive, PVE is highly probable. The duration of documented bacteremia is particularly important when the isolate is a common contaminant, such as coagulase-negative staphylococci or diphtheroids. A high rate of blood culture positivity, or molecular evidence that a sporadically isolated organism represents a single clone, helps to distinguish infecting pathogens from contaminants [28] .

If antibiotics have not been administered prior to obtaining blood cultures, it is unusual to have persistently negative blood cultures in patients with clinically overt PVE. Nevertheless, culture-negative cases can occur when infection is caused by fastidious organisms such as Legionella species, Bartonella species, Coxiella burnetii, Mycoplasma hominis, fungi other than Candida species, and the HACEK organisms. (See "Endocarditis caused by Bartonella" and see "Q fever endocarditis").

Detection of these and other unusual fastidious pathogens causing PVE relies upon the same evaluation used to assess culture-negative NVE [29] . (See "Diagnostic approach to infective endocarditis").

Echocardiography — The availability of transesophageal echocardiography (TEE) has greatly improved the diagnosis and management of PVE and is considered the procedure of choice if only one type of echocardiogram is to be obtained. Although transthoracic (TTE) and transesophageal echocardiograms are complementary in the diagnosis of PVE, TEE has a sensitivity of 82 to 96 percent compared with 17 to 36 percent for TTE [30-32] . This increased sensitivity is achieved without regard to valve position and without loss of specificity [30-34] (show table 3). (See "Diagnostic approach to infective endocarditis").

One prospective study compared TTE and TEE in 114 episodes of infective endocarditis suspected on clinical grounds (34 PVE, 80 NVE) [35] . The results of the two tests were concordant in 55 percent of cases, but TEE led to a reclassification of the case in 34 percent of patients with prosthetic valves compared to 11 percent of patients with native valves. Twenty-two patients were reclassified as definite infective endocarditis based upon the TEE results; 10 of these patients had prosthetic valves. In two patients with PVE the diagnosis would have been rejected if the evaluation had been limited to TTE data.

Echocardiography, including both TTE and TEE, is essential for both the diagnosis and management of PVE [36] . A high resolution biplane or multiplane transducer that allows continuous-wave and pulse-wave Doppler and color-flow imaging should be employed. TTE provides superior images of the ventricular surfaces of prostheses in the mitral, tricuspid, and aortic positions, whereas the atrial surfaces of the mitral and tricuspid valves and the aortic surface and outflow track of prostheses in the aortic position are better viewed by TEE. TEE is unquestionably superior to TTE for visualizing a mitral valve prosthesis.

TEE is also superior to TTE in the detection of abscesses, fistulae, and paraprosthetic leaks [37] . In one study that correlated the results of both types of echocardiography with anatomic findings at surgery in 88 valves from patients with endocarditis, the sensitivity of TEE for the detection of valve perforation was significantly higher than that of TTE [38] . TEE detected perforation in 21 of 22 cases compared to only 10 of 22 by TTE.

In patients with failing prosthetic valves, echocardiography may define the intracardiac pathology, which can provide evidence of a need for surgical therapy. However, TEE may miss some cases of prosthetic valve dehiscence. In a study that included 26 patients with prosthetic valve endocarditis, 14 (54 percent) had surgically identified valve dehiscence [43] . Dehiscence was missed on TEE in 4 cases which all involved an aortic prosthetic valve.

The negative predictive value of a full echocardiographic evaluation of a patient with suspected PVE is 86 to 94 percent. Nevertheless, if PVE is strongly suspected in the face of a negative evaluation, repeat echocardiography one week later can provide evidence of PVE in some cases [32,39] . Echocardiography has replaced other modalities of cardiac imaging in the diagnosis of PVE, including cardiac catheterization (which is now reserved for defining coronary artery anatomy).

Summary — Identifying patients with PVE requires a high index of suspicion and an appreciation of the subtle symptoms and signs of endocarditis. Obtaining three or four blood cultures over time, without confounding their utility by antibiotic administration, and an echocardiogram are paramount in the evaluation.

