Women's health encompasses a broad range of issues unique to the female patient, with a scope that has expanded beyond reproductive health. Providers who care for women must develop cross-disciplinary competencies and understand the complex role of sex and gender on disease expression and treatment outcomes. Staying current with the literature in this rapidly changing field can be challenging for the busy clinician.

This article reviews recent advances in the treatment of depression in pregnancy, nonhormonal therapies for menopausal symptoms, and heart failure therapy in women, highlighting notable studies published in 2014 and early 2015.

TREATMENT OF DEPRESSION IN PREGNANCY

A 32-year-old woman with well-controlled but recurrent depression presents to the clinic for preconception counseling. Her depression has been successfully managed with a selective serotonin reuptake inhibitor (SSRI). She and her husband would like to try to conceive soon, but she is worried that continuing on her current SSRI may harm her baby. How should you advise her?

Concern for teratogenic effects of SSRIs

Depression is common during pregnancy: 11.8% to 13.5% of pregnant women report symptoms of depression,¹ and 7.5% of pregnant women take an antidepressant.²

SSRI use during pregnancy has drawn attention due to mixed reports of teratogenic effects

SSRI use during pregnancy has drawn attention because of mixed reports of teratogenic effects on the newborn, such as omphalocele, congenital heart defects, and craniosynostosis.³ Previous observational studies have specifically linked paroxetine to small but significant increases in right ventricular outflow tract obstruction^4,5 and have linked sertraline to ventricular septal defects.⁶

However, reports of associations of congenital malformations and SSRI use in pregnancy in observational studies have been questioned, with concern that these studies had low statistical power, self-reported data leading to recall bias, and limited assessment for confounding factors.^3,7

Recent studies refute risk of cardiac malformations

Several newer studies have been published that further examine the association between SSRI use in pregnancy and congenital heart defects, and their findings suggest that once adjusted for confounding variables, SSRI use in pregnancy may not be associated with cardiac malformations.

Huybrechts et al,⁸ in a large study published in 2014, extracted data on 950,000 pregnant women from the Medicaid database over a 7-year period and examined it for SSRI use during the first 90 days of pregnancy. Though SSRI use was associated with cardiac malformations when unadjusted for confounding variables (unadjusted relative risk 1.25, 95% confidence interval [CI] 1.13–1.38), once the cohort was restricted to women with a diagnosis of only depression and was adjusted based on propensity scoring, the association was no longer statistically significant (adjusted relative risk 1.06, 95% CI 0.93–1.22).

Additionally, there was no association between sertraline and ventricular septal defects (63 cases in 14,040 women exposed to sertraline, adjusted relative risk 1.04, 95% CI 0.76–1.41), or between paroxetine and right ventricular outflow tract obstruction (93 cases in 11,126 women exposed to paroxetine, adjusted relative risk 1.07, 95% CI 0.59–1.93).⁸

Furu et al⁷ conducted a sibling-matched case-control comparison published in 2015, in which more than 2 million live births from five Nordic countries were examined in the full cohort study and 2,288 births in the sibling-matched case-control cohort. SSRI or venlafaxine use in the first 90 days of pregnancy was examined. There was a slightly higher rate of cardiac defects in infants born to SSRI or venlafaxine recipients in the cohort study (adjusted odds ratio 1.15, 95% CI 1.05–1.26). However, in the sibling-controlled analyses, neither an SSRI nor venlafaxine was associated with heart defects (adjusted odds ratio 0.92, 95% CI 0.72–1.17), leading the authors to conclude that there might be familial factors or other lifestyle factors that were not taken into consideration and that could have confounded the cohort results.

Bérard et al⁹ examined antidepressant use in the first trimester of pregnancy in a cohort of women in Canada and concluded that sertraline was associated with congenital atrial and ventricular defects (risk ratio 1.34; 95% CI 1.02–1.76).⁹ However, this association should be interpreted with caution, as the Canadian cohort was notably smaller than those in other studies we have discussed, with only 18,493 pregnancies in the total cohort, and this conclusion was drawn from 9 cases of ventricular or atrial septal defects in babies of 366 women exposed to sertraline.

Although at first glance SSRIs may appear to be associated with congenital heart defects, these recent studies are reassuring and suggest that the association may actually not be significant. As with any statistical analysis, thoughtful study design, adequate statistical power, and adjustment for confounding factors must be considered before drawing conclusions.

SSRIs, offspring psychiatric outcomes, and miscarriage rates

Clements et al¹⁰ studied a cohort extracted from Partners Healthcare consisting of newborns with autism spectrum disorder, newborns with attention-deficit hyperactivity disorder (ADHD), and healthy matched controls and found that SSRI use during pregnancy was not associated with offspring autism spectrum disorder (adjusted odds ratio 1.10, 95% CI 0.7–1.70). However, they did find an increased risk of ADHD with SSRI use during pregnancy (adjusted odds ratio 1.81, 95% CI 1.22–2.70).

Andersen et al¹¹ examined more than 1 million pregnancies in Denmark and found no difference in risk of miscarriage between women who used an SSRI during pregnancy (adjusted hazard ratio 1.27) and women who discontinued their SSRI at least 3 months before pregnancy (adjusted hazard ratio 1.24, P = .47). The authors concluded that because of the similar rate of miscarriage in both groups, there was no association between SSRI use and miscarriage, and that the small increased risk of miscarriage in both groups could have been attributable to a confounding factor that was not measured.

Should our patient continue her SSRI through pregnancy?

Our patient has recurrent depression, and her risk of relapse with antidepressant cessation is high. Though previous, less well-done studies suggested a small risk of congenital heart defects, recent larger high-quality studies provide significant reassurance that SSRI use in pregnancy is not strongly associated with cardiac malformations. Recent studies also show no association with miscarriage or autism spectrum disorder, though there may be risk of offspring ADHD.

She can be counseled that she may continue on her SSRI during pregnancy and can be reassured that the risk to her baby is small compared with her risk of recurrent or postpartum depression.

NONHORMONAL TREATMENT FOR VASOMOTOR SYMPTOMS OF MENOPAUSE

You see a patient who is struggling with symptoms of menopause. She tells you she has terrible hot flashes day and night, and she would like to try drug therapy. She does not want hormone replacement therapy because she is worried about the risk of adverse events. Are there safe and effective nonhormonal pharmacologic treatments for her vasomotor symptoms?

Paroxetine 7.5 mg is approved for vasomotor symptoms of menopause

As many as 75% of menopausal women in the United States experience vasomotor symptoms related to menopause, or hot flashes and night sweats.¹² These symptoms can disrupt sleep and negatively affect quality of life. Though previously thought to occur during a short and self-limited time period, a recently published large observational study reported the median duration of vasomotor symptoms was 7.4 years, and in African American women in the cohort the median duration of vasomotor symptoms was 10.1 years—an entire decade of life.¹³

In 2013, the US Food and Drug Administration (FDA) approved paroxetine 7.5 mg daily for treating moderate to severe hot flashes associated with menopause. It is the only approved nonhormonal treatment for vasomotor symptoms; the only other approved treatments are estrogen therapy for women who have had a hysterectomy and combination estrogen-progesterone therapy for women who have not had a hysterectomy.

Further studies of paroxetine for menopausal symptoms

Since its approval, further studies have been published supporting the use of paroxetine 7.5 mg in treating symptoms of menopause. In addition to reducing hot flashes, this treatment also improves sleep disturbance in women with menopause.¹⁴

Pinkerton et al,¹⁴ in a pooled analysis of the data from the phase 3 clinical trials of paroxetine 7.5 mg per day, found that participants in groups assigned to paroxetine reported a 62% reduction in nighttime awakenings due to hot flashes compared with a 43% reduction in the placebo group (P < .001). Those who took paroxetine also reported a statistically significantly greater increase in duration of sleep than those who took placebo (37 minutes in the treatment group vs 27 minutes in the placebo group, P = .03).

Some patients are hesitant to take an SSRI because of concerns about adverse effects when used for psychiatric conditions. However, the dose of paroxetine that was studied and approved for vasomotor symptoms is lower than doses used for psychiatric indications and does not appear to be associated with these adverse effects.

Portman et al¹⁵ in 2014 examined the effect of paroxetine 7.5 mg vs placebo on weight gain and sexual function in women with vasomotor symptoms of menopause and found no significant increase in weight or decrease in sexual function at 24 weeks of use. Participants were weighed during study visits, and those in the paroxetine group gained on average 0.48% from baseline at 24 weeks, compared with 0.09% in the placebo group (P = .29).

Sexual dysfunction was assessed using the Arizona Sexual Experience Scale, which has been validated in psychiatric patients using antidepressants, and there was no significant difference in symptoms such as sex drive, sexual arousal, vaginal lubrication, or ability to achieve orgasm between the treatment group and placebo group.¹⁵

Paroxetine inhibits CYP2D6 and thus decreases tamoxifen activity

Of note, paroxetine is a potent inhibitor of the cytochrome P-450 CYP2D6 enzyme, and concurrent use of paroxetine with tamoxifen decreases tamoxifen activity.^12,16 Since women with a history of breast cancer who cannot use estrogen for hot flashes may be seeking nonhormonal treatment for their vasomotor symptoms, providers should perform careful medication reconciliation and be aware that concomitant use of paroxetine and tamoxifen is not recommended.

Other antidepressants show promise but are not approved for menopausal symptoms

In addition to paroxetine, other nonhormonal drugs have been studied for treating hot flashes, but they have been unable to secure FDA approval for this indication. One of these is the serotonin-norepinephrine reuptake inhibitor venlafaxine, and a 2014 study¹⁷ confirmed its efficacy in treating menopausal vasomotor symptoms.

Joffe et al¹⁷ performed a three-armed trial comparing venlafaxine 75 mg/day, estradiol 0.5 mg/day, and placebo and found that both of the active treatments were better than placebo at reducing vasomotor symptoms. Compared with each other, estradiol 0.5 mg/day reduced hot flash frequency by an additional 0.6 events per day compared with venlafaxine 75 mg/day (P = .09). Though this difference was statistically significant, the authors pointed out that the clinical significance of such a small absolute difference is questionable. Additionally, providers should be aware that venlafaxine has little or no effect on the metabolism of tamoxifen.¹⁶

Shams et al,¹⁸ in a meta-analysis published in 2014, concluded that SSRIs as a class are more effective than placebo in treating hot flashes, supporting their widespread off-label use for this purpose. Their analysis examined the results of 11 studies, which included more than 2,000 patients in total, and found that compared with placebo, SSRI use was associated with a significant decrease in hot flashes (mean difference –0.93 events per day, 95% CI –1.49 to –0.37). A mixed treatment comparison analysis was also performed to try to model performance of individual SSRIs based on the pooled data, and the model suggests that escitalopram may be the most efficacious SSRI at reducing hot flash severity.

These studies support the effectiveness of SSRIs¹⁸ and venlafaxine¹⁷ in reducing hot flashes compared with placebo, though providers should be aware that they are still not FDA-approved for this indication.

Nonhormonal therapy for our patient

We would recommend paroxetine 7.5 mg nightly to this patient, as it is an FDA-approved nonhormonal medication that has been shown to help patients with vasomotor symptoms of menopause as well as sleep disturbance, without sexual side effects or weight gain. If the patient cannot tolerate paroxetine, off-label use of another SSRI or venlafaxine is supported by the recent literature.

HEART DISEASE IN WOMEN: CARDIAC RESYNCHRONIZATION THERAPY

A 68-year-old woman with a history of nonis­chemic cardiomyopathy presents for routine follow-up in your office. Despite maximal medical therapy on a beta-blocker, an angiotensin II receptor blocker, and a diuretic, she has New York Heart Association (NYHA) class III symptoms. Her most recent studies showed an ejection fraction of 30% by echocardiography and left bundle-branch block on electrocardiography, with a QRS duration of 140 ms. She recently saw her cardiologist, who recommended cardiac resynchronization therapy, and she wants your opinion as to whether or not to proceed with this recommendation. How should you counsel her?

Which patients are candidates for cardiac resynchronization therapy?

Heart disease continues to be the number one cause of death in the United States for both men and women, and almost the same number of women and men die from heart disease every year.¹⁹ Though coronary artery disease accounts for most cases of cardiovascular disease in the United States, heart failure is a significant and growing contributor. Approximately 6.6 million adults had heart failure in 2010 in the United States, and an additional 3 million are projected to have heart failure by 2030.²⁰ The burden of disease on our health system is high, with about 1 million hospitalizations and more than 3 million outpatient office visits attributable to heart failure yearly.²⁰

Patients with heart failure may have symptoms of dyspnea, fatigue, orthopnea, and periph­eral edema; laboratory and radiologic findings of pulmonary edema, renal insufficiency, and hyponatremia; and electrocardiographic findings of atrial fibrillation or prolonged QRS.²¹ Intraventricular conduction delay (QRS duration > 120 ms) is associated with dyssynchronous ventricular contraction and impaired pump function and is present in almost one-third of patients who have advanced heart failure.²¹

Heart disease continues to be the number one cause of death in both men and women

Cardiac resynchronization therapy, or biventricular pacing, can improve symptoms and pump function and has been shown to decrease rates of hospitalization and death in these patients.²² According to the joint 2012 guidelines of the American College of Cardiology Foundation, American Heart Association, and Heart Rhythm Society,²² it is indicated for patients with an ejection fraction of 35% or less, left bundle-branch block with QRS duration of 150 ms or more, and NYHA class II to IV symptoms who are in sinus rhythm (class I recommendation, level of evidence A).

Studies of cardiac resynchronization therapy in women

Recently published studies have suggested that women may derive greater benefit than men from cardiac resynchronization therapy.

Zusterzeel et al²³ (2014) evaluated sex-specific data from the National Cardiovascular Data Registry, which contains data on all biventricular pacemaker and implantable cardioverter-defibrillator implantations from 80% of US hospitals.²³ Of the 21,152 patients who had left bundle-branch block and received cardiac resynchronization therapy, women derived greater benefit in terms of death than men did, with a 21% lower risk of death than men (adjusted hazard ratio 0.79, 95% CI 0.74–0.84, P < .001). This study was also notable in that 36% of the patients were women, whereas in most earlier studies of cardiac resynchronization therapy women accounted for only 22% to 30% of the study population.²²

Goldenberg et al²⁴ (2014) performed a follow-up analysis of the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy. Subgroup analysis showed that although both men and women had a lower risk of death if they received cardiac resynchronization therapy compared with an implantable cardioverter-defibrillator only, the magnitude of benefit may be greater for women (hazard ratio 0.48, 95% CI 0.25–0.91, P = .03) than for men (hazard ratio 0.69, 95% CI 0.50–0.95, P = .02).

In addition to deriving greater mortality benefit, women may actually benefit from cardiac resynchronization therapy at shorter QRS durations than what is currently recommended. Women have a shorter baseline QRS than men, and a smaller left ventricular cavity.²⁵ In an FDA meta-analysis published in August 2014, pooled data from more than 4,000 patients in three studies suggested that women with left bundle-branch block benefited from cardiac resynchronization therapy more than men with left bundle-branch block.²⁶ Neither men nor women with left bundle-branch block benefited from it if their QRS duration was less than 130 ms, and both sexes benefited from it if they had left bundle-branch block and a QRS duration longer than 150 ms. However, women who received it who had left bundle-branch block and a QRS duration of 130 to 149 ms had a significant 76% reduction in the primary composite outcome of a heart failure event or death (hazard ratio 0.24, 95% CI 0.11–0.53, P < .001), while men in the same group did not derive significant benefit (hazard ratio 0.85, 95% CI 0.60–1.21, P = .38).

Despite the increasing evidence that there are sex-specific differences in the benefit from cardiac resynchronization therapy, what we know is limited by the low rates of female enrollment in most of the studies of this treatment. In a systematic review published in 2015, Herz et al²⁷ found that 90% of the 183 studies they reviewed enrolled 35% women or less, and half of the studies enrolled less than 23% women. Furthermore, only 20 of the 183 studies reported baseline characteristics by sex.

Recognizing this lack of adequate data, in August 2014 the FDA issued an official guidance statement outlining its expectations regarding sex-specific patient recruitment, data analysis, and data reporting in future medical device studies.²⁸ Hopefully, with this support for sex-specific research by the FDA, future studies will be able to identify therapeutic outcome differences that may exist between male and female patients.

Should our patient receive cardiac resynchronization therapy?

Regarding our patient with heart failure, the above studies suggest she will likely have a lower risk of death if she receives cardiac resynchronization therapy, even though her QRS interval is shorter than 150 ms. Providers who are aware of the emerging data regarding sex differences and treatment response can be powerful advocates for their patients, even in subspecialty areas, as highlighted by this case. We recommend counseling this patient to proceed with cardiac resynchronization therapy.

Women's health encompasses a broad range of issues unique to the female patient, with a scope that has expanded beyond reproductive health. Providers who care for women must develop cross-disciplinary competencies and understand the complex role of sex and gender on disease expression and treatment outcomes. Staying current with the literature in this rapidly changing field can be challenging for the busy clinician.

This article reviews recent advances in the treatment of depression in pregnancy, nonhormonal therapies for menopausal symptoms, and heart failure therapy in women, highlighting notable studies published in 2014 and early 2015.

TREATMENT OF DEPRESSION IN PREGNANCY

A 32-year-old woman with well-controlled but recurrent depression presents to the clinic for preconception counseling. Her depression has been successfully managed with a selective serotonin reuptake inhibitor (SSRI). She and her husband would like to try to conceive soon, but she is worried that continuing on her current SSRI may harm her baby. How should you advise her?

Concern for teratogenic effects of SSRIs

Depression is common during pregnancy: 11.8% to 13.5% of pregnant women report symptoms of depression,¹ and 7.5% of pregnant women take an antidepressant.²

SSRI use during pregnancy has drawn attention due to mixed reports of teratogenic effects

SSRI use during pregnancy has drawn attention because of mixed reports of teratogenic effects on the newborn, such as omphalocele, congenital heart defects, and craniosynostosis.³ Previous observational studies have specifically linked paroxetine to small but significant increases in right ventricular outflow tract obstruction^4,5 and have linked sertraline to ventricular septal defects.⁶

However, reports of associations of congenital malformations and SSRI use in pregnancy in observational studies have been questioned, with concern that these studies had low statistical power, self-reported data leading to recall bias, and limited assessment for confounding factors.^3,7

Recent studies refute risk of cardiac malformations

Several newer studies have been published that further examine the association between SSRI use in pregnancy and congenital heart defects, and their findings suggest that once adjusted for confounding variables, SSRI use in pregnancy may not be associated with cardiac malformations.

Huybrechts et al,⁸ in a large study published in 2014, extracted data on 950,000 pregnant women from the Medicaid database over a 7-year period and examined it for SSRI use during the first 90 days of pregnancy. Though SSRI use was associated with cardiac malformations when unadjusted for confounding variables (unadjusted relative risk 1.25, 95% confidence interval [CI] 1.13–1.38), once the cohort was restricted to women with a diagnosis of only depression and was adjusted based on propensity scoring, the association was no longer statistically significant (adjusted relative risk 1.06, 95% CI 0.93–1.22).

Additionally, there was no association between sertraline and ventricular septal defects (63 cases in 14,040 women exposed to sertraline, adjusted relative risk 1.04, 95% CI 0.76–1.41), or between paroxetine and right ventricular outflow tract obstruction (93 cases in 11,126 women exposed to paroxetine, adjusted relative risk 1.07, 95% CI 0.59–1.93).⁸

Furu et al⁷ conducted a sibling-matched case-control comparison published in 2015, in which more than 2 million live births from five Nordic countries were examined in the full cohort study and 2,288 births in the sibling-matched case-control cohort. SSRI or venlafaxine use in the first 90 days of pregnancy was examined. There was a slightly higher rate of cardiac defects in infants born to SSRI or venlafaxine recipients in the cohort study (adjusted odds ratio 1.15, 95% CI 1.05–1.26). However, in the sibling-controlled analyses, neither an SSRI nor venlafaxine was associated with heart defects (adjusted odds ratio 0.92, 95% CI 0.72–1.17), leading the authors to conclude that there might be familial factors or other lifestyle factors that were not taken into consideration and that could have confounded the cohort results.

Bérard et al⁹ examined antidepressant use in the first trimester of pregnancy in a cohort of women in Canada and concluded that sertraline was associated with congenital atrial and ventricular defects (risk ratio 1.34; 95% CI 1.02–1.76).⁹ However, this association should be interpreted with caution, as the Canadian cohort was notably smaller than those in other studies we have discussed, with only 18,493 pregnancies in the total cohort, and this conclusion was drawn from 9 cases of ventricular or atrial septal defects in babies of 366 women exposed to sertraline.

Although at first glance SSRIs may appear to be associated with congenital heart defects, these recent studies are reassuring and suggest that the association may actually not be significant. As with any statistical analysis, thoughtful study design, adequate statistical power, and adjustment for confounding factors must be considered before drawing conclusions.

SSRIs, offspring psychiatric outcomes, and miscarriage rates

Clements et al¹⁰ studied a cohort extracted from Partners Healthcare consisting of newborns with autism spectrum disorder, newborns with attention-deficit hyperactivity disorder (ADHD), and healthy matched controls and found that SSRI use during pregnancy was not associated with offspring autism spectrum disorder (adjusted odds ratio 1.10, 95% CI 0.7–1.70). However, they did find an increased risk of ADHD with SSRI use during pregnancy (adjusted odds ratio 1.81, 95% CI 1.22–2.70).

Andersen et al¹¹ examined more than 1 million pregnancies in Denmark and found no difference in risk of miscarriage between women who used an SSRI during pregnancy (adjusted hazard ratio 1.27) and women who discontinued their SSRI at least 3 months before pregnancy (adjusted hazard ratio 1.24, P = .47). The authors concluded that because of the similar rate of miscarriage in both groups, there was no association between SSRI use and miscarriage, and that the small increased risk of miscarriage in both groups could have been attributable to a confounding factor that was not measured.

Should our patient continue her SSRI through pregnancy?

Our patient has recurrent depression, and her risk of relapse with antidepressant cessation is high. Though previous, less well-done studies suggested a small risk of congenital heart defects, recent larger high-quality studies provide significant reassurance that SSRI use in pregnancy is not strongly associated with cardiac malformations. Recent studies also show no association with miscarriage or autism spectrum disorder, though there may be risk of offspring ADHD.

She can be counseled that she may continue on her SSRI during pregnancy and can be reassured that the risk to her baby is small compared with her risk of recurrent or postpartum depression.

NONHORMONAL TREATMENT FOR VASOMOTOR SYMPTOMS OF MENOPAUSE

You see a patient who is struggling with symptoms of menopause. She tells you she has terrible hot flashes day and night, and she would like to try drug therapy. She does not want hormone replacement therapy because she is worried about the risk of adverse events. Are there safe and effective nonhormonal pharmacologic treatments for her vasomotor symptoms?

Paroxetine 7.5 mg is approved for vasomotor symptoms of menopause

As many as 75% of menopausal women in the United States experience vasomotor symptoms related to menopause, or hot flashes and night sweats.¹² These symptoms can disrupt sleep and negatively affect quality of life. Though previously thought to occur during a short and self-limited time period, a recently published large observational study reported the median duration of vasomotor symptoms was 7.4 years, and in African American women in the cohort the median duration of vasomotor symptoms was 10.1 years—an entire decade of life.¹³

In 2013, the US Food and Drug Administration (FDA) approved paroxetine 7.5 mg daily for treating moderate to severe hot flashes associated with menopause. It is the only approved nonhormonal treatment for vasomotor symptoms; the only other approved treatments are estrogen therapy for women who have had a hysterectomy and combination estrogen-progesterone therapy for women who have not had a hysterectomy.

Further studies of paroxetine for menopausal symptoms

Since its approval, further studies have been published supporting the use of paroxetine 7.5 mg in treating symptoms of menopause. In addition to reducing hot flashes, this treatment also improves sleep disturbance in women with menopause.¹⁴

Pinkerton et al,¹⁴ in a pooled analysis of the data from the phase 3 clinical trials of paroxetine 7.5 mg per day, found that participants in groups assigned to paroxetine reported a 62% reduction in nighttime awakenings due to hot flashes compared with a 43% reduction in the placebo group (P < .001). Those who took paroxetine also reported a statistically significantly greater increase in duration of sleep than those who took placebo (37 minutes in the treatment group vs 27 minutes in the placebo group, P = .03).

Some patients are hesitant to take an SSRI because of concerns about adverse effects when used for psychiatric conditions. However, the dose of paroxetine that was studied and approved for vasomotor symptoms is lower than doses used for psychiatric indications and does not appear to be associated with these adverse effects.

Portman et al¹⁵ in 2014 examined the effect of paroxetine 7.5 mg vs placebo on weight gain and sexual function in women with vasomotor symptoms of menopause and found no significant increase in weight or decrease in sexual function at 24 weeks of use. Participants were weighed during study visits, and those in the paroxetine group gained on average 0.48% from baseline at 24 weeks, compared with 0.09% in the placebo group (P = .29).

Sexual dysfunction was assessed using the Arizona Sexual Experience Scale, which has been validated in psychiatric patients using antidepressants, and there was no significant difference in symptoms such as sex drive, sexual arousal, vaginal lubrication, or ability to achieve orgasm between the treatment group and placebo group.¹⁵

Paroxetine inhibits CYP2D6 and thus decreases tamoxifen activity

Of note, paroxetine is a potent inhibitor of the cytochrome P-450 CYP2D6 enzyme, and concurrent use of paroxetine with tamoxifen decreases tamoxifen activity.^12,16 Since women with a history of breast cancer who cannot use estrogen for hot flashes may be seeking nonhormonal treatment for their vasomotor symptoms, providers should perform careful medication reconciliation and be aware that concomitant use of paroxetine and tamoxifen is not recommended.

Other antidepressants show promise but are not approved for menopausal symptoms

In addition to paroxetine, other nonhormonal drugs have been studied for treating hot flashes, but they have been unable to secure FDA approval for this indication. One of these is the serotonin-norepinephrine reuptake inhibitor venlafaxine, and a 2014 study¹⁷ confirmed its efficacy in treating menopausal vasomotor symptoms.

Joffe et al¹⁷ performed a three-armed trial comparing venlafaxine 75 mg/day, estradiol 0.5 mg/day, and placebo and found that both of the active treatments were better than placebo at reducing vasomotor symptoms. Compared with each other, estradiol 0.5 mg/day reduced hot flash frequency by an additional 0.6 events per day compared with venlafaxine 75 mg/day (P = .09). Though this difference was statistically significant, the authors pointed out that the clinical significance of such a small absolute difference is questionable. Additionally, providers should be aware that venlafaxine has little or no effect on the metabolism of tamoxifen.¹⁶

Shams et al,¹⁸ in a meta-analysis published in 2014, concluded that SSRIs as a class are more effective than placebo in treating hot flashes, supporting their widespread off-label use for this purpose. Their analysis examined the results of 11 studies, which included more than 2,000 patients in total, and found that compared with placebo, SSRI use was associated with a significant decrease in hot flashes (mean difference –0.93 events per day, 95% CI –1.49 to –0.37). A mixed treatment comparison analysis was also performed to try to model performance of individual SSRIs based on the pooled data, and the model suggests that escitalopram may be the most efficacious SSRI at reducing hot flash severity.

These studies support the effectiveness of SSRIs¹⁸ and venlafaxine¹⁷ in reducing hot flashes compared with placebo, though providers should be aware that they are still not FDA-approved for this indication.

Nonhormonal therapy for our patient

We would recommend paroxetine 7.5 mg nightly to this patient, as it is an FDA-approved nonhormonal medication that has been shown to help patients with vasomotor symptoms of menopause as well as sleep disturbance, without sexual side effects or weight gain. If the patient cannot tolerate paroxetine, off-label use of another SSRI or venlafaxine is supported by the recent literature.

HEART DISEASE IN WOMEN: CARDIAC RESYNCHRONIZATION THERAPY

A 68-year-old woman with a history of nonis­chemic cardiomyopathy presents for routine follow-up in your office. Despite maximal medical therapy on a beta-blocker, an angiotensin II receptor blocker, and a diuretic, she has New York Heart Association (NYHA) class III symptoms. Her most recent studies showed an ejection fraction of 30% by echocardiography and left bundle-branch block on electrocardiography, with a QRS duration of 140 ms. She recently saw her cardiologist, who recommended cardiac resynchronization therapy, and she wants your opinion as to whether or not to proceed with this recommendation. How should you counsel her?

Which patients are candidates for cardiac resynchronization therapy?

Heart disease continues to be the number one cause of death in the United States for both men and women, and almost the same number of women and men die from heart disease every year.¹⁹ Though coronary artery disease accounts for most cases of cardiovascular disease in the United States, heart failure is a significant and growing contributor. Approximately 6.6 million adults had heart failure in 2010 in the United States, and an additional 3 million are projected to have heart failure by 2030.²⁰ The burden of disease on our health system is high, with about 1 million hospitalizations and more than 3 million outpatient office visits attributable to heart failure yearly.²⁰

Patients with heart failure may have symptoms of dyspnea, fatigue, orthopnea, and periph­eral edema; laboratory and radiologic findings of pulmonary edema, renal insufficiency, and hyponatremia; and electrocardiographic findings of atrial fibrillation or prolonged QRS.²¹ Intraventricular conduction delay (QRS duration > 120 ms) is associated with dyssynchronous ventricular contraction and impaired pump function and is present in almost one-third of patients who have advanced heart failure.²¹

Heart disease continues to be the number one cause of death in both men and women

Cardiac resynchronization therapy, or biventricular pacing, can improve symptoms and pump function and has been shown to decrease rates of hospitalization and death in these patients.²² According to the joint 2012 guidelines of the American College of Cardiology Foundation, American Heart Association, and Heart Rhythm Society,²² it is indicated for patients with an ejection fraction of 35% or less, left bundle-branch block with QRS duration of 150 ms or more, and NYHA class II to IV symptoms who are in sinus rhythm (class I recommendation, level of evidence A).

Studies of cardiac resynchronization therapy in women

Recently published studies have suggested that women may derive greater benefit than men from cardiac resynchronization therapy.

Zusterzeel et al²³ (2014) evaluated sex-specific data from the National Cardiovascular Data Registry, which contains data on all biventricular pacemaker and implantable cardioverter-defibrillator implantations from 80% of US hospitals.²³ Of the 21,152 patients who had left bundle-branch block and received cardiac resynchronization therapy, women derived greater benefit in terms of death than men did, with a 21% lower risk of death than men (adjusted hazard ratio 0.79, 95% CI 0.74–0.84, P < .001). This study was also notable in that 36% of the patients were women, whereas in most earlier studies of cardiac resynchronization therapy women accounted for only 22% to 30% of the study population.²²

Goldenberg et al²⁴ (2014) performed a follow-up analysis of the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy. Subgroup analysis showed that although both men and women had a lower risk of death if they received cardiac resynchronization therapy compared with an implantable cardioverter-defibrillator only, the magnitude of benefit may be greater for women (hazard ratio 0.48, 95% CI 0.25–0.91, P = .03) than for men (hazard ratio 0.69, 95% CI 0.50–0.95, P = .02).

In addition to deriving greater mortality benefit, women may actually benefit from cardiac resynchronization therapy at shorter QRS durations than what is currently recommended. Women have a shorter baseline QRS than men, and a smaller left ventricular cavity.²⁵ In an FDA meta-analysis published in August 2014, pooled data from more than 4,000 patients in three studies suggested that women with left bundle-branch block benefited from cardiac resynchronization therapy more than men with left bundle-branch block.²⁶ Neither men nor women with left bundle-branch block benefited from it if their QRS duration was less than 130 ms, and both sexes benefited from it if they had left bundle-branch block and a QRS duration longer than 150 ms. However, women who received it who had left bundle-branch block and a QRS duration of 130 to 149 ms had a significant 76% reduction in the primary composite outcome of a heart failure event or death (hazard ratio 0.24, 95% CI 0.11–0.53, P < .001), while men in the same group did not derive significant benefit (hazard ratio 0.85, 95% CI 0.60–1.21, P = .38).

Despite the increasing evidence that there are sex-specific differences in the benefit from cardiac resynchronization therapy, what we know is limited by the low rates of female enrollment in most of the studies of this treatment. In a systematic review published in 2015, Herz et al²⁷ found that 90% of the 183 studies they reviewed enrolled 35% women or less, and half of the studies enrolled less than 23% women. Furthermore, only 20 of the 183 studies reported baseline characteristics by sex.

Recognizing this lack of adequate data, in August 2014 the FDA issued an official guidance statement outlining its expectations regarding sex-specific patient recruitment, data analysis, and data reporting in future medical device studies.²⁸ Hopefully, with this support for sex-specific research by the FDA, future studies will be able to identify therapeutic outcome differences that may exist between male and female patients.

Should our patient receive cardiac resynchronization therapy?

Regarding our patient with heart failure, the above studies suggest she will likely have a lower risk of death if she receives cardiac resynchronization therapy, even though her QRS interval is shorter than 150 ms. Providers who are aware of the emerging data regarding sex differences and treatment response can be powerful advocates for their patients, even in subspecialty areas, as highlighted by this case. We recommend counseling this patient to proceed with cardiac resynchronization therapy.

Women's health encompasses a broad range of issues unique to the female patient, with a scope that has expanded beyond reproductive health. Providers who care for women must develop cross-disciplinary competencies and understand the complex role of sex and gender on disease expression and treatment outcomes. Staying current with the literature in this rapidly changing field can be challenging for the busy clinician.

This article reviews recent advances in the treatment of depression in pregnancy, nonhormonal therapies for menopausal symptoms, and heart failure therapy in women, highlighting notable studies published in 2014 and early 2015.

TREATMENT OF DEPRESSION IN PREGNANCY

A 32-year-old woman with well-controlled but recurrent depression presents to the clinic for preconception counseling. Her depression has been successfully managed with a selective serotonin reuptake inhibitor (SSRI). She and her husband would like to try to conceive soon, but she is worried that continuing on her current SSRI may harm her baby. How should you advise her?

Concern for teratogenic effects of SSRIs

Depression is common during pregnancy: 11.8% to 13.5% of pregnant women report symptoms of depression,¹ and 7.5% of pregnant women take an antidepressant.²

SSRI use during pregnancy has drawn attention due to mixed reports of teratogenic effects

SSRI use during pregnancy has drawn attention because of mixed reports of teratogenic effects on the newborn, such as omphalocele, congenital heart defects, and craniosynostosis.³ Previous observational studies have specifically linked paroxetine to small but significant increases in right ventricular outflow tract obstruction^4,5 and have linked sertraline to ventricular septal defects.⁶

However, reports of associations of congenital malformations and SSRI use in pregnancy in observational studies have been questioned, with concern that these studies had low statistical power, self-reported data leading to recall bias, and limited assessment for confounding factors.^3,7

Recent studies refute risk of cardiac malformations

Several newer studies have been published that further examine the association between SSRI use in pregnancy and congenital heart defects, and their findings suggest that once adjusted for confounding variables, SSRI use in pregnancy may not be associated with cardiac malformations.

Huybrechts et al,⁸ in a large study published in 2014, extracted data on 950,000 pregnant women from the Medicaid database over a 7-year period and examined it for SSRI use during the first 90 days of pregnancy. Though SSRI use was associated with cardiac malformations when unadjusted for confounding variables (unadjusted relative risk 1.25, 95% confidence interval [CI] 1.13–1.38), once the cohort was restricted to women with a diagnosis of only depression and was adjusted based on propensity scoring, the association was no longer statistically significant (adjusted relative risk 1.06, 95% CI 0.93–1.22).

Additionally, there was no association between sertraline and ventricular septal defects (63 cases in 14,040 women exposed to sertraline, adjusted relative risk 1.04, 95% CI 0.76–1.41), or between paroxetine and right ventricular outflow tract obstruction (93 cases in 11,126 women exposed to paroxetine, adjusted relative risk 1.07, 95% CI 0.59–1.93).⁸

Furu et al⁷ conducted a sibling-matched case-control comparison published in 2015, in which more than 2 million live births from five Nordic countries were examined in the full cohort study and 2,288 births in the sibling-matched case-control cohort. SSRI or venlafaxine use in the first 90 days of pregnancy was examined. There was a slightly higher rate of cardiac defects in infants born to SSRI or venlafaxine recipients in the cohort study (adjusted odds ratio 1.15, 95% CI 1.05–1.26). However, in the sibling-controlled analyses, neither an SSRI nor venlafaxine was associated with heart defects (adjusted odds ratio 0.92, 95% CI 0.72–1.17), leading the authors to conclude that there might be familial factors or other lifestyle factors that were not taken into consideration and that could have confounded the cohort results.

Bérard et al⁹ examined antidepressant use in the first trimester of pregnancy in a cohort of women in Canada and concluded that sertraline was associated with congenital atrial and ventricular defects (risk ratio 1.34; 95% CI 1.02–1.76).⁹ However, this association should be interpreted with caution, as the Canadian cohort was notably smaller than those in other studies we have discussed, with only 18,493 pregnancies in the total cohort, and this conclusion was drawn from 9 cases of ventricular or atrial septal defects in babies of 366 women exposed to sertraline.

Although at first glance SSRIs may appear to be associated with congenital heart defects, these recent studies are reassuring and suggest that the association may actually not be significant. As with any statistical analysis, thoughtful study design, adequate statistical power, and adjustment for confounding factors must be considered before drawing conclusions.

SSRIs, offspring psychiatric outcomes, and miscarriage rates

Clements et al¹⁰ studied a cohort extracted from Partners Healthcare consisting of newborns with autism spectrum disorder, newborns with attention-deficit hyperactivity disorder (ADHD), and healthy matched controls and found that SSRI use during pregnancy was not associated with offspring autism spectrum disorder (adjusted odds ratio 1.10, 95% CI 0.7–1.70). However, they did find an increased risk of ADHD with SSRI use during pregnancy (adjusted odds ratio 1.81, 95% CI 1.22–2.70).

Andersen et al¹¹ examined more than 1 million pregnancies in Denmark and found no difference in risk of miscarriage between women who used an SSRI during pregnancy (adjusted hazard ratio 1.27) and women who discontinued their SSRI at least 3 months before pregnancy (adjusted hazard ratio 1.24, P = .47). The authors concluded that because of the similar rate of miscarriage in both groups, there was no association between SSRI use and miscarriage, and that the small increased risk of miscarriage in both groups could have been attributable to a confounding factor that was not measured.

Should our patient continue her SSRI through pregnancy?

Our patient has recurrent depression, and her risk of relapse with antidepressant cessation is high. Though previous, less well-done studies suggested a small risk of congenital heart defects, recent larger high-quality studies provide significant reassurance that SSRI use in pregnancy is not strongly associated with cardiac malformations. Recent studies also show no association with miscarriage or autism spectrum disorder, though there may be risk of offspring ADHD.

She can be counseled that she may continue on her SSRI during pregnancy and can be reassured that the risk to her baby is small compared with her risk of recurrent or postpartum depression.

NONHORMONAL TREATMENT FOR VASOMOTOR SYMPTOMS OF MENOPAUSE

You see a patient who is struggling with symptoms of menopause. She tells you she has terrible hot flashes day and night, and she would like to try drug therapy. She does not want hormone replacement therapy because she is worried about the risk of adverse events. Are there safe and effective nonhormonal pharmacologic treatments for her vasomotor symptoms?

Paroxetine 7.5 mg is approved for vasomotor symptoms of menopause

As many as 75% of menopausal women in the United States experience vasomotor symptoms related to menopause, or hot flashes and night sweats.¹² These symptoms can disrupt sleep and negatively affect quality of life. Though previously thought to occur during a short and self-limited time period, a recently published large observational study reported the median duration of vasomotor symptoms was 7.4 years, and in African American women in the cohort the median duration of vasomotor symptoms was 10.1 years—an entire decade of life.¹³

In 2013, the US Food and Drug Administration (FDA) approved paroxetine 7.5 mg daily for treating moderate to severe hot flashes associated with menopause. It is the only approved nonhormonal treatment for vasomotor symptoms; the only other approved treatments are estrogen therapy for women who have had a hysterectomy and combination estrogen-progesterone therapy for women who have not had a hysterectomy.

Further studies of paroxetine for menopausal symptoms

Since its approval, further studies have been published supporting the use of paroxetine 7.5 mg in treating symptoms of menopause. In addition to reducing hot flashes, this treatment also improves sleep disturbance in women with menopause.¹⁴

Pinkerton et al,¹⁴ in a pooled analysis of the data from the phase 3 clinical trials of paroxetine 7.5 mg per day, found that participants in groups assigned to paroxetine reported a 62% reduction in nighttime awakenings due to hot flashes compared with a 43% reduction in the placebo group (P < .001). Those who took paroxetine also reported a statistically significantly greater increase in duration of sleep than those who took placebo (37 minutes in the treatment group vs 27 minutes in the placebo group, P = .03).

Some patients are hesitant to take an SSRI because of concerns about adverse effects when used for psychiatric conditions. However, the dose of paroxetine that was studied and approved for vasomotor symptoms is lower than doses used for psychiatric indications and does not appear to be associated with these adverse effects.

Portman et al¹⁵ in 2014 examined the effect of paroxetine 7.5 mg vs placebo on weight gain and sexual function in women with vasomotor symptoms of menopause and found no significant increase in weight or decrease in sexual function at 24 weeks of use. Participants were weighed during study visits, and those in the paroxetine group gained on average 0.48% from baseline at 24 weeks, compared with 0.09% in the placebo group (P = .29).

Sexual dysfunction was assessed using the Arizona Sexual Experience Scale, which has been validated in psychiatric patients using antidepressants, and there was no significant difference in symptoms such as sex drive, sexual arousal, vaginal lubrication, or ability to achieve orgasm between the treatment group and placebo group.¹⁵

Paroxetine inhibits CYP2D6 and thus decreases tamoxifen activity

Of note, paroxetine is a potent inhibitor of the cytochrome P-450 CYP2D6 enzyme, and concurrent use of paroxetine with tamoxifen decreases tamoxifen activity.^12,16 Since women with a history of breast cancer who cannot use estrogen for hot flashes may be seeking nonhormonal treatment for their vasomotor symptoms, providers should perform careful medication reconciliation and be aware that concomitant use of paroxetine and tamoxifen is not recommended.

Other antidepressants show promise but are not approved for menopausal symptoms

In addition to paroxetine, other nonhormonal drugs have been studied for treating hot flashes, but they have been unable to secure FDA approval for this indication. One of these is the serotonin-norepinephrine reuptake inhibitor venlafaxine, and a 2014 study¹⁷ confirmed its efficacy in treating menopausal vasomotor symptoms.

Joffe et al¹⁷ performed a three-armed trial comparing venlafaxine 75 mg/day, estradiol 0.5 mg/day, and placebo and found that both of the active treatments were better than placebo at reducing vasomotor symptoms. Compared with each other, estradiol 0.5 mg/day reduced hot flash frequency by an additional 0.6 events per day compared with venlafaxine 75 mg/day (P = .09). Though this difference was statistically significant, the authors pointed out that the clinical significance of such a small absolute difference is questionable. Additionally, providers should be aware that venlafaxine has little or no effect on the metabolism of tamoxifen.¹⁶

Shams et al,¹⁸ in a meta-analysis published in 2014, concluded that SSRIs as a class are more effective than placebo in treating hot flashes, supporting their widespread off-label use for this purpose. Their analysis examined the results of 11 studies, which included more than 2,000 patients in total, and found that compared with placebo, SSRI use was associated with a significant decrease in hot flashes (mean difference –0.93 events per day, 95% CI –1.49 to –0.37). A mixed treatment comparison analysis was also performed to try to model performance of individual SSRIs based on the pooled data, and the model suggests that escitalopram may be the most efficacious SSRI at reducing hot flash severity.

These studies support the effectiveness of SSRIs¹⁸ and venlafaxine¹⁷ in reducing hot flashes compared with placebo, though providers should be aware that they are still not FDA-approved for this indication.

Nonhormonal therapy for our patient

We would recommend paroxetine 7.5 mg nightly to this patient, as it is an FDA-approved nonhormonal medication that has been shown to help patients with vasomotor symptoms of menopause as well as sleep disturbance, without sexual side effects or weight gain. If the patient cannot tolerate paroxetine, off-label use of another SSRI or venlafaxine is supported by the recent literature.

HEART DISEASE IN WOMEN: CARDIAC RESYNCHRONIZATION THERAPY

A 68-year-old woman with a history of nonis­chemic cardiomyopathy presents for routine follow-up in your office. Despite maximal medical therapy on a beta-blocker, an angiotensin II receptor blocker, and a diuretic, she has New York Heart Association (NYHA) class III symptoms. Her most recent studies showed an ejection fraction of 30% by echocardiography and left bundle-branch block on electrocardiography, with a QRS duration of 140 ms. She recently saw her cardiologist, who recommended cardiac resynchronization therapy, and she wants your opinion as to whether or not to proceed with this recommendation. How should you counsel her?

Which patients are candidates for cardiac resynchronization therapy?

Heart disease continues to be the number one cause of death in the United States for both men and women, and almost the same number of women and men die from heart disease every year.¹⁹ Though coronary artery disease accounts for most cases of cardiovascular disease in the United States, heart failure is a significant and growing contributor. Approximately 6.6 million adults had heart failure in 2010 in the United States, and an additional 3 million are projected to have heart failure by 2030.²⁰ The burden of disease on our health system is high, with about 1 million hospitalizations and more than 3 million outpatient office visits attributable to heart failure yearly.²⁰

Patients with heart failure may have symptoms of dyspnea, fatigue, orthopnea, and periph­eral edema; laboratory and radiologic findings of pulmonary edema, renal insufficiency, and hyponatremia; and electrocardiographic findings of atrial fibrillation or prolonged QRS.²¹ Intraventricular conduction delay (QRS duration > 120 ms) is associated with dyssynchronous ventricular contraction and impaired pump function and is present in almost one-third of patients who have advanced heart failure.²¹

Heart disease continues to be the number one cause of death in both men and women

Cardiac resynchronization therapy, or biventricular pacing, can improve symptoms and pump function and has been shown to decrease rates of hospitalization and death in these patients.²² According to the joint 2012 guidelines of the American College of Cardiology Foundation, American Heart Association, and Heart Rhythm Society,²² it is indicated for patients with an ejection fraction of 35% or less, left bundle-branch block with QRS duration of 150 ms or more, and NYHA class II to IV symptoms who are in sinus rhythm (class I recommendation, level of evidence A).

Studies of cardiac resynchronization therapy in women

Recently published studies have suggested that women may derive greater benefit than men from cardiac resynchronization therapy.