When sporadic blood cultures yield coagulase-negative staphylococci or when only several cultures have been obtained and are positive for these organisms, molecular techniques, such as DNA examination by pulsed-field gel electrophoresis, should be used to compare the isolates. Establishing clonality of isolates from separate cultures argues against contamination and favors that the isolates are true pathogens [28] . However, there is a potential for polyclonal infections to arise, especially from direct contamination in the operating room.

The Duke criteria for the diagnosis of endocarditis provide a systematic approach for diagnosing both NVE and PVE [40] . Among pathologically confirmed cases of PVE, 76 percent have been categorized as definite PVE and 24 percent as possible PVE when judged by the Duke criteria [41,42] . The expanded use of TEE in the assessment of patients with possible PVE has enhanced the sensitivity of these criteria for the diagnosis of PVE [35] . The standard for assessing possible PVE should include appropriately obtained blood cultures and echocardiographic imaging, with the results interpreted according to the Duke criteria. Using this approach, few cases of PVE should be missed. (See "Infective endocarditis: Historical and Duke criteria" and see "Diagnostic approach to infective endocarditis").

Approach to the patient with a suspected spider bite: An overview

2008-08-30T22:23:00.000-07:00

Approach to the patient with a suspected spider bite: An overview

Author
Richard S Vetter, MS
David L Swanson, MD
Section Editor
Daniel F Danzl, MD
Stephen J Traub, MD
Deputy Editor
Anna M Feldweg, MD

Last literature review version 16.2: May 2008 | This topic last updated: June 12, 2008 (More)

INTRODUCTION — Spider bites are rare medical events. Of the thousands of spider species that exist around the world, only a handful cause problems in humans [1] . There are a variety of more common disorders that can mimic a spider bite, some of which represent a far greater threat to the patient if not recognized and treated appropriately.

Thus, accurate diagnosis is the initial goal of the clinician evaluating a patient with a lesion that might represent a spider bite. Discerning among the various conditions in the differential diagnosis of a spider bite requires familiarity with these disorders, as well as a rudimentary understanding of the distribution and behavior of medically important spiders.

This topic will discuss the spiders of medical importance and the clinical manifestations and diagnosis of spider bites. The differential diagnosis of bite-like lesions will be reviewed here, although disorders that mimic systemic reactions to bites of specific spiders are discussed in detail separately. Treatment of spider bites is discussed in the topics on bites of specific spiders. (See "Bites of recluse spiders").

MEDICALLY IMPORTANT SPIDERS — Spiders are arachnids (a group of arthropods), which have four pairs of legs, similar to scorpions, mites, and ticks (show figure 1). They use sharp fangs at the end of their chelicerae to bite prey (typically insects, other arthropods, or small vertebrates) and inject paralyzing venom.

Most spiders pose no threat to humans. The venom of most spiders has little or no effect on mammalian tissues [2] . In addition, only a few species have cheliceral muscles powerful enough to penetrate human skin, and most of these spiders bite humans only in rare and extreme circumstances (eg, as they are being fatally crushed between skin and some object).

The spiders most likely to inflict medically significant bites in humans include widow and false black widow spiders, recluse spiders, Australian funnel web spiders, and Phoneutria spiders. Each of these spiders are described briefly below, and their appearance and geographical distribution are summarized in the table (show table 1).

Widow spiders — Latrodectus, or widow spiders (found worldwide), include the Eastern black widow (show picture 1) and Western black widow in the United States, and the Australian redback spider. Widow bites cause unremarkable local lesions that are sometimes accompanied by a characteristic systemic reaction with prominent, proximally-spreading pain and localized diaphoresis surrounding the site of the bite. Antivenoms are available for several species.

False black widow spiders — Steatoda, or false black widow spiders (found worldwide) are less often implicated in human bites, and cause less severe symptoms that those of widows (show picture 2).