Zusterzeel et al²³ (2014) evaluated sex-specific data from the National Cardiovascular Data Registry, which contains data on all biventricular pacemaker and implantable cardioverter-defibrillator implantations from 80% of US hospitals.²³ Of the 21,152 patients who had left bundle-branch block and received cardiac resynchronization therapy, women derived greater benefit in terms of death than men did, with a 21% lower risk of death than men (adjusted hazard ratio 0.79, 95% CI 0.74–0.84, P < .001). This study was also notable in that 36% of the patients were women, whereas in most earlier studies of cardiac resynchronization therapy women accounted for only 22% to 30% of the study population.²²

Goldenberg et al²⁴ (2014) performed a follow-up analysis of the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy. Subgroup analysis showed that although both men and women had a lower risk of death if they received cardiac resynchronization therapy compared with an implantable cardioverter-defibrillator only, the magnitude of benefit may be greater for women (hazard ratio 0.48, 95% CI 0.25–0.91, P = .03) than for men (hazard ratio 0.69, 95% CI 0.50–0.95, P = .02).

In addition to deriving greater mortality benefit, women may actually benefit from cardiac resynchronization therapy at shorter QRS durations than what is currently recommended. Women have a shorter baseline QRS than men, and a smaller left ventricular cavity.²⁵ In an FDA meta-analysis published in August 2014, pooled data from more than 4,000 patients in three studies suggested that women with left bundle-branch block benefited from cardiac resynchronization therapy more than men with left bundle-branch block.²⁶ Neither men nor women with left bundle-branch block benefited from it if their QRS duration was less than 130 ms, and both sexes benefited from it if they had left bundle-branch block and a QRS duration longer than 150 ms. However, women who received it who had left bundle-branch block and a QRS duration of 130 to 149 ms had a significant 76% reduction in the primary composite outcome of a heart failure event or death (hazard ratio 0.24, 95% CI 0.11–0.53, P < .001), while men in the same group did not derive significant benefit (hazard ratio 0.85, 95% CI 0.60–1.21, P = .38).

Despite the increasing evidence that there are sex-specific differences in the benefit from cardiac resynchronization therapy, what we know is limited by the low rates of female enrollment in most of the studies of this treatment. In a systematic review published in 2015, Herz et al²⁷ found that 90% of the 183 studies they reviewed enrolled 35% women or less, and half of the studies enrolled less than 23% women. Furthermore, only 20 of the 183 studies reported baseline characteristics by sex.

Recognizing this lack of adequate data, in August 2014 the FDA issued an official guidance statement outlining its expectations regarding sex-specific patient recruitment, data analysis, and data reporting in future medical device studies.²⁸ Hopefully, with this support for sex-specific research by the FDA, future studies will be able to identify therapeutic outcome differences that may exist between male and female patients.

Should our patient receive cardiac resynchronization therapy?

Regarding our patient with heart failure, the above studies suggest she will likely have a lower risk of death if she receives cardiac resynchronization therapy, even though her QRS interval is shorter than 150 ms. Providers who are aware of the emerging data regarding sex differences and treatment response can be powerful advocates for their patients, even in subspecialty areas, as highlighted by this case. We recommend counseling this patient to proceed with cardiac resynchronization therapy.

A 58-year-old man with a history of cystoprostatectomy for prostate cancer, end-stage renal disease on hemodialysis, and distal ureteral obstruction requiring bilateral nephrostomy tubes noticed that one of the nephrostomy bags looked “purple” (Figure 1). A specimen collected from one bag was reddish purple (Figure 2). The urine in the other bag was normal. The condition was diagnosed as purple urine bag syndrome.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome, a relatively rare condition that appears after 2 to 3 months of indwelling urinary catheterization, is usually asymptomatic, the only signs being the purplish urine and staining of the urinary bags and catheters. However, it should be considered a sign of underlying urinary tract infection, which can disseminate causing local complications (Fournier gangrene), systemic complications (septicemia), and death.^1–3

The syndrome, first described in 1978 in children with spina bifida and urinary diversion,⁴ is more prevalent in women than in men, possibly because of the shorter urethra and closer proximity to the anus, which predispose women to bacterial colonization of the urinary tract. Predisposing conditions include dementia,⁵ female sex, increased dietary tryptophan, bacteriuria, urinary tract infection, constipation, older age, immobility, and alkaline urine.^6–8

The cause of the discoloration

The purple color is from indigo and indirubin compounds in the urine, the result of the breakdown of dietary tryptophan. The color varies depending on the proportions of the two pigments.

Dietary tryptophan is broken down into indole by colonic bacteria. After reaching the portal circulation, it is excreted into the urine as indoxyl sulfate, which is broken down to indoxyl by sulfatase-producing bacteria (eg, Klebsiella pneumonia, Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli, Providencia species, Morganella morganii). Indoxyl is then oxidized to indigo and indirubin.

These compounds do not discolor the urine directly, but rather precipitate after interacting with the lining of the urinary catheter and bags, thereby imparting a purple color.^1,9–13

Management

Effective initial measures are improved urinary hygiene (eg, frequent, careful changing of the urinary catheter) and management of constipation, as constipation leads to increased colonization of the intestine by bacteria that metabolize dietary tryptophan into indoxyl. Antibiotics should be given for symptomatic urinary tract infection (fever, increased urinary frequency, dysuria, abdominal pain) but not for color change alone. Coverage should be for gram-negative bacilli, although methicillin-resistant Staphylococcus aureus, which is gram-positive, has also been reported to cause purple urine bag syndrome.

In most cases, purple urine bag syndrome is benign and requires no therapy other than that mentioned above.^3,13–15 However, in rare cases, immunocompromised patients (eg, people with diabetes) can develop local complications and sepsis from dissemination of bacterial infection, requiring aggressive therapy.¹⁴ Therefore, purple urine bag syndrome should be recognized as an indicator of an underlying urinary tract infection and should be treated if symptomatic. Nevertheless, the long-term prognosis is generally good.

OUR PATIENT’S MANAGEMENT

Our patient was confirmed to have urinary colonization with P aeruginosa and E coli, and alkaline urine. He underwent replacement of the nephrostomy tubes and urinary bag during his hospital stay (he was already in the hospital for another indication), but he continued to produce purple-colored urine from his right side and normal-colored urine from his left side. The unilateral involvement was likely from selective colonization of the right-sided nephrostomy tube with gram-negative bacteria.

A 58-year-old man with a history of cystoprostatectomy for prostate cancer, end-stage renal disease on hemodialysis, and distal ureteral obstruction requiring bilateral nephrostomy tubes noticed that one of the nephrostomy bags looked “purple” (Figure 1). A specimen collected from one bag was reddish purple (Figure 2). The urine in the other bag was normal. The condition was diagnosed as purple urine bag syndrome.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome, a relatively rare condition that appears after 2 to 3 months of indwelling urinary catheterization, is usually asymptomatic, the only signs being the purplish urine and staining of the urinary bags and catheters. However, it should be considered a sign of underlying urinary tract infection, which can disseminate causing local complications (Fournier gangrene), systemic complications (septicemia), and death.^1–3

The syndrome, first described in 1978 in children with spina bifida and urinary diversion,⁴ is more prevalent in women than in men, possibly because of the shorter urethra and closer proximity to the anus, which predispose women to bacterial colonization of the urinary tract. Predisposing conditions include dementia,⁵ female sex, increased dietary tryptophan, bacteriuria, urinary tract infection, constipation, older age, immobility, and alkaline urine.^6–8

The cause of the discoloration

The purple color is from indigo and indirubin compounds in the urine, the result of the breakdown of dietary tryptophan. The color varies depending on the proportions of the two pigments.

Dietary tryptophan is broken down into indole by colonic bacteria. After reaching the portal circulation, it is excreted into the urine as indoxyl sulfate, which is broken down to indoxyl by sulfatase-producing bacteria (eg, Klebsiella pneumonia, Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli, Providencia species, Morganella morganii). Indoxyl is then oxidized to indigo and indirubin.

These compounds do not discolor the urine directly, but rather precipitate after interacting with the lining of the urinary catheter and bags, thereby imparting a purple color.^1,9–13

Management

Effective initial measures are improved urinary hygiene (eg, frequent, careful changing of the urinary catheter) and management of constipation, as constipation leads to increased colonization of the intestine by bacteria that metabolize dietary tryptophan into indoxyl. Antibiotics should be given for symptomatic urinary tract infection (fever, increased urinary frequency, dysuria, abdominal pain) but not for color change alone. Coverage should be for gram-negative bacilli, although methicillin-resistant Staphylococcus aureus, which is gram-positive, has also been reported to cause purple urine bag syndrome.

In most cases, purple urine bag syndrome is benign and requires no therapy other than that mentioned above.^3,13–15 However, in rare cases, immunocompromised patients (eg, people with diabetes) can develop local complications and sepsis from dissemination of bacterial infection, requiring aggressive therapy.¹⁴ Therefore, purple urine bag syndrome should be recognized as an indicator of an underlying urinary tract infection and should be treated if symptomatic. Nevertheless, the long-term prognosis is generally good.

OUR PATIENT’S MANAGEMENT

Our patient was confirmed to have urinary colonization with P aeruginosa and E coli, and alkaline urine. He underwent replacement of the nephrostomy tubes and urinary bag during his hospital stay (he was already in the hospital for another indication), but he continued to produce purple-colored urine from his right side and normal-colored urine from his left side. The unilateral involvement was likely from selective colonization of the right-sided nephrostomy tube with gram-negative bacteria.

A 58-year-old man with a history of cystoprostatectomy for prostate cancer, end-stage renal disease on hemodialysis, and distal ureteral obstruction requiring bilateral nephrostomy tubes noticed that one of the nephrostomy bags looked “purple” (Figure 1). A specimen collected from one bag was reddish purple (Figure 2). The urine in the other bag was normal. The condition was diagnosed as purple urine bag syndrome.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome, a relatively rare condition that appears after 2 to 3 months of indwelling urinary catheterization, is usually asymptomatic, the only signs being the purplish urine and staining of the urinary bags and catheters. However, it should be considered a sign of underlying urinary tract infection, which can disseminate causing local complications (Fournier gangrene), systemic complications (septicemia), and death.^1–3

The syndrome, first described in 1978 in children with spina bifida and urinary diversion,⁴ is more prevalent in women than in men, possibly because of the shorter urethra and closer proximity to the anus, which predispose women to bacterial colonization of the urinary tract. Predisposing conditions include dementia,⁵ female sex, increased dietary tryptophan, bacteriuria, urinary tract infection, constipation, older age, immobility, and alkaline urine.^6–8

The cause of the discoloration

The purple color is from indigo and indirubin compounds in the urine, the result of the breakdown of dietary tryptophan. The color varies depending on the proportions of the two pigments.

Dietary tryptophan is broken down into indole by colonic bacteria. After reaching the portal circulation, it is excreted into the urine as indoxyl sulfate, which is broken down to indoxyl by sulfatase-producing bacteria (eg, Klebsiella pneumonia, Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli, Providencia species, Morganella morganii). Indoxyl is then oxidized to indigo and indirubin.

These compounds do not discolor the urine directly, but rather precipitate after interacting with the lining of the urinary catheter and bags, thereby imparting a purple color.^1,9–13

Management

Effective initial measures are improved urinary hygiene (eg, frequent, careful changing of the urinary catheter) and management of constipation, as constipation leads to increased colonization of the intestine by bacteria that metabolize dietary tryptophan into indoxyl. Antibiotics should be given for symptomatic urinary tract infection (fever, increased urinary frequency, dysuria, abdominal pain) but not for color change alone. Coverage should be for gram-negative bacilli, although methicillin-resistant Staphylococcus aureus, which is gram-positive, has also been reported to cause purple urine bag syndrome.

In most cases, purple urine bag syndrome is benign and requires no therapy other than that mentioned above.^3,13–15 However, in rare cases, immunocompromised patients (eg, people with diabetes) can develop local complications and sepsis from dissemination of bacterial infection, requiring aggressive therapy.¹⁴ Therefore, purple urine bag syndrome should be recognized as an indicator of an underlying urinary tract infection and should be treated if symptomatic. Nevertheless, the long-term prognosis is generally good.

OUR PATIENT’S MANAGEMENT

Our patient was confirmed to have urinary colonization with P aeruginosa and E coli, and alkaline urine. He underwent replacement of the nephrostomy tubes and urinary bag during his hospital stay (he was already in the hospital for another indication), but he continued to produce purple-colored urine from his right side and normal-colored urine from his left side. The unilateral involvement was likely from selective colonization of the right-sided nephrostomy tube with gram-negative bacteria.

A 64-year-old man was admitted for extensive painful ulceration of the left lower leg (Figure 1) that occurred after a fall and that had worsened over the last 4 months.

His medical history included hyperuricemia, hypertension, and type 2 diabetes mellitus. He had no known cardiac or renal disease.

Results of initial laboratory testing showed the following:

• Hemoglobin 10.9 g/dL (reference range 13.5–17.5); red blood cells were normocytic and normochromic
• White blood cell count 10.2 × 10⁹/L (4.5–11.0)
• Neutrophil count 9.11 × 10⁹/L (2.0–8.5)
• C-reactive protein 259 mg/L (< 5)
• Creatinine, urea, sodium, potassium, calcium, and phosphate were within normal limits.

Doppler ultrasonography of the legs showed mild diffuse atheromatous arterial disease without significant blockage of blood flow, in addition to mild bilateral venous insufficiency.

Cutaneous biopsy showed intravascular calcium deposition in the hypodermis (Figure 2) and reticular dermis, erythrocyte extravasation in the superficial dermis, and epidermal necrosis, thus establishing the diagnosis of nonuremic calciphylaxis. The vascular occlusion with spreading necrosis gave the characteristic stellate appearance.

Aside from diabetes, our patient had none of the conditions usually associated with nonuremic calciphylaxis—namely, hyperparathyroidism, previous corticosteroid therapy, warfarin use, connective tissue disease, or malignancy.

A POORLY UNDERSTOOD SMALL-VESSEL VASCULOPATHY

Calciphylaxis is a poorly understood small-vessel vasculopathy, most often associated with end-stage renal disease, with a prevalence of 1% to 4% in patients on dialysis.¹ It carries a high risk of death, most often from sepsis.

The cause is still unclear, but several conditions have been implicated, including primary hyperparathyroidism, malignancies, alcoholic liver disease, connective tissue disease, and diabetes.²

Making the diagnosis may be challenging, especially in nonuremic patients. It is a rare condition, the presentation is not always typical, and it can occur with fully normal kidney function and normal indicators of calcium and phosphate metabolism.

The differential diagnosis includes:

• Vasculitis, either primary or secondary to an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or cryoglobulinemia
• Peripheral vascular disease
• Other inflammatory conditions such as pyoderma gangrenosum and panniculitis
• Infections such as cellulitis and necrotizing fasciitis
• Iatrogenic disorders such as warfarin necrosis and early-stage nephrogenic systemic fibrosis.^3,4

The current approach to treatment is multidisciplinary and is based only on case reports and small case series, since no randomized prospective trial has been done. The goal is optimal control of calcium and phosphate homeostasis and correction of hypercoagulability.⁵ Available data^4,5 support appropriate wound care and surgical debridement.^4,5 Intravenous sodium thiosulfate is the most widely used medical treatment and can be given regardless of the level of renal function. Resolution rates have been greater than 90% in patients with normal renal function, whereas improvement in cutaneous ulcers and pain has been observed in 70% of hemodialysis patients.⁴ However, it does not reduce the associated mortality rate.⁴

Awareness of nonuremic calciphylaxis and a high index of suspicion are needed when any patient presents with a leg ulcer and no clear cause. It should be considered in the differential diagnosis of leg ulcer in patients with chronic renal failure even if they have risk factors for more common causes of ulcers, and even occasionally in patients such as ours without chronic kidney disease or other risk factors for this condition.

OUR PATIENT’S MANAGEMENT

The patient developed profuse diarrhea, and infection with Clostridium difficile was confirmed. Despite treatment with metronidazole and vancomycin, he died several days later. No treatment directed to calciphylaxis was ever started because of the patient’s unstable condition during the entire hospitalization.

A 64-year-old man was admitted for extensive painful ulceration of the left lower leg (Figure 1) that occurred after a fall and that had worsened over the last 4 months.

His medical history included hyperuricemia, hypertension, and type 2 diabetes mellitus. He had no known cardiac or renal disease.

Results of initial laboratory testing showed the following:

• Hemoglobin 10.9 g/dL (reference range 13.5–17.5); red blood cells were normocytic and normochromic
• White blood cell count 10.2 × 10⁹/L (4.5–11.0)
• Neutrophil count 9.11 × 10⁹/L (2.0–8.5)
• C-reactive protein 259 mg/L (< 5)
• Creatinine, urea, sodium, potassium, calcium, and phosphate were within normal limits.

Doppler ultrasonography of the legs showed mild diffuse atheromatous arterial disease without significant blockage of blood flow, in addition to mild bilateral venous insufficiency.

Cutaneous biopsy showed intravascular calcium deposition in the hypodermis (Figure 2) and reticular dermis, erythrocyte extravasation in the superficial dermis, and epidermal necrosis, thus establishing the diagnosis of nonuremic calciphylaxis. The vascular occlusion with spreading necrosis gave the characteristic stellate appearance.

Aside from diabetes, our patient had none of the conditions usually associated with nonuremic calciphylaxis—namely, hyperparathyroidism, previous corticosteroid therapy, warfarin use, connective tissue disease, or malignancy.

A POORLY UNDERSTOOD SMALL-VESSEL VASCULOPATHY

Calciphylaxis is a poorly understood small-vessel vasculopathy, most often associated with end-stage renal disease, with a prevalence of 1% to 4% in patients on dialysis.¹ It carries a high risk of death, most often from sepsis.

The cause is still unclear, but several conditions have been implicated, including primary hyperparathyroidism, malignancies, alcoholic liver disease, connective tissue disease, and diabetes.²

Making the diagnosis may be challenging, especially in nonuremic patients. It is a rare condition, the presentation is not always typical, and it can occur with fully normal kidney function and normal indicators of calcium and phosphate metabolism.

The differential diagnosis includes:

• Vasculitis, either primary or secondary to an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or cryoglobulinemia
• Peripheral vascular disease
• Other inflammatory conditions such as pyoderma gangrenosum and panniculitis
• Infections such as cellulitis and necrotizing fasciitis
• Iatrogenic disorders such as warfarin necrosis and early-stage nephrogenic systemic fibrosis.^3,4

The current approach to treatment is multidisciplinary and is based only on case reports and small case series, since no randomized prospective trial has been done. The goal is optimal control of calcium and phosphate homeostasis and correction of hypercoagulability.⁵ Available data^4,5 support appropriate wound care and surgical debridement.^4,5 Intravenous sodium thiosulfate is the most widely used medical treatment and can be given regardless of the level of renal function. Resolution rates have been greater than 90% in patients with normal renal function, whereas improvement in cutaneous ulcers and pain has been observed in 70% of hemodialysis patients.⁴ However, it does not reduce the associated mortality rate.⁴

Awareness of nonuremic calciphylaxis and a high index of suspicion are needed when any patient presents with a leg ulcer and no clear cause. It should be considered in the differential diagnosis of leg ulcer in patients with chronic renal failure even if they have risk factors for more common causes of ulcers, and even occasionally in patients such as ours without chronic kidney disease or other risk factors for this condition.

OUR PATIENT’S MANAGEMENT

The patient developed profuse diarrhea, and infection with Clostridium difficile was confirmed. Despite treatment with metronidazole and vancomycin, he died several days later. No treatment directed to calciphylaxis was ever started because of the patient’s unstable condition during the entire hospitalization.

A 64-year-old man was admitted for extensive painful ulceration of the left lower leg (Figure 1) that occurred after a fall and that had worsened over the last 4 months.

His medical history included hyperuricemia, hypertension, and type 2 diabetes mellitus. He had no known cardiac or renal disease.

Results of initial laboratory testing showed the following:

• Hemoglobin 10.9 g/dL (reference range 13.5–17.5); red blood cells were normocytic and normochromic
• White blood cell count 10.2 × 10⁹/L (4.5–11.0)
• Neutrophil count 9.11 × 10⁹/L (2.0–8.5)
• C-reactive protein 259 mg/L (< 5)
• Creatinine, urea, sodium, potassium, calcium, and phosphate were within normal limits.

Doppler ultrasonography of the legs showed mild diffuse atheromatous arterial disease without significant blockage of blood flow, in addition to mild bilateral venous insufficiency.

Cutaneous biopsy showed intravascular calcium deposition in the hypodermis (Figure 2) and reticular dermis, erythrocyte extravasation in the superficial dermis, and epidermal necrosis, thus establishing the diagnosis of nonuremic calciphylaxis. The vascular occlusion with spreading necrosis gave the characteristic stellate appearance.

Aside from diabetes, our patient had none of the conditions usually associated with nonuremic calciphylaxis—namely, hyperparathyroidism, previous corticosteroid therapy, warfarin use, connective tissue disease, or malignancy.

A POORLY UNDERSTOOD SMALL-VESSEL VASCULOPATHY

Calciphylaxis is a poorly understood small-vessel vasculopathy, most often associated with end-stage renal disease, with a prevalence of 1% to 4% in patients on dialysis.¹ It carries a high risk of death, most often from sepsis.

The cause is still unclear, but several conditions have been implicated, including primary hyperparathyroidism, malignancies, alcoholic liver disease, connective tissue disease, and diabetes.²

Making the diagnosis may be challenging, especially in nonuremic patients. It is a rare condition, the presentation is not always typical, and it can occur with fully normal kidney function and normal indicators of calcium and phosphate metabolism.

The differential diagnosis includes:

• Vasculitis, either primary or secondary to an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or cryoglobulinemia
• Peripheral vascular disease
• Other inflammatory conditions such as pyoderma gangrenosum and panniculitis
• Infections such as cellulitis and necrotizing fasciitis
• Iatrogenic disorders such as warfarin necrosis and early-stage nephrogenic systemic fibrosis.^3,4

The current approach to treatment is multidisciplinary and is based only on case reports and small case series, since no randomized prospective trial has been done. The goal is optimal control of calcium and phosphate homeostasis and correction of hypercoagulability.⁵ Available data^4,5 support appropriate wound care and surgical debridement.^4,5 Intravenous sodium thiosulfate is the most widely used medical treatment and can be given regardless of the level of renal function. Resolution rates have been greater than 90% in patients with normal renal function, whereas improvement in cutaneous ulcers and pain has been observed in 70% of hemodialysis patients.⁴ However, it does not reduce the associated mortality rate.⁴

Awareness of nonuremic calciphylaxis and a high index of suspicion are needed when any patient presents with a leg ulcer and no clear cause. It should be considered in the differential diagnosis of leg ulcer in patients with chronic renal failure even if they have risk factors for more common causes of ulcers, and even occasionally in patients such as ours without chronic kidney disease or other risk factors for this condition.

OUR PATIENT’S MANAGEMENT

The patient developed profuse diarrhea, and infection with Clostridium difficile was confirmed. Despite treatment with metronidazole and vancomycin, he died several days later. No treatment directed to calciphylaxis was ever started because of the patient’s unstable condition during the entire hospitalization.

Most patients with proteinuria benefit from a renin-angiotensin-aldosterone system (RAAS) inhibitor. Exceptions due to adverse effects are discussed below.

WHY RAAS INHIBITORS?

RAAS inhibitors—particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—reduce proteinuria and slow the progression of chronic kidney disease by improving glomerular hemodynamics, restoring the altered glomerular barrier function, and limiting the nonhemodynamic effects of angiotensin II and aldosterone, such as fibrosis and vascular endothelial dysfunction.¹ Studies have shown that these protective effects are, at least in part, independent of the reduction in systemic blood pressure.^2,3

EVIDENCE FOR USING RAAS INHIBITORS IN PATIENTS WITH PROTEINURIA

In nondiabetic kidney disease, there is strong evidence from the REIN and AASK trials that treatment with ACE inhibitors results in slower decline in glomerular filtration rate (GFR), and this risk reduction is more pronounced in patients with a higher degree of proteinuria.^4–6

In type 1 diabetes, treatment with an ACE inhibitor in patients with overt proteinuria was associated with a 50% decrease in the risk of the combined end point of death, dialysis, or renal transplant.⁷ Patients with moderately increased albuminuria who were treated with an ACE inhibitor also had a reduced incidence of progression to overt proteinuria.⁸ Angiotensin inhibition may be beneficial even in normotensive patients with type 1 diabetes and persistent moderately increased albuminuria.^9,10

In type 2 diabetes, the IDNT and RENAAL trials showed that treatment with an ARB in patients with overt nephropathy was associated with a statistically significant decrease (20% in IDNT, 16% in RENAAL) in the risk of the combined end point of death, end-stage renal disease, or doubling of serum creatinine.^11,12 While there are more data for ARBs than for ACE inhibitors in type 2 diabetes, the DETAIL study showed that an ACE inhibitor was at least as effective as an ARB in providing long-term renal protection in type 2 diabetes and moderately increased albuminuria.¹³

Data are limited on the role of angiotensin inhibition in normotensive patients with type 2 diabetes and persistent moderately increased albuminuria, but consensus opinion suggests treatment with an ACE inhibitor or ARB in these patients if there are no contraindications.

LIMITATIONS

Adverse effects of ACE inhibitors and ARBs include cough (more with ACE inhibitors), angioedema (more with ACE inhibitors), and hyperkalemia.

The use of ARBs in patients with a history of ACE inhibitor-related angioedema has been previously discussed in this Journal.¹⁴ Guidelines advocate caution when prescribing ARBs for patients who will benefit from RAAS inhibition and have had ACE inhibitor-related angioedema.¹⁵

These drugs should be instituted and continued in patients with proteinuria who can tolerate them without adverse effects.

RAAS inhibitor therapy can cause a modest rise in creatinine due to reduction in intraglomerular pressure. An elevation in creatinine of up to 30% that stabilizes in the first 2 months is not necessarily a reason to discontinue therapy. However, a continued rise in creatinine should prompt evaluation for excessive fall in blood pressure (especially with volume depletion from concomitant diuretic use), possible bilateral renal artery stenosis, or both. There is no level of GFR or serum creatinine at which an ACE inhibitor or ARB is absolutely contraindicated, and this decision should be made on an individual basis in conjunction with a nephrologist.

Risks for hyperkalemia should always be kept in mind at lower GFR levels. It would be prudent to check serum creatinine and potassium levels within the first week or two after starting or intensifying RAAS inhibition in these patients.

CAUTION

Combination therapy with an ACE inhibitor and an ARB was hypothesized to provide more complete RAAS blockade, with the hope of better clinical outcomes. However, this strategy has been questioned with results from three studies—ONTARGET, ALTITUDE, and the VA NEPHRON-D study—all of which showed worse renal outcomes, hypertension, and hyperkalemia with use of dual RAAS blockade.^16–20 The combined evidence so far suggests that dual RAAS blockade should not be routinely prescribed.

RAAS INHIBITION IN PRACTICE

RAAS inhibition should be instituted and continued in patients with proteinuria who are able to tolerate the therapy and do not experience adverse effects as discussed above. Although there is no specific consensus guideline on the frequency of assessment of albumin excretion after diagnosis of albuminuria and institution of RAAS inhibition and blood pressure control in patients with diabetes, periodic surveillance at least once a year is reasonable to assess response to therapy and possible disease progression.²¹ If there is significant proteinuria or possibility of nondiabetic kidney disease, the patient should be referred to a nephrologist.

Most patients with proteinuria benefit from a renin-angiotensin-aldosterone system (RAAS) inhibitor. Exceptions due to adverse effects are discussed below.

WHY RAAS INHIBITORS?

RAAS inhibitors—particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—reduce proteinuria and slow the progression of chronic kidney disease by improving glomerular hemodynamics, restoring the altered glomerular barrier function, and limiting the nonhemodynamic effects of angiotensin II and aldosterone, such as fibrosis and vascular endothelial dysfunction.¹ Studies have shown that these protective effects are, at least in part, independent of the reduction in systemic blood pressure.^2,3

EVIDENCE FOR USING RAAS INHIBITORS IN PATIENTS WITH PROTEINURIA

In nondiabetic kidney disease, there is strong evidence from the REIN and AASK trials that treatment with ACE inhibitors results in slower decline in glomerular filtration rate (GFR), and this risk reduction is more pronounced in patients with a higher degree of proteinuria.^4–6

In type 1 diabetes, treatment with an ACE inhibitor in patients with overt proteinuria was associated with a 50% decrease in the risk of the combined end point of death, dialysis, or renal transplant.⁷ Patients with moderately increased albuminuria who were treated with an ACE inhibitor also had a reduced incidence of progression to overt proteinuria.⁸ Angiotensin inhibition may be beneficial even in normotensive patients with type 1 diabetes and persistent moderately increased albuminuria.^9,10

In type 2 diabetes, the IDNT and RENAAL trials showed that treatment with an ARB in patients with overt nephropathy was associated with a statistically significant decrease (20% in IDNT, 16% in RENAAL) in the risk of the combined end point of death, end-stage renal disease, or doubling of serum creatinine.^11,12 While there are more data for ARBs than for ACE inhibitors in type 2 diabetes, the DETAIL study showed that an ACE inhibitor was at least as effective as an ARB in providing long-term renal protection in type 2 diabetes and moderately increased albuminuria.¹³

Data are limited on the role of angiotensin inhibition in normotensive patients with type 2 diabetes and persistent moderately increased albuminuria, but consensus opinion suggests treatment with an ACE inhibitor or ARB in these patients if there are no contraindications.

LIMITATIONS

Adverse effects of ACE inhibitors and ARBs include cough (more with ACE inhibitors), angioedema (more with ACE inhibitors), and hyperkalemia.

The use of ARBs in patients with a history of ACE inhibitor-related angioedema has been previously discussed in this Journal.¹⁴ Guidelines advocate caution when prescribing ARBs for patients who will benefit from RAAS inhibition and have had ACE inhibitor-related angioedema.¹⁵

These drugs should be instituted and continued in patients with proteinuria who can tolerate them without adverse effects.

RAAS inhibitor therapy can cause a modest rise in creatinine due to reduction in intraglomerular pressure. An elevation in creatinine of up to 30% that stabilizes in the first 2 months is not necessarily a reason to discontinue therapy. However, a continued rise in creatinine should prompt evaluation for excessive fall in blood pressure (especially with volume depletion from concomitant diuretic use), possible bilateral renal artery stenosis, or both. There is no level of GFR or serum creatinine at which an ACE inhibitor or ARB is absolutely contraindicated, and this decision should be made on an individual basis in conjunction with a nephrologist.

Risks for hyperkalemia should always be kept in mind at lower GFR levels. It would be prudent to check serum creatinine and potassium levels within the first week or two after starting or intensifying RAAS inhibition in these patients.

CAUTION

Combination therapy with an ACE inhibitor and an ARB was hypothesized to provide more complete RAAS blockade, with the hope of better clinical outcomes. However, this strategy has been questioned with results from three studies—ONTARGET, ALTITUDE, and the VA NEPHRON-D study—all of which showed worse renal outcomes, hypertension, and hyperkalemia with use of dual RAAS blockade.^16–20 The combined evidence so far suggests that dual RAAS blockade should not be routinely prescribed.

RAAS INHIBITION IN PRACTICE

RAAS inhibition should be instituted and continued in patients with proteinuria who are able to tolerate the therapy and do not experience adverse effects as discussed above. Although there is no specific consensus guideline on the frequency of assessment of albumin excretion after diagnosis of albuminuria and institution of RAAS inhibition and blood pressure control in patients with diabetes, periodic surveillance at least once a year is reasonable to assess response to therapy and possible disease progression.²¹ If there is significant proteinuria or possibility of nondiabetic kidney disease, the patient should be referred to a nephrologist.

Most patients with proteinuria benefit from a renin-angiotensin-aldosterone system (RAAS) inhibitor. Exceptions due to adverse effects are discussed below.

WHY RAAS INHIBITORS?

RAAS inhibitors—particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—reduce proteinuria and slow the progression of chronic kidney disease by improving glomerular hemodynamics, restoring the altered glomerular barrier function, and limiting the nonhemodynamic effects of angiotensin II and aldosterone, such as fibrosis and vascular endothelial dysfunction.¹ Studies have shown that these protective effects are, at least in part, independent of the reduction in systemic blood pressure.^2,3

EVIDENCE FOR USING RAAS INHIBITORS IN PATIENTS WITH PROTEINURIA

In nondiabetic kidney disease, there is strong evidence from the REIN and AASK trials that treatment with ACE inhibitors results in slower decline in glomerular filtration rate (GFR), and this risk reduction is more pronounced in patients with a higher degree of proteinuria.^4–6

In type 1 diabetes, treatment with an ACE inhibitor in patients with overt proteinuria was associated with a 50% decrease in the risk of the combined end point of death, dialysis, or renal transplant.⁷ Patients with moderately increased albuminuria who were treated with an ACE inhibitor also had a reduced incidence of progression to overt proteinuria.⁸ Angiotensin inhibition may be beneficial even in normotensive patients with type 1 diabetes and persistent moderately increased albuminuria.^9,10

In type 2 diabetes, the IDNT and RENAAL trials showed that treatment with an ARB in patients with overt nephropathy was associated with a statistically significant decrease (20% in IDNT, 16% in RENAAL) in the risk of the combined end point of death, end-stage renal disease, or doubling of serum creatinine.^11,12 While there are more data for ARBs than for ACE inhibitors in type 2 diabetes, the DETAIL study showed that an ACE inhibitor was at least as effective as an ARB in providing long-term renal protection in type 2 diabetes and moderately increased albuminuria.¹³

Data are limited on the role of angiotensin inhibition in normotensive patients with type 2 diabetes and persistent moderately increased albuminuria, but consensus opinion suggests treatment with an ACE inhibitor or ARB in these patients if there are no contraindications.

LIMITATIONS

Adverse effects of ACE inhibitors and ARBs include cough (more with ACE inhibitors), angioedema (more with ACE inhibitors), and hyperkalemia.

The use of ARBs in patients with a history of ACE inhibitor-related angioedema has been previously discussed in this Journal.¹⁴ Guidelines advocate caution when prescribing ARBs for patients who will benefit from RAAS inhibition and have had ACE inhibitor-related angioedema.¹⁵

These drugs should be instituted and continued in patients with proteinuria who can tolerate them without adverse effects.

RAAS inhibitor therapy can cause a modest rise in creatinine due to reduction in intraglomerular pressure. An elevation in creatinine of up to 30% that stabilizes in the first 2 months is not necessarily a reason to discontinue therapy. However, a continued rise in creatinine should prompt evaluation for excessive fall in blood pressure (especially with volume depletion from concomitant diuretic use), possible bilateral renal artery stenosis, or both. There is no level of GFR or serum creatinine at which an ACE inhibitor or ARB is absolutely contraindicated, and this decision should be made on an individual basis in conjunction with a nephrologist.

Risks for hyperkalemia should always be kept in mind at lower GFR levels. It would be prudent to check serum creatinine and potassium levels within the first week or two after starting or intensifying RAAS inhibition in these patients.

CAUTION

Combination therapy with an ACE inhibitor and an ARB was hypothesized to provide more complete RAAS blockade, with the hope of better clinical outcomes. However, this strategy has been questioned with results from three studies—ONTARGET, ALTITUDE, and the VA NEPHRON-D study—all of which showed worse renal outcomes, hypertension, and hyperkalemia with use of dual RAAS blockade.^16–20 The combined evidence so far suggests that dual RAAS blockade should not be routinely prescribed.

RAAS INHIBITION IN PRACTICE

RAAS inhibition should be instituted and continued in patients with proteinuria who are able to tolerate the therapy and do not experience adverse effects as discussed above. Although there is no specific consensus guideline on the frequency of assessment of albumin excretion after diagnosis of albuminuria and institution of RAAS inhibition and blood pressure control in patients with diabetes, periodic surveillance at least once a year is reasonable to assess response to therapy and possible disease progression.²¹ If there is significant proteinuria or possibility of nondiabetic kidney disease, the patient should be referred to a nephrologist.

In Being Wrong,¹ her treatise on the psychology of human error, Kathryn Schulz quotes William James: “Our errors are surely not such awfully solemn things.”² Being wrong, she argues, is part of the human genome. Despite aphorisms such as “we learn from our mistakes,” we are far from accepting of mistakes in medical practice. Perhaps naively, I do not believe that our need to understand how clinical errors occur and how to avoid them is based on the fear of legal repercussion. And of course we do not want to harm our patients. But our relationship with medical errors is far more complex than that. We really don’t want to be wrong.

Dr. Atul Gawande³ has promoted using checklists and a structured system to limit errors of misapplication of knowledge. Diagnostic and therapeutic algorithms, once the province of trauma surgeons, are increasingly becoming part of internal medicine.

When I was a house officer we all had our “pocket brains” in our white coats—lists of disease complications, drug doses and interactions, causes of IgA deposition in the kidney, and treatment algorithms. But we believed (probably correctly) that our teachers expected us to commit all these facts to memory in our fleshy brains. The elitist and hubristic belief that this was uniformly possible has lingered in academic medicine, still permeating even the fabric of certification examinations. We learn that it is OK to be honest and say that we don’t know the answer, but we don’t like to have to say it. Physicians finish the academic game of Chutes and Ladders with a strong aversion to being wrong.

Younger doctors today seem more comfortable with not knowing so many facts and bits of medical trivia, being able to find answers instantly using their smart phones. But a challenge is knowing at a glance the context and veracity of the answers you find. And whether the knowledge comes from our anatomic, pocket, or cyber brain, the overarching challenge is to avoid Gawande’s error of misapplication.

In this issue of the Journal, Dr. Nikhil Mull and colleagues dissect a clinical case that did not proceed as expected. They discuss, in reference to the described patient, some of the published analyses of the clinical decision-making process, highlighting various ways that our reasoning can be led astray. Having just finished a stint on the inpatient consultation service, I wish I could have read the article a few weeks ago. A bit of reflection on how we reach decisions can be as powerful as knowing the source of the facts in our pocket brain.

Being wrong, as Schulz has written, is part of the human experience, but I don’t like it. Ways to limit the chances of it’s happening in the clinic are worth keeping on a personal checklist, or perhaps as an app on my smart phone.

In Being Wrong,¹ her treatise on the psychology of human error, Kathryn Schulz quotes William James: “Our errors are surely not such awfully solemn things.”² Being wrong, she argues, is part of the human genome. Despite aphorisms such as “we learn from our mistakes,” we are far from accepting of mistakes in medical practice. Perhaps naively, I do not believe that our need to understand how clinical errors occur and how to avoid them is based on the fear of legal repercussion. And of course we do not want to harm our patients. But our relationship with medical errors is far more complex than that. We really don’t want to be wrong.

Dr. Atul Gawande³ has promoted using checklists and a structured system to limit errors of misapplication of knowledge. Diagnostic and therapeutic algorithms, once the province of trauma surgeons, are increasingly becoming part of internal medicine.

When I was a house officer we all had our “pocket brains” in our white coats—lists of disease complications, drug doses and interactions, causes of IgA deposition in the kidney, and treatment algorithms. But we believed (probably correctly) that our teachers expected us to commit all these facts to memory in our fleshy brains. The elitist and hubristic belief that this was uniformly possible has lingered in academic medicine, still permeating even the fabric of certification examinations. We learn that it is OK to be honest and say that we don’t know the answer, but we don’t like to have to say it. Physicians finish the academic game of Chutes and Ladders with a strong aversion to being wrong.

Younger doctors today seem more comfortable with not knowing so many facts and bits of medical trivia, being able to find answers instantly using their smart phones. But a challenge is knowing at a glance the context and veracity of the answers you find. And whether the knowledge comes from our anatomic, pocket, or cyber brain, the overarching challenge is to avoid Gawande’s error of misapplication.

In this issue of the Journal, Dr. Nikhil Mull and colleagues dissect a clinical case that did not proceed as expected. They discuss, in reference to the described patient, some of the published analyses of the clinical decision-making process, highlighting various ways that our reasoning can be led astray. Having just finished a stint on the inpatient consultation service, I wish I could have read the article a few weeks ago. A bit of reflection on how we reach decisions can be as powerful as knowing the source of the facts in our pocket brain.

Being wrong, as Schulz has written, is part of the human experience, but I don’t like it. Ways to limit the chances of it’s happening in the clinic are worth keeping on a personal checklist, or perhaps as an app on my smart phone.

In Being Wrong,¹ her treatise on the psychology of human error, Kathryn Schulz quotes William James: “Our errors are surely not such awfully solemn things.”² Being wrong, she argues, is part of the human genome. Despite aphorisms such as “we learn from our mistakes,” we are far from accepting of mistakes in medical practice. Perhaps naively, I do not believe that our need to understand how clinical errors occur and how to avoid them is based on the fear of legal repercussion. And of course we do not want to harm our patients. But our relationship with medical errors is far more complex than that. We really don’t want to be wrong.

Dr. Atul Gawande³ has promoted using checklists and a structured system to limit errors of misapplication of knowledge. Diagnostic and therapeutic algorithms, once the province of trauma surgeons, are increasingly becoming part of internal medicine.

When I was a house officer we all had our “pocket brains” in our white coats—lists of disease complications, drug doses and interactions, causes of IgA deposition in the kidney, and treatment algorithms. But we believed (probably correctly) that our teachers expected us to commit all these facts to memory in our fleshy brains. The elitist and hubristic belief that this was uniformly possible has lingered in academic medicine, still permeating even the fabric of certification examinations. We learn that it is OK to be honest and say that we don’t know the answer, but we don’t like to have to say it. Physicians finish the academic game of Chutes and Ladders with a strong aversion to being wrong.

Younger doctors today seem more comfortable with not knowing so many facts and bits of medical trivia, being able to find answers instantly using their smart phones. But a challenge is knowing at a glance the context and veracity of the answers you find. And whether the knowledge comes from our anatomic, pocket, or cyber brain, the overarching challenge is to avoid Gawande’s error of misapplication.

In this issue of the Journal, Dr. Nikhil Mull and colleagues dissect a clinical case that did not proceed as expected. They discuss, in reference to the described patient, some of the published analyses of the clinical decision-making process, highlighting various ways that our reasoning can be led astray. Having just finished a stint on the inpatient consultation service, I wish I could have read the article a few weeks ago. A bit of reflection on how we reach decisions can be as powerful as knowing the source of the facts in our pocket brain.

Being wrong, as Schulz has written, is part of the human experience, but I don’t like it. Ways to limit the chances of it’s happening in the clinic are worth keeping on a personal checklist, or perhaps as an app on my smart phone.

An elderly Spanish-speaking woman with morbid obesity, diabetes, hypertension, and rheumatoid arthritis presents to the emergency department with worsening shortness of breath and cough. She speaks only Spanish, so her son provides the history without the aid of an interpreter.

Her shortness of breath is most noticeable with exertion and has increased gradually over the past 2 months. She has a nonproductive cough. Her son has noticed decreased oral intake and weight loss over the past few weeks.  She has neither traveled recently nor been in contact with anyone known to have an infectious disease.

A review of systems is otherwise negative: specifically, she denies chest pain, fevers, or chills. She saw her primary care physician 3 weeks ago for these complaints and was prescribed a 3-day course of azithromycin with no improvement.

Her medications include lisinopril, atenolol, glipizide, and metformin; her son believes she may be taking others as well but is not sure. He is also unsure of what treatment his mother has received for her rheumatoid arthritis, and most of her medical records are within another health system.

The patient’s son believes she may be taking other medications but is not sure; her records are at another institution

On physical examination, the patient is coughing and appears ill. Her temperature is 99.9°F (37.7°C), heart rate 105 beats per minute, blood pressure 140/70 mm Hg, res­piratory rate 24 per minute, and oxygen saturation by pulse oximetry 89% on room air. Heart sounds are normal, jugular venous pressure cannot be assessed because of her obese body habitus, pulmonary examination demonstrates crackles in all lung fields, and lower-extremity edema is not present. Her extremities are warm and well perfused. Musculoskeletal examination reveals deformities of the joints in both hands consistent with rheumatoid arthritis.

Laboratory data:

• White blood cell count 13.0 × 10⁹/L (reference range 3.7–11.0)
• Hemoglobin level 10 g/dL (11.5–15)
• Serum creatinine 1.0 mg/dL (0.7–1.4)
• Pro-brain-type natriuretic peptide (pro-BNP) level greater than the upper limit of normal.

A chest radiograph is obtained, and the resident radiologist’s preliminary impression is that it is consistent with pulmonary vascular congestion.

The patient is admitted for further diagnostic evaluation. The emergency department resident orders intravenous furosemide and signs out to the night float medicine resident that this is an “elderly woman with hypertension, diabetes, and heart failure being admitted for a heart failure exacerbation.”

What is the accuracy of a physician’s initial working diagnosis?

Diagnostic accuracy requires both clinical knowledge and problem-solving skills.¹

A decade ago, a National Patient Safety Foundation survey² found that one in six patients had suffered a medical error related to misdiagnosis. In a large systematic review of autopsy-based diagnostic errors, the theorized rate of major errors ranged from 8.4% to as high as 24.4%.³ A study by Neale et al⁴ found that admitting diagnoses were incorrect in 6% of cases. In emergency departments, inaccuracy rates of up to 12% have been described.⁵

What factors influence the prevalence of diagnostic errors?

Initial empiric treatments, such as intravenous furosemide in the above scenario, add to the challenge of diagnosis in acute care settings and can influence clinical decisions made by subsequent providers.⁶

Nonspecific or vague symptoms make diagnosis especially challenging. Shortness of breath, for example, is a common chief complaint in medical patients, as in this case. Green et al⁷ found emergency department physicians reported clinical uncertainty for a diagnosis of heart failure in 31% of patients evaluated for “dyspnea.” Pulmonary embolism and pulmonary tuberculosis are also in the differential diagnosis for our patient, with studies reporting a misdiagnosis rate of 55% for pulmonary embolism⁸ and 50% for pulmonary tuberculosis.⁹

Hertwig et al,¹⁰ describing the diagnostic process in patients presenting to emergency departments with a nonspecific constellation of symptoms, found particularly low rates of agreement between the initial diagnostic impression and the final, correct one. In fact, the actual diagnosis was only in the physician’s initial “top three” differential diagnoses 29% to 83% of the time.

Atypical presentations of common diseases, initial nonspecific presentations of common diseases, and confounding comorbid conditions have also been associated with misdiagnosis.¹¹ Our case scenario illustrates the frequent challenges physicians face when diagnosing patients who present with nonspecific symptoms and signs on a background of multiple, chronic comorbidities.

Contextual factors in the system and environment contribute to the potential for error.¹² Examples include frequent interruptions, time pressure, poor handoffs, insufficient data, and multitasking.

In our scenario, incomplete data, time constraints, and multitasking in a busy work environment compelled the emergency department resident to rapidly synthesize information to establish a working diagnosis. Interpretations of radiographs by on-call radiology residents are similarly at risk of diagnostic error for the same reasons.¹³

Physician factors also influence diagnosis. Interestingly, physician certainty or uncertainty at the time of initial diagnosis does not uniformly appear to correlate with diagnostic accuracy. A recent study showed that physician confidence remained high regardless of the degree of difficulty in a given case, and degree of confidence also correlated poorly with whether the physician’s diagnosis was accurate.¹⁴

For patients admitted with a chief complaint of dyspnea, as in our scenario, Zwaan et al¹⁵ showed that “inappropriate selectivity” in reasoning contributed to an inaccurate diagnosis 23% of the time. Inappropriate selectivity, as defined by these authors, occurs when a probable diagnosis is not sufficiently considered and therefore is neither confirmed nor ruled out.