Recluse spiders — Loxosceles, or recluse spiders are found in predominantly in North and South America (show picture 3). Their bites are notorious for becoming necrotic, although this happens in a minority of cases. Systemic reactions to bites are usually mild, and consist of non-specific systemic signs and symptoms. (See "Bites of recluse spiders").

Australian funnel web spiders — Australian funnel web spiders are found in limited areas of eastern coastal Australia. Their bites can cause dramatic systemic reactions that mimic organophosphate poisoning and include salivation, diaphoresis, muscle spasms, tachycardia, hypertension, and pulmonary edema. An antivenom is available.

South American Phoneutria — Phoneutria or armed spiders are large spiders found in South America, especially urban areas of Brazil. The bites of these spiders can lead to severe systemic reactions, with occasional fatalities in children. An antivenom is available.

TYPES OF REACTIONS — A spider bite usually presents acutely as a solitary papule, pustule, or wheal. Systemic symptoms can accompany some envenomations, particularly those of widow spiders, funnel web spiders, and less often, recluse spiders. Allergic reactions typically result from contact with spiders (rather than bites).

Local reactions — Photographs of verified spider bites are rare in the medical literature, although dramatic images of necrotic lesions attributed to spider bites are commonplace in both medical journals and on the Internet. In reality, the majority of spider bites result in unremarkable wheals, papules, or pustules (show picture 4). Local redness with a tender nodule at the site of the bite appears within minutes. The lesions are similar to those induced by a bee sting. In some cases, the markings of the fangs (one or two small puncture marks) are visible. Some bites also itch or burn.

Spider bites may or may not be painful, and some go unnoticed. Pain can develop gradually over the ensuring hours after a bite, and can range from a slight prickly sensation to severe pain. The variability among bites and patients limits the clinical utility of this information in implicating a specific type of spider.

Most local reactions to spider bites resolve spontaneously in approximately 7 to 10 days. They occasionally become secondarily infected with skin-derived bacteria.

Necrotizing local reactions — Recluse (Loxosceles) spiders inflict bites that may become necrotic, although this is an uncommon complication. Other types of spiders have been implicated in causing necrotic bites, but this is based largely upon circumstantial evidence. The management of necrotic recluse spider bites is discussed separately. (See "Bites of recluse spiders").

Systemic reactions — Systemic symptoms are reported in a minority of patients, and occur when venom enters the circulation in sufficient amounts.

The bites of certain spiders are known for distinct and potentially severe systemic reactions, including bites of the widow, Australian funnel web, and Phoneutria spiders.

Allergic reactions — Allergic reactions to spiders are rare and have been reported mostly in response to contact with spiders [3-6] . In the United States, tarantulas are increasingly popular pets (show picture 5). These nonaggressive spiders rarely bite. When threatened, they dislodge small (about 1 mm long) barbed hairs at the posterior of their abdomens and launch them at their attacker. These hairs, as well as airborne material from crushed tarantulas, may cause irritation or urticaria if they come in contact with skin, eyes, or mucous membranes [1,6] . In addition, airborne material from tarantulas can cause foreign body reactions in the eye [7] .

Contact with tarantulas has also induced rare anaphylactic reactions in sensitized individuals [8] . The acute management of anaphylaxis (from any cause) is reviewed separately. (See "Anaphylaxis: Rapid recognition and treatment").

DIAGNOSIS — A presumptive diagnosis of a spider bite is most often based on the history and clinical presentation. However, the diagnosis of a spider bite can be considered definitive ONLY if both of the criteria below are fulfilled:

• A spider was observed inflicting the bite.
• The spider was recovered, collected, and properly identified by an expert entomologist.

If these criteria are not met, then other conditions such as vasculitis, infection, vascular problems, or other relevant disorders must be ruled out. (See "Differential diagnosis" below).