In our patient scenario, the failure to consider diagnoses other than heart failure and the inability to confirm a prior diagnosis of heart failure in the emergency department may contribute to a diagnostic error.

CASE CONTINUED: NO IMPROVEMENT OVER 3 DAYS

The night float resident, who has six other admissions this night, cannot ask the resident who evaluated this patient in the emergency department for further information because the shift has ended. The patient’s son left at the time of admission and is not available when the patient arrives on the medical ward.

The night float resident quickly examines the patient, enters admission orders, and signs the patient out to the intern and resident who will be caring for her during her hospitalization. The verbal handoff notes that the history was limited due to a language barrier. The initial problem list includes heart failure without a differential diagnosis, but notes that an elevated pro-BNP and chest radiograph confirm heart failure as the likely diagnosis.

Several hours after the night float resident has left, the resident presents this history to the attending physician, and together they decide to order her regular at-home medications, as well as deep vein thrombosis prophylaxis and echocardiography. In writing the orders, subcutaneous heparin once daily is erroneously entered instead of low-molecular-weight heparin daily, as this is the default in the medical record system. The tired resident fails to recognize this, and the pharmacist does not question it.

Over the next 2 days, the patient’s cough and shortness of breath persist.

After the attending physician dismisses their concerns, the residents do not bring up their idea again

On hospital day 3, two junior residents on the team (who finished their internship 2 weeks ago) review the attending radiologist’s interpretation of the chest radiograph. Unflagged, it confirms the resident’s interpretation but notes ill-defined, scattered, faint opacities. The residents believe that an interstitial pattern may be present and suggest that the patient may not have heart failure but rather a primary pulmonary disease. They bring this to the attention of their attending physician, who dismisses their concerns and comments that heart failure is a clinical diagnosis. The residents do not bring this idea up again to the attending physician.

That night, the float team is called by the nursing staff because of worsening oxygenation and cough. They add an intravenous corticosteroid, a broad-spectrum antibiotic, and an inhaled bronchodilator to the patient’s drug regimen.

How do cognitive errors predispose physicians to diagnostic errors?

When errors in diagnosis are reviewed retrospectively, cognitive or “thinking” errors are generally found, especially in nonprocedural or primary care specialties such as internal medicine, pediatrics, and emergency medicine.^16,17

A widely accepted theory on how humans make decisions was described by the psychologists Tversky and Kahneman in 1974¹⁸ and has been applied more recently to physicians’ diagnostic processes.¹⁹ Their dual process model theory states that persons with a requisite level of expertise use either the intuitive “system 1” process of thinking, based on pattern-recognition and heuristics, or the slower, more analytical “system 2” process.²⁰ Experts disagree as to whether in medicine these processes represent a binary either-or model or a continuum²¹ with relative contributions of each process determined by the physician and the task.

What are some common types of cognitive error?

Experts agree that many diagnostic errors in medicine stem from decisions arrived at by inappropriate system 1 thinking due to biases. These biases have been identified and described as they relate to medicine, most notably by Croskerry.²²

Several cognitive biases are illustrated in our clinical scenario:

The framing effect occurred when the emergency department resident listed the patient’s admitting diagnosis as heart failure during the clinical handoff of care.

Anchoring bias, as defined by Croskerry,²² is the tendency to lock onto salient features of the case too early in the diagnostic process and then to fail to adjust this initial diagnostic impression. This bias affected the admitting night float resident, primary intern, resident, and attending physician.

Diagnostic momentum, in turn, is a well-described phenomenon that clinical providers are especially vulnerable to in today’s environment of “copy-and-paste” medical records and numerous handovers of care as a consequence of residency duty-hour restrictions.²³

Availability bias refers to commonly seen diagnoses like heart failure or recently seen diagnoses, which are more “available” to the human memory. These diagnoses, which spring to mind quickly, often trick providers into thinking that because they are more easily recalled, they are also more common or more likely.

Confirmation bias. The initial working diagnosis of heart failure may have led the medical team to place greater emphasis on the elevated pro-BNP and the chest radiograph to support the initial impression while ignoring findings such as weight loss that do not support this impression.

Blind obedience. Although the residents recognized the possibility of a primary pulmonary disease, they did not investigate this further. And when the attending physician dismissed their suggestion, they thus deferred to the person in authority or with a reputation of expertise.

Overconfidence bias. Despite minimal improvement in the patient’s clinical status after effective diuresis and the suggestion of alternative diagnoses by the residents, the attending physician remained confident—perhaps overconfident—in the diagnosis of heart failure and would not consider alternatives. Overconfidence bias has been well described and occurs when a medical provider believes too strongly in his or her ability to be correct and therefore fails to consider alternative diagnoses.²⁴

Despite succumbing to overconfidence bias, the attending physician was able to overcome base-rate neglect, ie, failure to consider the prevalence of potential diagnoses in diagnostic reasoning.

Each of these biases, and others not mentioned, can lead to premature closure, which is the unfortunate root cause of many diagnostic errors and delays. We have illustrated several biases in our case scenario that led several physicians on the medical team to prematurely “close” on the diagnosis of heart failure (Table 1).

CASE CONTINUED: SURPRISES AND REASSESSMENT

On hospital day 4, the patient’s medication lists from her previous hospitalizations arrive, and the team is surprised to discover that she has been receiving infliximab for the past 3 to 4 months for her rheumatoid arthritis.

Additionally, an echocardiogram that was ordered on hospital day 1 but was lost in the cardiologist’s reading queue comes in and shows a normal ejection fraction with no evidence of elevated filling pressures.

Computed tomography of the chest reveals a reticular pattern with innumerable, tiny, 1- to 2-mm pulmonary nodules. The differential diagnosis is expanded to include hypersensitivity pneumonitis, lymphoma, fungal infection, and miliary tuberculosis.

How do faulty systems contribute to diagnostic error?

It is increasingly recognized that diagnostic errors can occur as a result of cognitive error, systems-based error, or quite commonly, both. Graber et al¹⁷ analyzed 100 cases of diagnostic error and determined that while cognitive errors did occur in most of them, nearly half the time both cognitive and systems-based errors contributed simultaneously.¹⁷ Observers have further delineated the importance of the systems context and how it affects our thinking.²⁵

In this case, the language barrier, lack of availability of family, and inability to promptly utilize interpreter services contributed to early problems in acquiring a detailed history and a complete medication list that included the immunosuppressant infliximab. Later, a systems error led to a delay in the interpretation of an echocardiogram. Each of these factors, if prevented, would have presumably resulted in expansion of the differential diagnosis and earlier arrival at the correct diagnosis.

CASE CONTINUED: THE PATIENT DIES OF TUBERCULOSIS

The patient is moved to a negative pressure room, and the pulmonary consultants recommend bronchoscopy. During the procedure, the patient suffers acute respiratory failure, is intubated, and is transferred to the medical intensive care unit, where a saddle pulmonary embolism is diagnosed by computed tomographic angiography.

One day later, the sputum culture from the bronchoscopy returns as positive for acid-fast bacilli. A four-drug regimen for tuberculosis is started. The patient continues to have a downward course and expires 2 weeks later. Autopsy reveals miliary tuberculosis.

What is the frequency of diagnostic error in medicine?

Diagnostic error is estimated to have a frequency of 10% to 20%.²⁴ Rates of diagnostic error are similar irrespective of method of determination, eg, from autopsy,³ standardized patients (ie, actors presenting with scripted scenarios),²⁶ or case reviews.²⁷ Patient surveys report patient-perceived harm from diagnostic error at a rate of 35% to 42%.^28,29 The landmark Harvard Medical Practice Study found that 17% of all adverse events were attributable to diagnostic error.³⁰

Diagnostic error is the most common type of medical error in nonprocedural medical fields.³¹ It causes a disproportionately large amount of morbidity and death.

Diagnostic error is the most common cause of malpractice claims in the United States. In inpatient and outpatient settings, for both medical and surgical patients, it accounted for 45.9% of all outpatient malpractice claims in 2009, making it the most common reason for medical malpractice litigation.³² A 2013 study indicated that diagnostic error is more common, more expensive, and two times more likely to result in death than any other category of error.³³

CASE CONTINUED: MORBIDITY AND MORTALITY CONFERENCE

The patient’s case is brought to a morbidity and mortality conference for discussion. The systems issues in the case—including medication reconciliation, availability of interpreters, and timing and process of echocardiogram readings—are all discussed, but clinical reasoning and cognitive errors made in the case are avoided.

Why are cognitive errors often neglected in discussions of medical error?

Historically, openly discussing error in medicine has been difficult. Over the past decade, however, and fueled by the landmark Institute of Medicine report To Err is Human,³⁴ the healthcare community has made substantial strides in identifying and talking about systems factors as a cause of preventable medical error.^34,35

While systems contributions to medical error are inherently “external” to physicians and other healthcare providers, the cognitive contributions to error are inherently “internal” and are often considered personal. This has led to diagnostic error being kept out of many patient safety conversations. Further, while the solutions to systems errors are often tangible, such as implementing a fall prevention program or changing the physical packaging of a medication to reduce a medication dispensing or administration error, solutions to cognitive errors are generally considered more challenging to address by organizations trying to improve patient safety.

How can hospitals and department leaders do better?

Healthcare organizations and leaders of clinical teams or departments can implement several strategies.³⁶

First, they can seek out and analyze the causes of diagnostic errors that are occurring locally in their institution and learn from their diagnostic errors, such as the one in our clinical scenario.

Trainees, physicians, and nurses should be comfortable questioning each other

Second, they can promote a culture of open communication and questioning around diagnosis. Trainees, physicians, and nurses should be comfortable questioning each other, including those higher up in the hierarchy, by saying, “I’m not sure” or “What else could this be?” to help reduce cognitive bias and expand the diagnostic possibilities.

Similarly, developing strategies to promote feedback on diagnosis among physicians will allow us all to learn from our diagnostic mistakes.

Use of the electronic medical record to assist in follow-up of pending diagnostic studies and patient return visits is yet another strategy.

Finally, healthcare organizations can adopt strategies to promote patient involvement in diagnosis, such as providing patients with copies of their test results and discharge summaries, encouraging the use of electronic patient communication portals, and empowering patients to ask questions related to their diagnosis. Prioritizing potential solutions to reduce diagnostic errors may be helpful in situations, depending on the context and environment, in which all proposed interventions may not be possible.

CASE CONTINUED: LEARNING FROM MISTAKES

The attending physician and resident in the case meet after the conference to review their clinical decision-making. Both are interested in learning from this case and improving their diagnostic skills in the future.

What specific steps can clinicians take to mitigate cognitive bias in daily practice?

In addition to continuing to expand one’s medical knowledge and gain more clinical experience, we can suggest several small steps to busy clinicians, taken individually or in combination with others that may improve diagnostic skills by reducing the potential for biased thinking in clinical practice.

From Croskerry P. Clinical cognition and diagnostic error: applications of a dual process model of reasoning. Adv Health Sci Educ 2009; 14:27–35. With kind permission from Springer Science and Business Media.

Think about your thinking. Our first recommendation would be to become more familiar with the dual process theory of clinical cognition (Figure 1).^37,38 This theoretical framework may be very helpful as a foundation from which to build better thinking skills. Physicians, especially residents, and students can be taught these concepts and their potential to contribute to diagnostic errors, and can use these skills to recognize those contributions in others’ diagnostic practices and even in their own.³⁹

Facilitating metacognition, or “thinking about one’s thinking,” may help clinicians catch themselves in thinking traps and provide the opportunity to reflect on biases retrospectively, as a double check or an opportunity to learn from a mistake.

Recognize your emotions. Gaining an understanding of the effect of one’s emotions on decision-making also can help clinicians free themselves of bias. As human beings, healthcare professionals are  susceptible to emotion, and the best approach to mitigate the emotional influences may be to consciously name them and adjust for them.⁴⁰

Because it is impractical to apply slow, analytical system 2 approaches to every case, skills that hone and develop more accurate, reliable system 1 thinking are crucial. Gaining broad exposure to increased numbers of cases may be the most reliable way to build an experiential repertoire of “illness scripts,” but there are ways to increase the experiential value of any case with a few techniques that have potential to promote better intuition.⁴¹

Embracing uncertainty in the early diagnostic process and envisioning the worst-case scenario in a case allows the consideration of additional diagnostic paths outside of the current working diagnosis, potentially priming the clinician to look for and recognize early warning signs that could argue against the initial diagnosis at a time when an adjustment could be made to prevent a bad outcome.

Practice progressive problem-solving,⁴² a technique in which the physician creates additional challenges to increase the cognitive burden of a “routine” case in an effort to train his or her mind and sharpen intuition. An example of this practice is contemplating a backup treatment plan in advance in the event of a poor response to or an adverse effect of treatment. Highly rated physicians and teachers perform this regularly.^43,44 Other ways to maximize the learning value of an individual case include seeking feedback on patient outcomes, especially when a patient has been discharged or transferred to another provider’s care, or when the physician goes off service.

Simulation, traditionally used for procedural training, has potential as well. Cognitive simulation, such as case reports or virtual patient modules, have potential to enhance clinical reasoning skills as well, though possibly at greater cost of time and expense.

Decreased reliance on memory is likely to improve diagnostic reasoning. Systems tools such as checklists⁴⁵ and health information technology⁴⁶ have potential to reduce diagnostic errors, not by taking thinking away from the clinician but by relieving the cognitive load enough to facilitate greater effort toward reasoning.

Slow down. Finally, and perhaps most important, recent models of clinical expertise have suggested that mastery comes from having a robust intuitive method, with a sense of the limitations of the intuitive approach, an ability to recognize the need to perform more analytical reasoning in select cases, and the willingness to do so. In short, it may well be that the hallmark of a master clinician is the propensity to slow down when necessary.⁴⁷

A ‘diagnostic time-out’ for safety might catch opportunities to recognize and mitigate biases and errors

If one considers diagnosis a cognitive procedure, perhaps a brief “diagnostic time-out” for safety might afford an opportunity to recognize and mitigate biases and errors. There are likely many potential scripts for a good diagnostic time-out, but to be functional it should be brief and simple to facilitate consistent use. We have recommended the following four questions to our residents as a starting point, any of which could signal the need to switch to a slower, analytic approach.

Four-step diagnostic time-out

• What else can it be?
• Is there anything about the case that does not fit?
• Is it possible that multiple processes are going on?
• Do I need to slow down?

These questions can serve as a double check for an intuitively formed initial working diagnosis, incorporating many of the principles discussed above, in a way that would hopefully avoid undue burden on a busy clinician. These techniques, it must be acknowledged, have not yet been directly tied to reductions in diagnostic errors. However, diagnostic errors, as discussed, are very difficult to identify and study, and these techniques will serve mainly to improve habits that are likely to show benefits over much longer time periods than most studies can measure.

An elderly Spanish-speaking woman with morbid obesity, diabetes, hypertension, and rheumatoid arthritis presents to the emergency department with worsening shortness of breath and cough. She speaks only Spanish, so her son provides the history without the aid of an interpreter.

Her shortness of breath is most noticeable with exertion and has increased gradually over the past 2 months. She has a nonproductive cough. Her son has noticed decreased oral intake and weight loss over the past few weeks.  She has neither traveled recently nor been in contact with anyone known to have an infectious disease.

A review of systems is otherwise negative: specifically, she denies chest pain, fevers, or chills. She saw her primary care physician 3 weeks ago for these complaints and was prescribed a 3-day course of azithromycin with no improvement.

Her medications include lisinopril, atenolol, glipizide, and metformin; her son believes she may be taking others as well but is not sure. He is also unsure of what treatment his mother has received for her rheumatoid arthritis, and most of her medical records are within another health system.

The patient’s son believes she may be taking other medications but is not sure; her records are at another institution

On physical examination, the patient is coughing and appears ill. Her temperature is 99.9°F (37.7°C), heart rate 105 beats per minute, blood pressure 140/70 mm Hg, res­piratory rate 24 per minute, and oxygen saturation by pulse oximetry 89% on room air. Heart sounds are normal, jugular venous pressure cannot be assessed because of her obese body habitus, pulmonary examination demonstrates crackles in all lung fields, and lower-extremity edema is not present. Her extremities are warm and well perfused. Musculoskeletal examination reveals deformities of the joints in both hands consistent with rheumatoid arthritis.

Laboratory data:

• White blood cell count 13.0 × 10⁹/L (reference range 3.7–11.0)
• Hemoglobin level 10 g/dL (11.5–15)
• Serum creatinine 1.0 mg/dL (0.7–1.4)
• Pro-brain-type natriuretic peptide (pro-BNP) level greater than the upper limit of normal.

A chest radiograph is obtained, and the resident radiologist’s preliminary impression is that it is consistent with pulmonary vascular congestion.

The patient is admitted for further diagnostic evaluation. The emergency department resident orders intravenous furosemide and signs out to the night float medicine resident that this is an “elderly woman with hypertension, diabetes, and heart failure being admitted for a heart failure exacerbation.”

What is the accuracy of a physician’s initial working diagnosis?

Diagnostic accuracy requires both clinical knowledge and problem-solving skills.¹

A decade ago, a National Patient Safety Foundation survey² found that one in six patients had suffered a medical error related to misdiagnosis. In a large systematic review of autopsy-based diagnostic errors, the theorized rate of major errors ranged from 8.4% to as high as 24.4%.³ A study by Neale et al⁴ found that admitting diagnoses were incorrect in 6% of cases. In emergency departments, inaccuracy rates of up to 12% have been described.⁵

What factors influence the prevalence of diagnostic errors?

Initial empiric treatments, such as intravenous furosemide in the above scenario, add to the challenge of diagnosis in acute care settings and can influence clinical decisions made by subsequent providers.⁶

Nonspecific or vague symptoms make diagnosis especially challenging. Shortness of breath, for example, is a common chief complaint in medical patients, as in this case. Green et al⁷ found emergency department physicians reported clinical uncertainty for a diagnosis of heart failure in 31% of patients evaluated for “dyspnea.” Pulmonary embolism and pulmonary tuberculosis are also in the differential diagnosis for our patient, with studies reporting a misdiagnosis rate of 55% for pulmonary embolism⁸ and 50% for pulmonary tuberculosis.⁹

Hertwig et al,¹⁰ describing the diagnostic process in patients presenting to emergency departments with a nonspecific constellation of symptoms, found particularly low rates of agreement between the initial diagnostic impression and the final, correct one. In fact, the actual diagnosis was only in the physician’s initial “top three” differential diagnoses 29% to 83% of the time.

Atypical presentations of common diseases, initial nonspecific presentations of common diseases, and confounding comorbid conditions have also been associated with misdiagnosis.¹¹ Our case scenario illustrates the frequent challenges physicians face when diagnosing patients who present with nonspecific symptoms and signs on a background of multiple, chronic comorbidities.

Contextual factors in the system and environment contribute to the potential for error.¹² Examples include frequent interruptions, time pressure, poor handoffs, insufficient data, and multitasking.

In our scenario, incomplete data, time constraints, and multitasking in a busy work environment compelled the emergency department resident to rapidly synthesize information to establish a working diagnosis. Interpretations of radiographs by on-call radiology residents are similarly at risk of diagnostic error for the same reasons.¹³

Physician factors also influence diagnosis. Interestingly, physician certainty or uncertainty at the time of initial diagnosis does not uniformly appear to correlate with diagnostic accuracy. A recent study showed that physician confidence remained high regardless of the degree of difficulty in a given case, and degree of confidence also correlated poorly with whether the physician’s diagnosis was accurate.¹⁴

For patients admitted with a chief complaint of dyspnea, as in our scenario, Zwaan et al¹⁵ showed that “inappropriate selectivity” in reasoning contributed to an inaccurate diagnosis 23% of the time. Inappropriate selectivity, as defined by these authors, occurs when a probable diagnosis is not sufficiently considered and therefore is neither confirmed nor ruled out.

In our patient scenario, the failure to consider diagnoses other than heart failure and the inability to confirm a prior diagnosis of heart failure in the emergency department may contribute to a diagnostic error.

CASE CONTINUED: NO IMPROVEMENT OVER 3 DAYS

The night float resident, who has six other admissions this night, cannot ask the resident who evaluated this patient in the emergency department for further information because the shift has ended. The patient’s son left at the time of admission and is not available when the patient arrives on the medical ward.

The night float resident quickly examines the patient, enters admission orders, and signs the patient out to the intern and resident who will be caring for her during her hospitalization. The verbal handoff notes that the history was limited due to a language barrier. The initial problem list includes heart failure without a differential diagnosis, but notes that an elevated pro-BNP and chest radiograph confirm heart failure as the likely diagnosis.

Several hours after the night float resident has left, the resident presents this history to the attending physician, and together they decide to order her regular at-home medications, as well as deep vein thrombosis prophylaxis and echocardiography. In writing the orders, subcutaneous heparin once daily is erroneously entered instead of low-molecular-weight heparin daily, as this is the default in the medical record system. The tired resident fails to recognize this, and the pharmacist does not question it.

Over the next 2 days, the patient’s cough and shortness of breath persist.

After the attending physician dismisses their concerns, the residents do not bring up their idea again

On hospital day 3, two junior residents on the team (who finished their internship 2 weeks ago) review the attending radiologist’s interpretation of the chest radiograph. Unflagged, it confirms the resident’s interpretation but notes ill-defined, scattered, faint opacities. The residents believe that an interstitial pattern may be present and suggest that the patient may not have heart failure but rather a primary pulmonary disease. They bring this to the attention of their attending physician, who dismisses their concerns and comments that heart failure is a clinical diagnosis. The residents do not bring this idea up again to the attending physician.

That night, the float team is called by the nursing staff because of worsening oxygenation and cough. They add an intravenous corticosteroid, a broad-spectrum antibiotic, and an inhaled bronchodilator to the patient’s drug regimen.

How do cognitive errors predispose physicians to diagnostic errors?

When errors in diagnosis are reviewed retrospectively, cognitive or “thinking” errors are generally found, especially in nonprocedural or primary care specialties such as internal medicine, pediatrics, and emergency medicine.^16,17

A widely accepted theory on how humans make decisions was described by the psychologists Tversky and Kahneman in 1974¹⁸ and has been applied more recently to physicians’ diagnostic processes.¹⁹ Their dual process model theory states that persons with a requisite level of expertise use either the intuitive “system 1” process of thinking, based on pattern-recognition and heuristics, or the slower, more analytical “system 2” process.²⁰ Experts disagree as to whether in medicine these processes represent a binary either-or model or a continuum²¹ with relative contributions of each process determined by the physician and the task.

What are some common types of cognitive error?

Experts agree that many diagnostic errors in medicine stem from decisions arrived at by inappropriate system 1 thinking due to biases. These biases have been identified and described as they relate to medicine, most notably by Croskerry.²²

Several cognitive biases are illustrated in our clinical scenario:

The framing effect occurred when the emergency department resident listed the patient’s admitting diagnosis as heart failure during the clinical handoff of care.

Anchoring bias, as defined by Croskerry,²² is the tendency to lock onto salient features of the case too early in the diagnostic process and then to fail to adjust this initial diagnostic impression. This bias affected the admitting night float resident, primary intern, resident, and attending physician.

Diagnostic momentum, in turn, is a well-described phenomenon that clinical providers are especially vulnerable to in today’s environment of “copy-and-paste” medical records and numerous handovers of care as a consequence of residency duty-hour restrictions.²³

Availability bias refers to commonly seen diagnoses like heart failure or recently seen diagnoses, which are more “available” to the human memory. These diagnoses, which spring to mind quickly, often trick providers into thinking that because they are more easily recalled, they are also more common or more likely.

Confirmation bias. The initial working diagnosis of heart failure may have led the medical team to place greater emphasis on the elevated pro-BNP and the chest radiograph to support the initial impression while ignoring findings such as weight loss that do not support this impression.

Blind obedience. Although the residents recognized the possibility of a primary pulmonary disease, they did not investigate this further. And when the attending physician dismissed their suggestion, they thus deferred to the person in authority or with a reputation of expertise.

Overconfidence bias. Despite minimal improvement in the patient’s clinical status after effective diuresis and the suggestion of alternative diagnoses by the residents, the attending physician remained confident—perhaps overconfident—in the diagnosis of heart failure and would not consider alternatives. Overconfidence bias has been well described and occurs when a medical provider believes too strongly in his or her ability to be correct and therefore fails to consider alternative diagnoses.²⁴

Despite succumbing to overconfidence bias, the attending physician was able to overcome base-rate neglect, ie, failure to consider the prevalence of potential diagnoses in diagnostic reasoning.

Each of these biases, and others not mentioned, can lead to premature closure, which is the unfortunate root cause of many diagnostic errors and delays. We have illustrated several biases in our case scenario that led several physicians on the medical team to prematurely “close” on the diagnosis of heart failure (Table 1).

CASE CONTINUED: SURPRISES AND REASSESSMENT

On hospital day 4, the patient’s medication lists from her previous hospitalizations arrive, and the team is surprised to discover that she has been receiving infliximab for the past 3 to 4 months for her rheumatoid arthritis.

Additionally, an echocardiogram that was ordered on hospital day 1 but was lost in the cardiologist’s reading queue comes in and shows a normal ejection fraction with no evidence of elevated filling pressures.

Computed tomography of the chest reveals a reticular pattern with innumerable, tiny, 1- to 2-mm pulmonary nodules. The differential diagnosis is expanded to include hypersensitivity pneumonitis, lymphoma, fungal infection, and miliary tuberculosis.

How do faulty systems contribute to diagnostic error?

It is increasingly recognized that diagnostic errors can occur as a result of cognitive error, systems-based error, or quite commonly, both. Graber et al¹⁷ analyzed 100 cases of diagnostic error and determined that while cognitive errors did occur in most of them, nearly half the time both cognitive and systems-based errors contributed simultaneously.¹⁷ Observers have further delineated the importance of the systems context and how it affects our thinking.²⁵

In this case, the language barrier, lack of availability of family, and inability to promptly utilize interpreter services contributed to early problems in acquiring a detailed history and a complete medication list that included the immunosuppressant infliximab. Later, a systems error led to a delay in the interpretation of an echocardiogram. Each of these factors, if prevented, would have presumably resulted in expansion of the differential diagnosis and earlier arrival at the correct diagnosis.

CASE CONTINUED: THE PATIENT DIES OF TUBERCULOSIS

The patient is moved to a negative pressure room, and the pulmonary consultants recommend bronchoscopy. During the procedure, the patient suffers acute respiratory failure, is intubated, and is transferred to the medical intensive care unit, where a saddle pulmonary embolism is diagnosed by computed tomographic angiography.

One day later, the sputum culture from the bronchoscopy returns as positive for acid-fast bacilli. A four-drug regimen for tuberculosis is started. The patient continues to have a downward course and expires 2 weeks later. Autopsy reveals miliary tuberculosis.

What is the frequency of diagnostic error in medicine?

Diagnostic error is estimated to have a frequency of 10% to 20%.²⁴ Rates of diagnostic error are similar irrespective of method of determination, eg, from autopsy,³ standardized patients (ie, actors presenting with scripted scenarios),²⁶ or case reviews.²⁷ Patient surveys report patient-perceived harm from diagnostic error at a rate of 35% to 42%.^28,29 The landmark Harvard Medical Practice Study found that 17% of all adverse events were attributable to diagnostic error.³⁰

Diagnostic error is the most common type of medical error in nonprocedural medical fields.³¹ It causes a disproportionately large amount of morbidity and death.

Diagnostic error is the most common cause of malpractice claims in the United States. In inpatient and outpatient settings, for both medical and surgical patients, it accounted for 45.9% of all outpatient malpractice claims in 2009, making it the most common reason for medical malpractice litigation.³² A 2013 study indicated that diagnostic error is more common, more expensive, and two times more likely to result in death than any other category of error.³³

CASE CONTINUED: MORBIDITY AND MORTALITY CONFERENCE

The patient’s case is brought to a morbidity and mortality conference for discussion. The systems issues in the case—including medication reconciliation, availability of interpreters, and timing and process of echocardiogram readings—are all discussed, but clinical reasoning and cognitive errors made in the case are avoided.

Why are cognitive errors often neglected in discussions of medical error?

Historically, openly discussing error in medicine has been difficult. Over the past decade, however, and fueled by the landmark Institute of Medicine report To Err is Human,³⁴ the healthcare community has made substantial strides in identifying and talking about systems factors as a cause of preventable medical error.^34,35

While systems contributions to medical error are inherently “external” to physicians and other healthcare providers, the cognitive contributions to error are inherently “internal” and are often considered personal. This has led to diagnostic error being kept out of many patient safety conversations. Further, while the solutions to systems errors are often tangible, such as implementing a fall prevention program or changing the physical packaging of a medication to reduce a medication dispensing or administration error, solutions to cognitive errors are generally considered more challenging to address by organizations trying to improve patient safety.

How can hospitals and department leaders do better?

Healthcare organizations and leaders of clinical teams or departments can implement several strategies.³⁶

First, they can seek out and analyze the causes of diagnostic errors that are occurring locally in their institution and learn from their diagnostic errors, such as the one in our clinical scenario.

Trainees, physicians, and nurses should be comfortable questioning each other

Second, they can promote a culture of open communication and questioning around diagnosis. Trainees, physicians, and nurses should be comfortable questioning each other, including those higher up in the hierarchy, by saying, “I’m not sure” or “What else could this be?” to help reduce cognitive bias and expand the diagnostic possibilities.

Similarly, developing strategies to promote feedback on diagnosis among physicians will allow us all to learn from our diagnostic mistakes.

Use of the electronic medical record to assist in follow-up of pending diagnostic studies and patient return visits is yet another strategy.

Finally, healthcare organizations can adopt strategies to promote patient involvement in diagnosis, such as providing patients with copies of their test results and discharge summaries, encouraging the use of electronic patient communication portals, and empowering patients to ask questions related to their diagnosis. Prioritizing potential solutions to reduce diagnostic errors may be helpful in situations, depending on the context and environment, in which all proposed interventions may not be possible.

CASE CONTINUED: LEARNING FROM MISTAKES

The attending physician and resident in the case meet after the conference to review their clinical decision-making. Both are interested in learning from this case and improving their diagnostic skills in the future.

What specific steps can clinicians take to mitigate cognitive bias in daily practice?

In addition to continuing to expand one’s medical knowledge and gain more clinical experience, we can suggest several small steps to busy clinicians, taken individually or in combination with others that may improve diagnostic skills by reducing the potential for biased thinking in clinical practice.

From Croskerry P. Clinical cognition and diagnostic error: applications of a dual process model of reasoning. Adv Health Sci Educ 2009; 14:27–35. With kind permission from Springer Science and Business Media.

Think about your thinking. Our first recommendation would be to become more familiar with the dual process theory of clinical cognition (Figure 1).^37,38 This theoretical framework may be very helpful as a foundation from which to build better thinking skills. Physicians, especially residents, and students can be taught these concepts and their potential to contribute to diagnostic errors, and can use these skills to recognize those contributions in others’ diagnostic practices and even in their own.³⁹

Facilitating metacognition, or “thinking about one’s thinking,” may help clinicians catch themselves in thinking traps and provide the opportunity to reflect on biases retrospectively, as a double check or an opportunity to learn from a mistake.

Recognize your emotions. Gaining an understanding of the effect of one’s emotions on decision-making also can help clinicians free themselves of bias. As human beings, healthcare professionals are  susceptible to emotion, and the best approach to mitigate the emotional influences may be to consciously name them and adjust for them.⁴⁰

Because it is impractical to apply slow, analytical system 2 approaches to every case, skills that hone and develop more accurate, reliable system 1 thinking are crucial. Gaining broad exposure to increased numbers of cases may be the most reliable way to build an experiential repertoire of “illness scripts,” but there are ways to increase the experiential value of any case with a few techniques that have potential to promote better intuition.⁴¹

Embracing uncertainty in the early diagnostic process and envisioning the worst-case scenario in a case allows the consideration of additional diagnostic paths outside of the current working diagnosis, potentially priming the clinician to look for and recognize early warning signs that could argue against the initial diagnosis at a time when an adjustment could be made to prevent a bad outcome.

Practice progressive problem-solving,⁴² a technique in which the physician creates additional challenges to increase the cognitive burden of a “routine” case in an effort to train his or her mind and sharpen intuition. An example of this practice is contemplating a backup treatment plan in advance in the event of a poor response to or an adverse effect of treatment. Highly rated physicians and teachers perform this regularly.^43,44 Other ways to maximize the learning value of an individual case include seeking feedback on patient outcomes, especially when a patient has been discharged or transferred to another provider’s care, or when the physician goes off service.

Simulation, traditionally used for procedural training, has potential as well. Cognitive simulation, such as case reports or virtual patient modules, have potential to enhance clinical reasoning skills as well, though possibly at greater cost of time and expense.

Decreased reliance on memory is likely to improve diagnostic reasoning. Systems tools such as checklists⁴⁵ and health information technology⁴⁶ have potential to reduce diagnostic errors, not by taking thinking away from the clinician but by relieving the cognitive load enough to facilitate greater effort toward reasoning.

Slow down. Finally, and perhaps most important, recent models of clinical expertise have suggested that mastery comes from having a robust intuitive method, with a sense of the limitations of the intuitive approach, an ability to recognize the need to perform more analytical reasoning in select cases, and the willingness to do so. In short, it may well be that the hallmark of a master clinician is the propensity to slow down when necessary.⁴⁷

A ‘diagnostic time-out’ for safety might catch opportunities to recognize and mitigate biases and errors

If one considers diagnosis a cognitive procedure, perhaps a brief “diagnostic time-out” for safety might afford an opportunity to recognize and mitigate biases and errors. There are likely many potential scripts for a good diagnostic time-out, but to be functional it should be brief and simple to facilitate consistent use. We have recommended the following four questions to our residents as a starting point, any of which could signal the need to switch to a slower, analytic approach.

Four-step diagnostic time-out

• What else can it be?
• Is there anything about the case that does not fit?
• Is it possible that multiple processes are going on?
• Do I need to slow down?

These questions can serve as a double check for an intuitively formed initial working diagnosis, incorporating many of the principles discussed above, in a way that would hopefully avoid undue burden on a busy clinician. These techniques, it must be acknowledged, have not yet been directly tied to reductions in diagnostic errors. However, diagnostic errors, as discussed, are very difficult to identify and study, and these techniques will serve mainly to improve habits that are likely to show benefits over much longer time periods than most studies can measure.

An elderly Spanish-speaking woman with morbid obesity, diabetes, hypertension, and rheumatoid arthritis presents to the emergency department with worsening shortness of breath and cough. She speaks only Spanish, so her son provides the history without the aid of an interpreter.

Her shortness of breath is most noticeable with exertion and has increased gradually over the past 2 months. She has a nonproductive cough. Her son has noticed decreased oral intake and weight loss over the past few weeks.  She has neither traveled recently nor been in contact with anyone known to have an infectious disease.

A review of systems is otherwise negative: specifically, she denies chest pain, fevers, or chills. She saw her primary care physician 3 weeks ago for these complaints and was prescribed a 3-day course of azithromycin with no improvement.

Her medications include lisinopril, atenolol, glipizide, and metformin; her son believes she may be taking others as well but is not sure. He is also unsure of what treatment his mother has received for her rheumatoid arthritis, and most of her medical records are within another health system.

The patient’s son believes she may be taking other medications but is not sure; her records are at another institution

On physical examination, the patient is coughing and appears ill. Her temperature is 99.9°F (37.7°C), heart rate 105 beats per minute, blood pressure 140/70 mm Hg, res­piratory rate 24 per minute, and oxygen saturation by pulse oximetry 89% on room air. Heart sounds are normal, jugular venous pressure cannot be assessed because of her obese body habitus, pulmonary examination demonstrates crackles in all lung fields, and lower-extremity edema is not present. Her extremities are warm and well perfused. Musculoskeletal examination reveals deformities of the joints in both hands consistent with rheumatoid arthritis.

Laboratory data:

• White blood cell count 13.0 × 10⁹/L (reference range 3.7–11.0)
• Hemoglobin level 10 g/dL (11.5–15)
• Serum creatinine 1.0 mg/dL (0.7–1.4)
• Pro-brain-type natriuretic peptide (pro-BNP) level greater than the upper limit of normal.

A chest radiograph is obtained, and the resident radiologist’s preliminary impression is that it is consistent with pulmonary vascular congestion.

The patient is admitted for further diagnostic evaluation. The emergency department resident orders intravenous furosemide and signs out to the night float medicine resident that this is an “elderly woman with hypertension, diabetes, and heart failure being admitted for a heart failure exacerbation.”

What is the accuracy of a physician’s initial working diagnosis?

Diagnostic accuracy requires both clinical knowledge and problem-solving skills.¹

A decade ago, a National Patient Safety Foundation survey² found that one in six patients had suffered a medical error related to misdiagnosis. In a large systematic review of autopsy-based diagnostic errors, the theorized rate of major errors ranged from 8.4% to as high as 24.4%.³ A study by Neale et al⁴ found that admitting diagnoses were incorrect in 6% of cases. In emergency departments, inaccuracy rates of up to 12% have been described.⁵

What factors influence the prevalence of diagnostic errors?

Initial empiric treatments, such as intravenous furosemide in the above scenario, add to the challenge of diagnosis in acute care settings and can influence clinical decisions made by subsequent providers.⁶

Nonspecific or vague symptoms make diagnosis especially challenging. Shortness of breath, for example, is a common chief complaint in medical patients, as in this case. Green et al⁷ found emergency department physicians reported clinical uncertainty for a diagnosis of heart failure in 31% of patients evaluated for “dyspnea.” Pulmonary embolism and pulmonary tuberculosis are also in the differential diagnosis for our patient, with studies reporting a misdiagnosis rate of 55% for pulmonary embolism⁸ and 50% for pulmonary tuberculosis.⁹

Hertwig et al,¹⁰ describing the diagnostic process in patients presenting to emergency departments with a nonspecific constellation of symptoms, found particularly low rates of agreement between the initial diagnostic impression and the final, correct one. In fact, the actual diagnosis was only in the physician’s initial “top three” differential diagnoses 29% to 83% of the time.

Atypical presentations of common diseases, initial nonspecific presentations of common diseases, and confounding comorbid conditions have also been associated with misdiagnosis.¹¹ Our case scenario illustrates the frequent challenges physicians face when diagnosing patients who present with nonspecific symptoms and signs on a background of multiple, chronic comorbidities.

Contextual factors in the system and environment contribute to the potential for error.¹² Examples include frequent interruptions, time pressure, poor handoffs, insufficient data, and multitasking.

In our scenario, incomplete data, time constraints, and multitasking in a busy work environment compelled the emergency department resident to rapidly synthesize information to establish a working diagnosis. Interpretations of radiographs by on-call radiology residents are similarly at risk of diagnostic error for the same reasons.¹³

Physician factors also influence diagnosis. Interestingly, physician certainty or uncertainty at the time of initial diagnosis does not uniformly appear to correlate with diagnostic accuracy. A recent study showed that physician confidence remained high regardless of the degree of difficulty in a given case, and degree of confidence also correlated poorly with whether the physician’s diagnosis was accurate.¹⁴

For patients admitted with a chief complaint of dyspnea, as in our scenario, Zwaan et al¹⁵ showed that “inappropriate selectivity” in reasoning contributed to an inaccurate diagnosis 23% of the time. Inappropriate selectivity, as defined by these authors, occurs when a probable diagnosis is not sufficiently considered and therefore is neither confirmed nor ruled out.

In our patient scenario, the failure to consider diagnoses other than heart failure and the inability to confirm a prior diagnosis of heart failure in the emergency department may contribute to a diagnostic error.

CASE CONTINUED: NO IMPROVEMENT OVER 3 DAYS

The night float resident, who has six other admissions this night, cannot ask the resident who evaluated this patient in the emergency department for further information because the shift has ended. The patient’s son left at the time of admission and is not available when the patient arrives on the medical ward.

The night float resident quickly examines the patient, enters admission orders, and signs the patient out to the intern and resident who will be caring for her during her hospitalization. The verbal handoff notes that the history was limited due to a language barrier. The initial problem list includes heart failure without a differential diagnosis, but notes that an elevated pro-BNP and chest radiograph confirm heart failure as the likely diagnosis.

Several hours after the night float resident has left, the resident presents this history to the attending physician, and together they decide to order her regular at-home medications, as well as deep vein thrombosis prophylaxis and echocardiography. In writing the orders, subcutaneous heparin once daily is erroneously entered instead of low-molecular-weight heparin daily, as this is the default in the medical record system. The tired resident fails to recognize this, and the pharmacist does not question it.

Over the next 2 days, the patient’s cough and shortness of breath persist.

After the attending physician dismisses their concerns, the residents do not bring up their idea again

On hospital day 3, two junior residents on the team (who finished their internship 2 weeks ago) review the attending radiologist’s interpretation of the chest radiograph. Unflagged, it confirms the resident’s interpretation but notes ill-defined, scattered, faint opacities. The residents believe that an interstitial pattern may be present and suggest that the patient may not have heart failure but rather a primary pulmonary disease. They bring this to the attention of their attending physician, who dismisses their concerns and comments that heart failure is a clinical diagnosis. The residents do not bring this idea up again to the attending physician.

That night, the float team is called by the nursing staff because of worsening oxygenation and cough. They add an intravenous corticosteroid, a broad-spectrum antibiotic, and an inhaled bronchodilator to the patient’s drug regimen.

How do cognitive errors predispose physicians to diagnostic errors?

When errors in diagnosis are reviewed retrospectively, cognitive or “thinking” errors are generally found, especially in nonprocedural or primary care specialties such as internal medicine, pediatrics, and emergency medicine.^16,17

A widely accepted theory on how humans make decisions was described by the psychologists Tversky and Kahneman in 1974¹⁸ and has been applied more recently to physicians’ diagnostic processes.¹⁹ Their dual process model theory states that persons with a requisite level of expertise use either the intuitive “system 1” process of thinking, based on pattern-recognition and heuristics, or the slower, more analytical “system 2” process.²⁰ Experts disagree as to whether in medicine these processes represent a binary either-or model or a continuum²¹ with relative contributions of each process determined by the physician and the task.

What are some common types of cognitive error?

Experts agree that many diagnostic errors in medicine stem from decisions arrived at by inappropriate system 1 thinking due to biases. These biases have been identified and described as they relate to medicine, most notably by Croskerry.²²

Several cognitive biases are illustrated in our clinical scenario:

The framing effect occurred when the emergency department resident listed the patient’s admitting diagnosis as heart failure during the clinical handoff of care.

Anchoring bias, as defined by Croskerry,²² is the tendency to lock onto salient features of the case too early in the diagnostic process and then to fail to adjust this initial diagnostic impression. This bias affected the admitting night float resident, primary intern, resident, and attending physician.

Diagnostic momentum, in turn, is a well-described phenomenon that clinical providers are especially vulnerable to in today’s environment of “copy-and-paste” medical records and numerous handovers of care as a consequence of residency duty-hour restrictions.²³

Availability bias refers to commonly seen diagnoses like heart failure or recently seen diagnoses, which are more “available” to the human memory. These diagnoses, which spring to mind quickly, often trick providers into thinking that because they are more easily recalled, they are also more common or more likely.

Confirmation bias. The initial working diagnosis of heart failure may have led the medical team to place greater emphasis on the elevated pro-BNP and the chest radiograph to support the initial impression while ignoring findings such as weight loss that do not support this impression.

Blind obedience. Although the residents recognized the possibility of a primary pulmonary disease, they did not investigate this further. And when the attending physician dismissed their suggestion, they thus deferred to the person in authority or with a reputation of expertise.

Overconfidence bias. Despite minimal improvement in the patient’s clinical status after effective diuresis and the suggestion of alternative diagnoses by the residents, the attending physician remained confident—perhaps overconfident—in the diagnosis of heart failure and would not consider alternatives. Overconfidence bias has been well described and occurs when a medical provider believes too strongly in his or her ability to be correct and therefore fails to consider alternative diagnoses.²⁴

Despite succumbing to overconfidence bias, the attending physician was able to overcome base-rate neglect, ie, failure to consider the prevalence of potential diagnoses in diagnostic reasoning.

Each of these biases, and others not mentioned, can lead to premature closure, which is the unfortunate root cause of many diagnostic errors and delays. We have illustrated several biases in our case scenario that led several physicians on the medical team to prematurely “close” on the diagnosis of heart failure (Table 1).

CASE CONTINUED: SURPRISES AND REASSESSMENT

On hospital day 4, the patient’s medication lists from her previous hospitalizations arrive, and the team is surprised to discover that she has been receiving infliximab for the past 3 to 4 months for her rheumatoid arthritis.

Additionally, an echocardiogram that was ordered on hospital day 1 but was lost in the cardiologist’s reading queue comes in and shows a normal ejection fraction with no evidence of elevated filling pressures.

Computed tomography of the chest reveals a reticular pattern with innumerable, tiny, 1- to 2-mm pulmonary nodules. The differential diagnosis is expanded to include hypersensitivity pneumonitis, lymphoma, fungal infection, and miliary tuberculosis.

How do faulty systems contribute to diagnostic error?

It is increasingly recognized that diagnostic errors can occur as a result of cognitive error, systems-based error, or quite commonly, both. Graber et al¹⁷ analyzed 100 cases of diagnostic error and determined that while cognitive errors did occur in most of them, nearly half the time both cognitive and systems-based errors contributed simultaneously.¹⁷ Observers have further delineated the importance of the systems context and how it affects our thinking.²⁵

In this case, the language barrier, lack of availability of family, and inability to promptly utilize interpreter services contributed to early problems in acquiring a detailed history and a complete medication list that included the immunosuppressant infliximab. Later, a systems error led to a delay in the interpretation of an echocardiogram. Each of these factors, if prevented, would have presumably resulted in expansion of the differential diagnosis and earlier arrival at the correct diagnosis.

CASE CONTINUED: THE PATIENT DIES OF TUBERCULOSIS

The patient is moved to a negative pressure room, and the pulmonary consultants recommend bronchoscopy. During the procedure, the patient suffers acute respiratory failure, is intubated, and is transferred to the medical intensive care unit, where a saddle pulmonary embolism is diagnosed by computed tomographic angiography.

One day later, the sputum culture from the bronchoscopy returns as positive for acid-fast bacilli. A four-drug regimen for tuberculosis is started. The patient continues to have a downward course and expires 2 weeks later. Autopsy reveals miliary tuberculosis.

What is the frequency of diagnostic error in medicine?