Unfortunately, the criteria above are rarely met, even in published medical reports. This has resulted in a body of literature and considerable media attention falsely attributing various lesions and symptoms to spider bites [1] . The extent of this problem was illustrated in a review of 600 cases of suspected spider bites, which found that 80 percent of presumed bites could be more reasonably attributed to other causes [9] . These other causes included bites of different arthropods such as ants, fleas, bedbugs, ticks, mites, mosquitoes, and biting flies, as well as erysipelas, cellulitis, ecthyma, vasculitis, pyoderma, ophthalmic zoster, urticaria, angioedema, and burns. (See "Differential diagnosis" below).

History — Most patients' reports of spider bites are unreliable. The bite history is often speculative and retrospective and a spider was never visualized, either inflicting the bite or even present [10] . Even when a bite is witnessed by the patient, the "spider" is commonly found to be some other arthropod [9] .

The diagnosis of a spider bite is thus highly suspect unless the patient actually observed a spider inflicting the bite and can retrieve it for identification. In the absence of this history and supporting evidence, another explanation should be sought.

The setting in which the patient sustained the alleged bite should be carefully reviewed to see if it is consistent with the known habitat and behavior of the venomous spiders that live in the area. People may worry about the possibility that a venomous spider was transported into a non-indigenous area on fruit or other produce. However, it is rare for spiders to survive intact through the many steps involved in produce transportation, and then end up in a situation in which they would bite. The risk may be more significant for people working in food transport and handling, but it is minimal in the general community. (See "Bites of recluse spiders").

Clinical clues that essentially EXCLUDE the diagnosis of spider bite include the following:
• Multiple lesions or more than one lesion on widely-separated parts of the body suggest another etiology. Spider bites are typically single lesions.
• Bites are generally not simultaneously sustained by multiple residents of the same household.

Spider bites capture the imagination. Reports exist of patients both feigning spider bites as part of drug seeking behavior [11] and attempting suicide with genuine spider bites [12] .

Influence of geographic location — Each of the venomous spiders lives in specific parts of the world (show table 1). Clinicians should know which spiders are indigenous to their area.
• Widows and false black widows are found worldwide.
• Recluse spiders are found predominantly in North and South America. Within the United States, they are limited to the mid-western and southern portions of the country (show figure 2). (See "Bites of recluse spiders").
• Phoneutria spiders are limited to South America.
• Australian funnel web spiders are limited to southeastern and coastal Australia.

Laboratory data — There are no commercially available laboratory tests for identifying the presence of spider venom. Thus, the diagnosis is made clinically.

DIFFERENTIAL DIAGNOSIS — A spider bite usually presents as a local lesion (possibly with necrosis in the case of recluse bites) with or without systemic symptoms. (See "Types of reactions" above). The differential diagnoses for local and systemic symptoms are reviewed in this section. Disorders that can mimic the bites of specific spiders are discussed in appropriate topic reviews. (See "Bites of recluse spiders").

As discussed previously, many other conditions are more common than spider bites and pose a more immediate threat to the patient's health if not accurately diagnosed. A patient who did not clearly witness a spider inflicting the bite should be presumed to have some other disorder, and the presence of multiple lesions essentially excludes the diagnosis of spider bite. (See "History" above).

The clinician can usually determine whether a spider bite is possible based upon a careful history of the patient's recent activities, details of the onset and evolution of the lesion, and knowledge of biting spiders found in the area. Despite this, it is not uncommon for patients to present with nondescript lesions, suggest that it might be a spider bite because of some circumstantial detail, and have that history accepted without further questioning.

A spider bite may present as a papule, pustule, wheal, plaque (possibly ecchymotic), or ulcer. The most common disorders that are mistaken for local reactions to spider bites include infections and the bites of other insects.

Infections — Papules and pustules should be carefully unroofed and cultured to identify infectious causes. Common infections that could be mistaken for spider bites include staphylococcus and streptococcal infections, the skin lesion of early Lyme disease, and atypical presentations of herpes zoster or herpes simplex.

• Community-acquired methicillin-resistance Staphylococcus aureus (CA-MRSA) skin infections can begin with singular or papules or pustules that may evolve to necrotic lesions [13] . CA-MRSA is far more prevalent than spider bites. Infections occur both sporadically and as institutional epidemics in nursing homes, prisons, military barracks, and athletic facilities. Risk factors and epidemiology of CA-MRSA are discussed separately. (See "Epidemiology of methicillin-resistant Staphylococcus aureus infection in adults" and see "Epidemiology and clinical spectrum of methicillin-resistant Staphylococcus aureus infections in children").

• Erythema migrans, the target-like skin lesion of early Lyme disease, may be mistaken for a spider bite (show picture 6). Southern tick-associated rash illness (STARI) is a similar infection with similar skin findings, which occurs in the southern United States (below Maryland). (See "Diagnosis of Lyme disease" and (See "Southern tick-associated rash illness (STARI)").

• Herpes zoster and herpes simplex infections (especially herpetic whitlow) may occasionally present with singular lesions (show picture 7). Acute onset is associated with vesicles, vesicopustules, severe edema, erythema, or pain. Tzanck staining of vesicles will demonstrate multinucleated giant cells and viral culture will grow HSV. (See "Epidemiology and pathogenesis of varicella-zoster virus infection" and see "Paronychia, herpetic whitlow, and ingrown toenails").

Other bites and stings — A wide variety of insects sting or bite humans, including triatomid bugs, ants, fleas, bedbugs, blister beetles, ticks, mites, mosquitoes, and biting flies (show table 2) [9] . Spiders are less likely to do so than many others. With the exception of tick-borne illnesses and allergic reactions, the exact insect inflicting the bite is of little clinical importance and local care suffices.

Scorpion stings are more common than spider envenomations worldwide, and most stings have been reported in Africa, the Middle East, southern Asia, and Central and South America. In the United States, scorpion stings are most common in Arizona and nearby areas of the southwest. Stings are instantaneously painful, and so patients usually capture or at least clearly witness the scorpion inflicting the sting [14,15] . Local pain is the most common presenting symptom. Systemic symptoms include hypertension, tachycardia, diaphoresis, and salivation [14] .

Other common dermatoses — Poison ivy, poison oak, and other plants in the Anacardiaceae family may occasionally cause dermatitis that presents as a single lesion, although linear lesions are more typical (show picture 8). These lesions tend to be pruritic, rather than painful. (See "Poison ivy (Toxicodendron) dermatitis").

SUMMARY AND RECOMMENDATIONS — Spider bites are uncommon medical events, since there are limited number of spiders worldwide with fangs strong enough to pierce human skin, and most spiders bite humans only as a final defense when being crushed between skin and another object. Thus, most lesions attributed to spider bites are caused by some other etiology. (See "Introduction" above).

• The spiders that can cause medically significant bites include widow and false widow spiders (worldwide), recluse spiders (mostly North and South America), Australian funnel web spiders (eastern coastal Australia) and Phoneutria spiders (Brazil) (show table 1). (See "Medically important spiders" above).

• Acute spider bites most commonly result in a solitary papule, pustule, or wheal (show picture 4). Systemic symptoms can accompany envenomations of widow, funnel web, and Phoneutria spiders, and less often, those of recluse spiders. The bites of recluse spiders can become necrotic, although most bites do not necrose. Allergic reactions to contact with spiders (rather than bites) occur most often in response to tarantulas. (See "Types of reactions" above).

• Clinicians should know which of the biting spiders (if any) are found in the areas in which they practice, and have a basic understanding of the entomology of those species (show table 1). (See "Influence of geographic location" above).

• The working diagnosis of a spider bite is based upon suggestive history and clinical presentation. However, definitive identification of a spider bite requires all of the following: a spider was observed inflicting the bite, the spider was recovered, collected, and properly identified by an expert entomologist, and other disorders have been ruled out. (See "Diagnosis" above).

• In the majority of cases, another etiology is responsible for the lesion, other than a spider bite. The differential diagnosis includes infections, bites and stings of other arthropods, and several other more common dermatosis. Culture should be performed in most cases. (See "Differential diagnosis" above).