Diagnostic error is estimated to have a frequency of 10% to 20%.²⁴ Rates of diagnostic error are similar irrespective of method of determination, eg, from autopsy,³ standardized patients (ie, actors presenting with scripted scenarios),²⁶ or case reviews.²⁷ Patient surveys report patient-perceived harm from diagnostic error at a rate of 35% to 42%.^28,29 The landmark Harvard Medical Practice Study found that 17% of all adverse events were attributable to diagnostic error.³⁰

Diagnostic error is the most common type of medical error in nonprocedural medical fields.³¹ It causes a disproportionately large amount of morbidity and death.

Diagnostic error is the most common cause of malpractice claims in the United States. In inpatient and outpatient settings, for both medical and surgical patients, it accounted for 45.9% of all outpatient malpractice claims in 2009, making it the most common reason for medical malpractice litigation.³² A 2013 study indicated that diagnostic error is more common, more expensive, and two times more likely to result in death than any other category of error.³³

CASE CONTINUED: MORBIDITY AND MORTALITY CONFERENCE

The patient’s case is brought to a morbidity and mortality conference for discussion. The systems issues in the case—including medication reconciliation, availability of interpreters, and timing and process of echocardiogram readings—are all discussed, but clinical reasoning and cognitive errors made in the case are avoided.

Why are cognitive errors often neglected in discussions of medical error?

Historically, openly discussing error in medicine has been difficult. Over the past decade, however, and fueled by the landmark Institute of Medicine report To Err is Human,³⁴ the healthcare community has made substantial strides in identifying and talking about systems factors as a cause of preventable medical error.^34,35

While systems contributions to medical error are inherently “external” to physicians and other healthcare providers, the cognitive contributions to error are inherently “internal” and are often considered personal. This has led to diagnostic error being kept out of many patient safety conversations. Further, while the solutions to systems errors are often tangible, such as implementing a fall prevention program or changing the physical packaging of a medication to reduce a medication dispensing or administration error, solutions to cognitive errors are generally considered more challenging to address by organizations trying to improve patient safety.

How can hospitals and department leaders do better?

Healthcare organizations and leaders of clinical teams or departments can implement several strategies.³⁶

First, they can seek out and analyze the causes of diagnostic errors that are occurring locally in their institution and learn from their diagnostic errors, such as the one in our clinical scenario.

Trainees, physicians, and nurses should be comfortable questioning each other

Second, they can promote a culture of open communication and questioning around diagnosis. Trainees, physicians, and nurses should be comfortable questioning each other, including those higher up in the hierarchy, by saying, “I’m not sure” or “What else could this be?” to help reduce cognitive bias and expand the diagnostic possibilities.

Similarly, developing strategies to promote feedback on diagnosis among physicians will allow us all to learn from our diagnostic mistakes.

Use of the electronic medical record to assist in follow-up of pending diagnostic studies and patient return visits is yet another strategy.

Finally, healthcare organizations can adopt strategies to promote patient involvement in diagnosis, such as providing patients with copies of their test results and discharge summaries, encouraging the use of electronic patient communication portals, and empowering patients to ask questions related to their diagnosis. Prioritizing potential solutions to reduce diagnostic errors may be helpful in situations, depending on the context and environment, in which all proposed interventions may not be possible.

CASE CONTINUED: LEARNING FROM MISTAKES

The attending physician and resident in the case meet after the conference to review their clinical decision-making. Both are interested in learning from this case and improving their diagnostic skills in the future.

What specific steps can clinicians take to mitigate cognitive bias in daily practice?

In addition to continuing to expand one’s medical knowledge and gain more clinical experience, we can suggest several small steps to busy clinicians, taken individually or in combination with others that may improve diagnostic skills by reducing the potential for biased thinking in clinical practice.

From Croskerry P. Clinical cognition and diagnostic error: applications of a dual process model of reasoning. Adv Health Sci Educ 2009; 14:27–35. With kind permission from Springer Science and Business Media.

Think about your thinking. Our first recommendation would be to become more familiar with the dual process theory of clinical cognition (Figure 1).^37,38 This theoretical framework may be very helpful as a foundation from which to build better thinking skills. Physicians, especially residents, and students can be taught these concepts and their potential to contribute to diagnostic errors, and can use these skills to recognize those contributions in others’ diagnostic practices and even in their own.³⁹

Facilitating metacognition, or “thinking about one’s thinking,” may help clinicians catch themselves in thinking traps and provide the opportunity to reflect on biases retrospectively, as a double check or an opportunity to learn from a mistake.

Recognize your emotions. Gaining an understanding of the effect of one’s emotions on decision-making also can help clinicians free themselves of bias. As human beings, healthcare professionals are  susceptible to emotion, and the best approach to mitigate the emotional influences may be to consciously name them and adjust for them.⁴⁰

Because it is impractical to apply slow, analytical system 2 approaches to every case, skills that hone and develop more accurate, reliable system 1 thinking are crucial. Gaining broad exposure to increased numbers of cases may be the most reliable way to build an experiential repertoire of “illness scripts,” but there are ways to increase the experiential value of any case with a few techniques that have potential to promote better intuition.⁴¹

Embracing uncertainty in the early diagnostic process and envisioning the worst-case scenario in a case allows the consideration of additional diagnostic paths outside of the current working diagnosis, potentially priming the clinician to look for and recognize early warning signs that could argue against the initial diagnosis at a time when an adjustment could be made to prevent a bad outcome.

Practice progressive problem-solving,⁴² a technique in which the physician creates additional challenges to increase the cognitive burden of a “routine” case in an effort to train his or her mind and sharpen intuition. An example of this practice is contemplating a backup treatment plan in advance in the event of a poor response to or an adverse effect of treatment. Highly rated physicians and teachers perform this regularly.^43,44 Other ways to maximize the learning value of an individual case include seeking feedback on patient outcomes, especially when a patient has been discharged or transferred to another provider’s care, or when the physician goes off service.

Simulation, traditionally used for procedural training, has potential as well. Cognitive simulation, such as case reports or virtual patient modules, have potential to enhance clinical reasoning skills as well, though possibly at greater cost of time and expense.

Decreased reliance on memory is likely to improve diagnostic reasoning. Systems tools such as checklists⁴⁵ and health information technology⁴⁶ have potential to reduce diagnostic errors, not by taking thinking away from the clinician but by relieving the cognitive load enough to facilitate greater effort toward reasoning.

Slow down. Finally, and perhaps most important, recent models of clinical expertise have suggested that mastery comes from having a robust intuitive method, with a sense of the limitations of the intuitive approach, an ability to recognize the need to perform more analytical reasoning in select cases, and the willingness to do so. In short, it may well be that the hallmark of a master clinician is the propensity to slow down when necessary.⁴⁷

A ‘diagnostic time-out’ for safety might catch opportunities to recognize and mitigate biases and errors

If one considers diagnosis a cognitive procedure, perhaps a brief “diagnostic time-out” for safety might afford an opportunity to recognize and mitigate biases and errors. There are likely many potential scripts for a good diagnostic time-out, but to be functional it should be brief and simple to facilitate consistent use. We have recommended the following four questions to our residents as a starting point, any of which could signal the need to switch to a slower, analytic approach.

Four-step diagnostic time-out

• What else can it be?
• Is there anything about the case that does not fit?
• Is it possible that multiple processes are going on?
• Do I need to slow down?

These questions can serve as a double check for an intuitively formed initial working diagnosis, incorporating many of the principles discussed above, in a way that would hopefully avoid undue burden on a busy clinician. These techniques, it must be acknowledged, have not yet been directly tied to reductions in diagnostic errors. However, diagnostic errors, as discussed, are very difficult to identify and study, and these techniques will serve mainly to improve habits that are likely to show benefits over much longer time periods than most studies can measure.

SAN ANTONIO – Patients who have low-risk, human papillomavirus (HPV)–associated oropharyngeal cancers may be effectively and safely treated with a reduced intensity chemoradiotherapy regimen, according to research presented at the annual meeting of the American Society for Radiation Oncology.

In the prospective, multi-institutional, phase II trial, complete pathologic responses (pCR) were seen in 86% of the 43 patients treated. The six cases that did not show a pCR were limited to microscopic areas of residual cancer.

ASTRO/Adam Donohue

The study provides strong preliminary evidence that reduced intensity chemoradiotherapy may be as effective as standard-dose chemoradiotherapy, Dr. Bhishamjit Chera of the University of North Carolina at Chapel Hill said at a press briefing. While it is too early to use outside of a clinical trial at present, he said, there is the potential for less intensive treatment to be given, and it could be the standard practice in years to come.

“At most institutions, the standard treatment for oropharynx cancer is definite chemoradiation,” Dr. Chera explained. This typically involves delivery of 70 Gy of radiation, given in 2-Gy fractions over 7 weeks for a total 35 days of treatment, and administration of three doses of cisplatin 100 mg/m² concurrently.

“This treatment provides the best chances of sparing the tonsil, the throat, and the tongue, basically preserving organ function,” he added. Surgery is not usually performed unless there are signs on imaging that the cancer has not completely resolved 12 weeks after treatment.

“We know that many patients are cured with oropharyngeal carcinoma, but many patients live with significant long-term side effects such as dry mouth and difficulty swallowing,” Dr. Chera observed. Thus the aim of the present trial was to see if reducing the intensity of the chemoradiotherapy might avoid some of the side effects seen.

The deintensified regimen used in the study consisted of a 10-Gy reduction in the total dose of radiation delivered to 60 Gy, which was given in 2-Gy fractions once daily over a period of 6 weeks. The dose of cisplatin also was reduced by approximately 40% to 30 mg/m² given in 6 weekly doses

Patients were eligible for inclusion if they had stage 0-3 squamous cell carcinoma of the oropharynx, with limited nodal (N0-N2c) and no metastatic involvement. Patients had to have a minimal smoking history and be HPV or p16 positive.

After the chemoradiation, all patients underwent a planned biopsy and limited neck dissection to remove any lymph nodes that had cancer in them prior to treatment. Thus the primary endpoint was the pCR rather a radiographically measured tumor response rate, Dr. Chera observed.

Considering just the primary site of the cancer (the base of tongue and tonsil), there were 41 patients who could be evaluated and all but one of these (98%) achieved a pCR. Looking at patients with neck involvement at baseline (n = 39), 84% achieved a pCR.

“All of these 43 patients are alive with no evidence of cancer recurrence with a follow-up of 21 months,” Dr. Chera reported.

Throughout the study, patient-reported outcomes were captured using the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the European Organization for Cancer Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ).

While patients did report an increase in adverse effects 6-8 weeks after the chemoradiation, the intensity of these side effects decreased to baseline levels over time. Not surprisingly, the two most common symptoms were dry mouth and problems with swallowing, with 75% and 55% of patients, respectively, experiencing severe or very severe xerostomia and dysphagia. Other grade 3-4 adverse events included mucositis in 45%, pain in 48%, nausea in 52%, and vomiting in 34%.

Results of the quality of life analyses show that patients’ quality of life is returning to baseline levels after 1 year.

“There is a lot of interest in reducing the intensity of treatment in these patients,” Dr. Chera said, adding that patients are likely being overtreated at present. In the current clinical environment, patients are very savvy, he said, so performing a large randomized phase III trial may not be possible if patients learn that deintensified therapy may be an option. So the results of larger and longer phase II trials may be the best evidence that will be obtained.

The NRG Oncology group is going to evaluate the same deintensified chemotherapy regimen in another, larger phase II trial, the NRG-HN002 trial, Dr. Chera said. This trial aims to accrue almost 300 patients and will compare the University of North Carolina regimen versus radiation alone, which will be given at a total dose of 50 Gy 5 days a week for 5 weeks.

And, as for his group’s further research plans, Dr. Chera noted in an interview that further follow-up would be required to determine if the regimen used was efficacious and safe. A second phase II trial with the same deintensified regimen in which surgery or biopsies were not mandated is about to close soon, and there is a third study that will look at using genetic information to determine if it is safe to deintensifty patients’ treatment.

Dr. Chera had no conflicts of interest to disclose.

[email protected]

SAN ANTONIO – Patients who have low-risk, human papillomavirus (HPV)–associated oropharyngeal cancers may be effectively and safely treated with a reduced intensity chemoradiotherapy regimen, according to research presented at the annual meeting of the American Society for Radiation Oncology.

In the prospective, multi-institutional, phase II trial, complete pathologic responses (pCR) were seen in 86% of the 43 patients treated. The six cases that did not show a pCR were limited to microscopic areas of residual cancer.

ASTRO/Adam Donohue

The study provides strong preliminary evidence that reduced intensity chemoradiotherapy may be as effective as standard-dose chemoradiotherapy, Dr. Bhishamjit Chera of the University of North Carolina at Chapel Hill said at a press briefing. While it is too early to use outside of a clinical trial at present, he said, there is the potential for less intensive treatment to be given, and it could be the standard practice in years to come.

“At most institutions, the standard treatment for oropharynx cancer is definite chemoradiation,” Dr. Chera explained. This typically involves delivery of 70 Gy of radiation, given in 2-Gy fractions over 7 weeks for a total 35 days of treatment, and administration of three doses of cisplatin 100 mg/m² concurrently.

“This treatment provides the best chances of sparing the tonsil, the throat, and the tongue, basically preserving organ function,” he added. Surgery is not usually performed unless there are signs on imaging that the cancer has not completely resolved 12 weeks after treatment.

“We know that many patients are cured with oropharyngeal carcinoma, but many patients live with significant long-term side effects such as dry mouth and difficulty swallowing,” Dr. Chera observed. Thus the aim of the present trial was to see if reducing the intensity of the chemoradiotherapy might avoid some of the side effects seen.

The deintensified regimen used in the study consisted of a 10-Gy reduction in the total dose of radiation delivered to 60 Gy, which was given in 2-Gy fractions once daily over a period of 6 weeks. The dose of cisplatin also was reduced by approximately 40% to 30 mg/m² given in 6 weekly doses

Patients were eligible for inclusion if they had stage 0-3 squamous cell carcinoma of the oropharynx, with limited nodal (N0-N2c) and no metastatic involvement. Patients had to have a minimal smoking history and be HPV or p16 positive.

After the chemoradiation, all patients underwent a planned biopsy and limited neck dissection to remove any lymph nodes that had cancer in them prior to treatment. Thus the primary endpoint was the pCR rather a radiographically measured tumor response rate, Dr. Chera observed.

Considering just the primary site of the cancer (the base of tongue and tonsil), there were 41 patients who could be evaluated and all but one of these (98%) achieved a pCR. Looking at patients with neck involvement at baseline (n = 39), 84% achieved a pCR.

“All of these 43 patients are alive with no evidence of cancer recurrence with a follow-up of 21 months,” Dr. Chera reported.

Throughout the study, patient-reported outcomes were captured using the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the European Organization for Cancer Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ).

While patients did report an increase in adverse effects 6-8 weeks after the chemoradiation, the intensity of these side effects decreased to baseline levels over time. Not surprisingly, the two most common symptoms were dry mouth and problems with swallowing, with 75% and 55% of patients, respectively, experiencing severe or very severe xerostomia and dysphagia. Other grade 3-4 adverse events included mucositis in 45%, pain in 48%, nausea in 52%, and vomiting in 34%.

Results of the quality of life analyses show that patients’ quality of life is returning to baseline levels after 1 year.

“There is a lot of interest in reducing the intensity of treatment in these patients,” Dr. Chera said, adding that patients are likely being overtreated at present. In the current clinical environment, patients are very savvy, he said, so performing a large randomized phase III trial may not be possible if patients learn that deintensified therapy may be an option. So the results of larger and longer phase II trials may be the best evidence that will be obtained.

The NRG Oncology group is going to evaluate the same deintensified chemotherapy regimen in another, larger phase II trial, the NRG-HN002 trial, Dr. Chera said. This trial aims to accrue almost 300 patients and will compare the University of North Carolina regimen versus radiation alone, which will be given at a total dose of 50 Gy 5 days a week for 5 weeks.

And, as for his group’s further research plans, Dr. Chera noted in an interview that further follow-up would be required to determine if the regimen used was efficacious and safe. A second phase II trial with the same deintensified regimen in which surgery or biopsies were not mandated is about to close soon, and there is a third study that will look at using genetic information to determine if it is safe to deintensifty patients’ treatment.

Dr. Chera had no conflicts of interest to disclose.

[email protected]

SAN ANTONIO – Patients who have low-risk, human papillomavirus (HPV)–associated oropharyngeal cancers may be effectively and safely treated with a reduced intensity chemoradiotherapy regimen, according to research presented at the annual meeting of the American Society for Radiation Oncology.

In the prospective, multi-institutional, phase II trial, complete pathologic responses (pCR) were seen in 86% of the 43 patients treated. The six cases that did not show a pCR were limited to microscopic areas of residual cancer.

ASTRO/Adam Donohue

The study provides strong preliminary evidence that reduced intensity chemoradiotherapy may be as effective as standard-dose chemoradiotherapy, Dr. Bhishamjit Chera of the University of North Carolina at Chapel Hill said at a press briefing. While it is too early to use outside of a clinical trial at present, he said, there is the potential for less intensive treatment to be given, and it could be the standard practice in years to come.

“At most institutions, the standard treatment for oropharynx cancer is definite chemoradiation,” Dr. Chera explained. This typically involves delivery of 70 Gy of radiation, given in 2-Gy fractions over 7 weeks for a total 35 days of treatment, and administration of three doses of cisplatin 100 mg/m² concurrently.

“This treatment provides the best chances of sparing the tonsil, the throat, and the tongue, basically preserving organ function,” he added. Surgery is not usually performed unless there are signs on imaging that the cancer has not completely resolved 12 weeks after treatment.

“We know that many patients are cured with oropharyngeal carcinoma, but many patients live with significant long-term side effects such as dry mouth and difficulty swallowing,” Dr. Chera observed. Thus the aim of the present trial was to see if reducing the intensity of the chemoradiotherapy might avoid some of the side effects seen.

The deintensified regimen used in the study consisted of a 10-Gy reduction in the total dose of radiation delivered to 60 Gy, which was given in 2-Gy fractions once daily over a period of 6 weeks. The dose of cisplatin also was reduced by approximately 40% to 30 mg/m² given in 6 weekly doses

Patients were eligible for inclusion if they had stage 0-3 squamous cell carcinoma of the oropharynx, with limited nodal (N0-N2c) and no metastatic involvement. Patients had to have a minimal smoking history and be HPV or p16 positive.

After the chemoradiation, all patients underwent a planned biopsy and limited neck dissection to remove any lymph nodes that had cancer in them prior to treatment. Thus the primary endpoint was the pCR rather a radiographically measured tumor response rate, Dr. Chera observed.

Considering just the primary site of the cancer (the base of tongue and tonsil), there were 41 patients who could be evaluated and all but one of these (98%) achieved a pCR. Looking at patients with neck involvement at baseline (n = 39), 84% achieved a pCR.

“All of these 43 patients are alive with no evidence of cancer recurrence with a follow-up of 21 months,” Dr. Chera reported.

Throughout the study, patient-reported outcomes were captured using the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the European Organization for Cancer Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ).

While patients did report an increase in adverse effects 6-8 weeks after the chemoradiation, the intensity of these side effects decreased to baseline levels over time. Not surprisingly, the two most common symptoms were dry mouth and problems with swallowing, with 75% and 55% of patients, respectively, experiencing severe or very severe xerostomia and dysphagia. Other grade 3-4 adverse events included mucositis in 45%, pain in 48%, nausea in 52%, and vomiting in 34%.

Results of the quality of life analyses show that patients’ quality of life is returning to baseline levels after 1 year.

“There is a lot of interest in reducing the intensity of treatment in these patients,” Dr. Chera said, adding that patients are likely being overtreated at present. In the current clinical environment, patients are very savvy, he said, so performing a large randomized phase III trial may not be possible if patients learn that deintensified therapy may be an option. So the results of larger and longer phase II trials may be the best evidence that will be obtained.

The NRG Oncology group is going to evaluate the same deintensified chemotherapy regimen in another, larger phase II trial, the NRG-HN002 trial, Dr. Chera said. This trial aims to accrue almost 300 patients and will compare the University of North Carolina regimen versus radiation alone, which will be given at a total dose of 50 Gy 5 days a week for 5 weeks.

And, as for his group’s further research plans, Dr. Chera noted in an interview that further follow-up would be required to determine if the regimen used was efficacious and safe. A second phase II trial with the same deintensified regimen in which surgery or biopsies were not mandated is about to close soon, and there is a third study that will look at using genetic information to determine if it is safe to deintensifty patients’ treatment.

Dr. Chera had no conflicts of interest to disclose.

[email protected]

Red blood cells

ANAHEIM, CA—Interim results of a large study suggest a blood donor’s genetic background and frequency of donation influence

red blood cell (RBC) storage and stress hemolysis.

Investigators found that donor ethnicity and gender both affected hemolysis, but the effects sometimes differed between storage and stress hemolysis.

Similarly, RBCs from frequent donors were more susceptible to storage and osmotic hemolysis but less susceptible to oxidative hemolysis.

Tamir Kanias, PhD, of the University of Pittsburgh in Pennsylvania, presented these findings at the 2015 AABB Annual Meeting (abstract S73-040A).

“We now know that some donor red cells store very well, and, even after 42 days of storage, there is hardly any hemolysis,” Dr Kanias noted. “[But for] some donors, their red cells are starting to degrade maybe 5 or 6 days after collection.”

With that in mind, Dr Kanias and his colleagues set out to define the genetic and metabolic basis for donor-specific differences in hemolysis in stored RBCs.

They analyzed RBCs collected at 4 centers as part of the REDS-III study. The team took 15 mL of RBCs from fresh units donated for transfusion and stored the cells in transfer bags to measure hemolysis. The transfer bags are miniature versions of the bags used to store RBCs for transfusion.

Dr Kanias presented interim findings in samples from more than 8000 donors. He and his colleagues looked at donor ethnicity, gender, and age. The team also assessed whether subjects were “high-intensity” donors, which was defined as donating RBCs 10 or more times in the previous 24 months without a low-hemoglobin deferral.

The donors’ samples were stored for 39 to 42 days before the investigators assessed hemolysis. They measured end-of-storage hemolysis in unwashed red cells, then washed the RBCs and assessed osmotic hemolysis (Pink test) and oxidative hemolysis (AAPH).

Ethnicity and intensity

Tests showed that RBCs from African American and high-intensity donors (more than 90% of whom were Caucasian) were more susceptible to storage hemolysis than RBCs from the other donor groups analyzed.

RBCs from Caucasian donors and high-intensity donors were susceptible to osmotic hemolysis, while RBCs from African American and Asian donors were more resistant.

“We hypothesize that this [resistance] may be related to some of these donors carrying traits for sickle cell disease or thalassemia,” Dr Kanias said. “Both diseases are known to render red cells more resistant to osmotic hemolysis, but of course, it could be [explained by] new mutations that we don’t know of.”

RBCs from Hispanic donors and African American donors were more susceptible to oxidative hemolysis, but the opposite was true of RBCs from high-intensity donors.

“What was really interesting is that the high-intensity donors that had higher end-of-storage hemolysis and higher susceptibility to osmotic hemolysis actually became more resistant to oxidative hemolysis,” Dr Kanias said.

“It is possible that the lower levels of iron in the red cells of these donors actually protects from oxidative hemolysis. Iron is redox-active, and a lot of the AAPH-induced hemolysis is mediated by iron interactions.”

Group comparisons

Looking at the data another way, the investigators compared samples from Caucasians to samples from the other ethnic groups and the high-intensity donors.

RBCs from African American donors had significantly higher storage hemolysis (P=0.0078), lower osmotic hemolysis (P<0.0001), and higher oxidative hemolysis (P=0.0008) than RBCs from Caucasians.

RBCs from Asians had significantly lower osmotic hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference in storage hemolysis (P=0.69) or oxidative hemolysis (P=0.41) between the 2 groups.

RBCs from Hispanic donors were significantly more susceptible to oxidative hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference between the groups with regard to storage hemolysis (P=0.89) or osmotic hemolysis (P=0.10).

RBCs from high-intensity donors had significantly higher storage hemolysis (P<0.0001) and lower oxidative hemolysis (P<0.0001) than Caucasian RBCs. There was no significant difference in osmotic hemolysis (P=0.84)

Gender and age

As in other studies, Dr Kanias and his colleagues found that RBCs from females hemolyzed significantly less than RBCs from males. This was true for storage hemolysis, osmotic hemolysis, and oxidative hemolysis (P<0.0001 for all).

“Just to note, the gender effect was more dramatic in storage and osmotic rather than oxidative, which suggests that the gender effect is more on the membrane or membrane integrity rather than antioxidant capacity,” Dr Kanias said.

He and his colleagues then looked at donor age and observed the gender effect at every age analyzed (18 to 65+). He noted that hemolysis fluctuated throughout the age groups, so the investigators couldn’t draw any concrete conclusions about hemolysis and donor age.

“One interesting thing to note is that, in all the assays, in young males—like around 20—there’s an increase in hemolysis where there’s a decrease in females,” Dr Kanias said. “This may be related to the effect of sex hormones.”

Genetic modifiers

The investigators also assessed how the 3 hemolytic assays relate to each other and found very weak correlations between them. Pearson correlations were 0.12 between storage and osmotic hemolysis, 0.0041 between storage and oxidative hemolysis, and 0.058 between osmotic and oxidative hemolysis.

“This is kind of cool because it may mean that there is a different genetic modifier affecting each of these phenomena,” Dr Kanias said.

He and his colleagues are now working to identify genetic and metabolic modifiers of hemolysis.

Red blood cells

ANAHEIM, CA—Interim results of a large study suggest a blood donor’s genetic background and frequency of donation influence

red blood cell (RBC) storage and stress hemolysis.

Investigators found that donor ethnicity and gender both affected hemolysis, but the effects sometimes differed between storage and stress hemolysis.

Similarly, RBCs from frequent donors were more susceptible to storage and osmotic hemolysis but less susceptible to oxidative hemolysis.

Tamir Kanias, PhD, of the University of Pittsburgh in Pennsylvania, presented these findings at the 2015 AABB Annual Meeting (abstract S73-040A).

“We now know that some donor red cells store very well, and, even after 42 days of storage, there is hardly any hemolysis,” Dr Kanias noted. “[But for] some donors, their red cells are starting to degrade maybe 5 or 6 days after collection.”

With that in mind, Dr Kanias and his colleagues set out to define the genetic and metabolic basis for donor-specific differences in hemolysis in stored RBCs.

They analyzed RBCs collected at 4 centers as part of the REDS-III study. The team took 15 mL of RBCs from fresh units donated for transfusion and stored the cells in transfer bags to measure hemolysis. The transfer bags are miniature versions of the bags used to store RBCs for transfusion.

Dr Kanias presented interim findings in samples from more than 8000 donors. He and his colleagues looked at donor ethnicity, gender, and age. The team also assessed whether subjects were “high-intensity” donors, which was defined as donating RBCs 10 or more times in the previous 24 months without a low-hemoglobin deferral.

The donors’ samples were stored for 39 to 42 days before the investigators assessed hemolysis. They measured end-of-storage hemolysis in unwashed red cells, then washed the RBCs and assessed osmotic hemolysis (Pink test) and oxidative hemolysis (AAPH).

Ethnicity and intensity

Tests showed that RBCs from African American and high-intensity donors (more than 90% of whom were Caucasian) were more susceptible to storage hemolysis than RBCs from the other donor groups analyzed.

RBCs from Caucasian donors and high-intensity donors were susceptible to osmotic hemolysis, while RBCs from African American and Asian donors were more resistant.

“We hypothesize that this [resistance] may be related to some of these donors carrying traits for sickle cell disease or thalassemia,” Dr Kanias said. “Both diseases are known to render red cells more resistant to osmotic hemolysis, but of course, it could be [explained by] new mutations that we don’t know of.”

RBCs from Hispanic donors and African American donors were more susceptible to oxidative hemolysis, but the opposite was true of RBCs from high-intensity donors.

“What was really interesting is that the high-intensity donors that had higher end-of-storage hemolysis and higher susceptibility to osmotic hemolysis actually became more resistant to oxidative hemolysis,” Dr Kanias said.

“It is possible that the lower levels of iron in the red cells of these donors actually protects from oxidative hemolysis. Iron is redox-active, and a lot of the AAPH-induced hemolysis is mediated by iron interactions.”

Group comparisons

Looking at the data another way, the investigators compared samples from Caucasians to samples from the other ethnic groups and the high-intensity donors.

RBCs from African American donors had significantly higher storage hemolysis (P=0.0078), lower osmotic hemolysis (P<0.0001), and higher oxidative hemolysis (P=0.0008) than RBCs from Caucasians.

RBCs from Asians had significantly lower osmotic hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference in storage hemolysis (P=0.69) or oxidative hemolysis (P=0.41) between the 2 groups.

RBCs from Hispanic donors were significantly more susceptible to oxidative hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference between the groups with regard to storage hemolysis (P=0.89) or osmotic hemolysis (P=0.10).

RBCs from high-intensity donors had significantly higher storage hemolysis (P<0.0001) and lower oxidative hemolysis (P<0.0001) than Caucasian RBCs. There was no significant difference in osmotic hemolysis (P=0.84)

Gender and age

As in other studies, Dr Kanias and his colleagues found that RBCs from females hemolyzed significantly less than RBCs from males. This was true for storage hemolysis, osmotic hemolysis, and oxidative hemolysis (P<0.0001 for all).

“Just to note, the gender effect was more dramatic in storage and osmotic rather than oxidative, which suggests that the gender effect is more on the membrane or membrane integrity rather than antioxidant capacity,” Dr Kanias said.

He and his colleagues then looked at donor age and observed the gender effect at every age analyzed (18 to 65+). He noted that hemolysis fluctuated throughout the age groups, so the investigators couldn’t draw any concrete conclusions about hemolysis and donor age.

“One interesting thing to note is that, in all the assays, in young males—like around 20—there’s an increase in hemolysis where there’s a decrease in females,” Dr Kanias said. “This may be related to the effect of sex hormones.”

Genetic modifiers

The investigators also assessed how the 3 hemolytic assays relate to each other and found very weak correlations between them. Pearson correlations were 0.12 between storage and osmotic hemolysis, 0.0041 between storage and oxidative hemolysis, and 0.058 between osmotic and oxidative hemolysis.

“This is kind of cool because it may mean that there is a different genetic modifier affecting each of these phenomena,” Dr Kanias said.

He and his colleagues are now working to identify genetic and metabolic modifiers of hemolysis.

Red blood cells

ANAHEIM, CA—Interim results of a large study suggest a blood donor’s genetic background and frequency of donation influence

red blood cell (RBC) storage and stress hemolysis.

Investigators found that donor ethnicity and gender both affected hemolysis, but the effects sometimes differed between storage and stress hemolysis.

Similarly, RBCs from frequent donors were more susceptible to storage and osmotic hemolysis but less susceptible to oxidative hemolysis.

Tamir Kanias, PhD, of the University of Pittsburgh in Pennsylvania, presented these findings at the 2015 AABB Annual Meeting (abstract S73-040A).

“We now know that some donor red cells store very well, and, even after 42 days of storage, there is hardly any hemolysis,” Dr Kanias noted. “[But for] some donors, their red cells are starting to degrade maybe 5 or 6 days after collection.”

With that in mind, Dr Kanias and his colleagues set out to define the genetic and metabolic basis for donor-specific differences in hemolysis in stored RBCs.

They analyzed RBCs collected at 4 centers as part of the REDS-III study. The team took 15 mL of RBCs from fresh units donated for transfusion and stored the cells in transfer bags to measure hemolysis. The transfer bags are miniature versions of the bags used to store RBCs for transfusion.

Dr Kanias presented interim findings in samples from more than 8000 donors. He and his colleagues looked at donor ethnicity, gender, and age. The team also assessed whether subjects were “high-intensity” donors, which was defined as donating RBCs 10 or more times in the previous 24 months without a low-hemoglobin deferral.

The donors’ samples were stored for 39 to 42 days before the investigators assessed hemolysis. They measured end-of-storage hemolysis in unwashed red cells, then washed the RBCs and assessed osmotic hemolysis (Pink test) and oxidative hemolysis (AAPH).

Ethnicity and intensity

Tests showed that RBCs from African American and high-intensity donors (more than 90% of whom were Caucasian) were more susceptible to storage hemolysis than RBCs from the other donor groups analyzed.

RBCs from Caucasian donors and high-intensity donors were susceptible to osmotic hemolysis, while RBCs from African American and Asian donors were more resistant.

“We hypothesize that this [resistance] may be related to some of these donors carrying traits for sickle cell disease or thalassemia,” Dr Kanias said. “Both diseases are known to render red cells more resistant to osmotic hemolysis, but of course, it could be [explained by] new mutations that we don’t know of.”

RBCs from Hispanic donors and African American donors were more susceptible to oxidative hemolysis, but the opposite was true of RBCs from high-intensity donors.

“What was really interesting is that the high-intensity donors that had higher end-of-storage hemolysis and higher susceptibility to osmotic hemolysis actually became more resistant to oxidative hemolysis,” Dr Kanias said.

“It is possible that the lower levels of iron in the red cells of these donors actually protects from oxidative hemolysis. Iron is redox-active, and a lot of the AAPH-induced hemolysis is mediated by iron interactions.”

Group comparisons

Looking at the data another way, the investigators compared samples from Caucasians to samples from the other ethnic groups and the high-intensity donors.

RBCs from African American donors had significantly higher storage hemolysis (P=0.0078), lower osmotic hemolysis (P<0.0001), and higher oxidative hemolysis (P=0.0008) than RBCs from Caucasians.

RBCs from Asians had significantly lower osmotic hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference in storage hemolysis (P=0.69) or oxidative hemolysis (P=0.41) between the 2 groups.

RBCs from Hispanic donors were significantly more susceptible to oxidative hemolysis (P<0.0001) than Caucasian RBCs, but there was no significant difference between the groups with regard to storage hemolysis (P=0.89) or osmotic hemolysis (P=0.10).

RBCs from high-intensity donors had significantly higher storage hemolysis (P<0.0001) and lower oxidative hemolysis (P<0.0001) than Caucasian RBCs. There was no significant difference in osmotic hemolysis (P=0.84)

Gender and age

As in other studies, Dr Kanias and his colleagues found that RBCs from females hemolyzed significantly less than RBCs from males. This was true for storage hemolysis, osmotic hemolysis, and oxidative hemolysis (P<0.0001 for all).

“Just to note, the gender effect was more dramatic in storage and osmotic rather than oxidative, which suggests that the gender effect is more on the membrane or membrane integrity rather than antioxidant capacity,” Dr Kanias said.

He and his colleagues then looked at donor age and observed the gender effect at every age analyzed (18 to 65+). He noted that hemolysis fluctuated throughout the age groups, so the investigators couldn’t draw any concrete conclusions about hemolysis and donor age.

“One interesting thing to note is that, in all the assays, in young males—like around 20—there’s an increase in hemolysis where there’s a decrease in females,” Dr Kanias said. “This may be related to the effect of sex hormones.”

Genetic modifiers

The investigators also assessed how the 3 hemolytic assays relate to each other and found very weak correlations between them. Pearson correlations were 0.12 between storage and osmotic hemolysis, 0.0041 between storage and oxidative hemolysis, and 0.058 between osmotic and oxidative hemolysis.

“This is kind of cool because it may mean that there is a different genetic modifier affecting each of these phenomena,” Dr Kanias said.

He and his colleagues are now working to identify genetic and metabolic modifiers of hemolysis.

Interstitial cystitis (IC) is a debilitating disease that presents with a constellation of symptoms, including pain, urinary urgency, frequency, nocturia, and small voided volumes in the absence of other identifiable etiologies.¹ The overall prevalence of IC among US women is between 2.7% and 6.5%—affecting approximately 3.3 to 7.9 million women²—and it results in substantial costs^1,3 and impairments in health-related quality of life.⁴ Unfortunately, there is a lack of consensus on the pathophysiology and etiology of this prevalent and costly disorder. Thus, therapies are often empiric, with limited evidence and variable levels of improvement.⁵

There has been no clear evidence that bladder inflammation (cystitis) is involved in the etiology or pathophysiology of the condition. As a result, there has been a movement to rename it “bladder pain syndrome.” Current literature refers to the spectrum of symptoms as interstitial cystitis/bladder pain syndrome (IC/BPS).

Currently, the American Urological Association (AUA) defines IC/BPS as an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder,
 associated with lower urinary tract symptoms of more than 6 weeks’ duration, in the absence of infection or other identifiable causes.⁶ This is still a broad, clinical diagnosis that has significant overlap with other pain syndromes but allows for treatment to begin after a relatively short symptomatic period.⁷ Because gynecologists are frequently the main care providers for women, understanding the diagnosis and treatment options for IC/BPS is important to avoid delayed treatment in a difficult to diagnose population.

Recently, the AUA published an amendment to their 2011 management guidelines to provide direction to clinicians and patients regarding how to recognize IC/BPS, conduct valid diagnostic testing, and approach treatment with the goals of maximizing symptom control and patient quality of life.⁷

In this article, we review the AUA diagnostic and treatment algorithms and the results of recently published randomized trials comparing the efficacy of various treatment modalities for IC/BPS, including pentosoan polysulfate sodium (PPS; Elmiron, Janssen Pharmaceuticals, Titusville, New Jersey) and botulinum toxin (Botox, Allergan, Irvine, California) with hydrodistension.

Evaluation and treatment algorithms for IC/BPS: AUA guidelines

Hanno PM, Erickson D, Moldwin R, Faraday MM; American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545−1553.

The diagnosis of IC/BPS can be challenging due to a wide spectrum of symptoms, physical examination findings, and clinical test responses. The AUA developed its diagnostic and treatment guidelines mostly based on expert opinion, but they do provide a framework to help clinicians determine whether or not treatment for IC/BPS is warranted. The primary principles for evaluation are presented in FIGURE 1.

 

7,8

It is important to establish baseline voiding symptoms and pain levels with objective, validated instruments, including a voiding diary (FIGURE 2)⁹ and such patient questionnaires as the O’Leary Sant Interstitial Cystitis Index (ICSI; FIGURE 3).¹⁰ Characteristic IC/BPS voiding frequency is 10 or more times per day (to relieve pain, not to relieve a fear of wetting, which would be expected in a patient with overactive bladder).⁸ The ICSI questionnaire
should be used primarily to establish baseline symptoms, not as a diagnostic tool. A score higher than 8 has been used as inclusion criteria for therapeutic trials, however.¹¹

 

FIGURE 2 Voiding diary9

FIGURE 3 O’Leary Sant Interstitial Cystitis Index10

It is unnecessary to primarily perform cystoscopy or urodynamics, as there are no agreed-upon diagnostic criteria for these modalities for IC/BPS. They may be considered, however, if the patient does not respond to first- and second-line therapies. Additionally, potassium sensitivity testing is painful and, in view of the paucity of benefits, the risk/benefit ratio is too high to recommend for clinical care.

Treatment: Conservative first
The treatment for IC/BPS should start with more conservative therapy (including behavioral management and physical therapy). If symptom control is inadequate, other modalities should be employed. Behavioral modifications should include:

 

• local heat/cold over the bladder and perineum
• avoidance of foods and fluids that are known to be common irritants (such as coffee and citrus)
• trial of elimination diet
• bladder training with urge suppression techniques.

As noted in FIGURE 1, first make sure that patients do not have a urinary tract infection. If culture results are negative and other criteria fit, consider the diagnosis of IC/BPS and offer therapies as outlined in the ­treat‑
ment algorithm (FIGURE 4).⁷ Repeated 
treatment for negative results of urine cultures in patients with frequency, urgency, and bladder pain can lead to unnecessary antibiotics and delayed treatment of IC/BPS.

 

7

Treatments in FIGURE 4 are ordered from most to least conservative, and initial treatment depends on symptom severity, 
clinician judgment, and patient preference. If at any point in the patient’s care the diagnosis is questioned or treatments have been ineffective, referral to a specialist, including urogynecology or urology, may be appropriate.

Managing pain
Pain management is an important component at all levels of therapy, and pharmacologic pain management principles for 
IC/BPS should be similar to those for management of other chronic pain states. Options primarily include nonsteroidal anti-
inflammatory drugs (NSAIDs) and urinary analgesics (pyridium). The use of narcotics presents the risks of tolerance and dependence. If their use is necessary, all narcotic prescriptions must come from a single source and should be used as a component of multimodality therapy to minimize narcotic use.

Interstitial cystitis (IC) is a debilitating disease that presents with a constellation of symptoms, including pain, urinary urgency, frequency, nocturia, and small voided volumes in the absence of other identifiable etiologies.¹ The overall prevalence of IC among US women is between 2.7% and 6.5%—affecting approximately 3.3 to 7.9 million women²—and it results in substantial costs^1,3 and impairments in health-related quality of life.⁴ Unfortunately, there is a lack of consensus on the pathophysiology and etiology of this prevalent and costly disorder. Thus, therapies are often empiric, with limited evidence and variable levels of improvement.⁵

There has been no clear evidence that bladder inflammation (cystitis) is involved in the etiology or pathophysiology of the condition. As a result, there has been a movement to rename it “bladder pain syndrome.” Current literature refers to the spectrum of symptoms as interstitial cystitis/bladder pain syndrome (IC/BPS).

Currently, the American Urological Association (AUA) defines IC/BPS as an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder,
 associated with lower urinary tract symptoms of more than 6 weeks’ duration, in the absence of infection or other identifiable causes.⁶ This is still a broad, clinical diagnosis that has significant overlap with other pain syndromes but allows for treatment to begin after a relatively short symptomatic period.⁷ Because gynecologists are frequently the main care providers for women, understanding the diagnosis and treatment options for IC/BPS is important to avoid delayed treatment in a difficult to diagnose population.

Recently, the AUA published an amendment to their 2011 management guidelines to provide direction to clinicians and patients regarding how to recognize IC/BPS, conduct valid diagnostic testing, and approach treatment with the goals of maximizing symptom control and patient quality of life.⁷

In this article, we review the AUA diagnostic and treatment algorithms and the results of recently published randomized trials comparing the efficacy of various treatment modalities for IC/BPS, including pentosoan polysulfate sodium (PPS; Elmiron, Janssen Pharmaceuticals, Titusville, New Jersey) and botulinum toxin (Botox, Allergan, Irvine, California) with hydrodistension.

Evaluation and treatment algorithms for IC/BPS: AUA guidelines

Hanno PM, Erickson D, Moldwin R, Faraday MM; American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545−1553.

The diagnosis of IC/BPS can be challenging due to a wide spectrum of symptoms, physical examination findings, and clinical test responses. The AUA developed its diagnostic and treatment guidelines mostly based on expert opinion, but they do provide a framework to help clinicians determine whether or not treatment for IC/BPS is warranted. The primary principles for evaluation are presented in FIGURE 1.

 

7,8

It is important to establish baseline voiding symptoms and pain levels with objective, validated instruments, including a voiding diary (FIGURE 2)⁹ and such patient questionnaires as the O’Leary Sant Interstitial Cystitis Index (ICSI; FIGURE 3).¹⁰ Characteristic IC/BPS voiding frequency is 10 or more times per day (to relieve pain, not to relieve a fear of wetting, which would be expected in a patient with overactive bladder).⁸ The ICSI questionnaire
should be used primarily to establish baseline symptoms, not as a diagnostic tool. A score higher than 8 has been used as inclusion criteria for therapeutic trials, however.¹¹

 

FIGURE 2 Voiding diary9

FIGURE 3 O’Leary Sant Interstitial Cystitis Index10

It is unnecessary to primarily perform cystoscopy or urodynamics, as there are no agreed-upon diagnostic criteria for these modalities for IC/BPS. They may be considered, however, if the patient does not respond to first- and second-line therapies. Additionally, potassium sensitivity testing is painful and, in view of the paucity of benefits, the risk/benefit ratio is too high to recommend for clinical care.

Treatment: Conservative first
The treatment for IC/BPS should start with more conservative therapy (including behavioral management and physical therapy). If symptom control is inadequate, other modalities should be employed. Behavioral modifications should include:

 

• local heat/cold over the bladder and perineum
• avoidance of foods and fluids that are known to be common irritants (such as coffee and citrus)
• trial of elimination diet
• bladder training with urge suppression techniques.

As noted in FIGURE 1, first make sure that patients do not have a urinary tract infection. If culture results are negative and other criteria fit, consider the diagnosis of IC/BPS and offer therapies as outlined in the ­treat‑
ment algorithm (FIGURE 4).⁷ Repeated 
treatment for negative results of urine cultures in patients with frequency, urgency, and bladder pain can lead to unnecessary antibiotics and delayed treatment of IC/BPS.

 

7

Treatments in FIGURE 4 are ordered from most to least conservative, and initial treatment depends on symptom severity, 
clinician judgment, and patient preference. If at any point in the patient’s care the diagnosis is questioned or treatments have been ineffective, referral to a specialist, including urogynecology or urology, may be appropriate.

Managing pain
Pain management is an important component at all levels of therapy, and pharmacologic pain management principles for 
IC/BPS should be similar to those for management of other chronic pain states. Options primarily include nonsteroidal anti-
inflammatory drugs (NSAIDs) and urinary analgesics (pyridium). The use of narcotics presents the risks of tolerance and dependence. If their use is necessary, all narcotic prescriptions must come from a single source and should be used as a component of multimodality therapy to minimize narcotic use.

Interstitial cystitis (IC) is a debilitating disease that presents with a constellation of symptoms, including pain, urinary urgency, frequency, nocturia, and small voided volumes in the absence of other identifiable etiologies.¹ The overall prevalence of IC among US women is between 2.7% and 6.5%—affecting approximately 3.3 to 7.9 million women²—and it results in substantial costs^1,3 and impairments in health-related quality of life.⁴ Unfortunately, there is a lack of consensus on the pathophysiology and etiology of this prevalent and costly disorder. Thus, therapies are often empiric, with limited evidence and variable levels of improvement.⁵

There has been no clear evidence that bladder inflammation (cystitis) is involved in the etiology or pathophysiology of the condition. As a result, there has been a movement to rename it “bladder pain syndrome.” Current literature refers to the spectrum of symptoms as interstitial cystitis/bladder pain syndrome (IC/BPS).

Currently, the American Urological Association (AUA) defines IC/BPS as an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder,
 associated with lower urinary tract symptoms of more than 6 weeks’ duration, in the absence of infection or other identifiable causes.⁶ This is still a broad, clinical diagnosis that has significant overlap with other pain syndromes but allows for treatment to begin after a relatively short symptomatic period.⁷ Because gynecologists are frequently the main care providers for women, understanding the diagnosis and treatment options for IC/BPS is important to avoid delayed treatment in a difficult to diagnose population.

Recently, the AUA published an amendment to their 2011 management guidelines to provide direction to clinicians and patients regarding how to recognize IC/BPS, conduct valid diagnostic testing, and approach treatment with the goals of maximizing symptom control and patient quality of life.⁷

In this article, we review the AUA diagnostic and treatment algorithms and the results of recently published randomized trials comparing the efficacy of various treatment modalities for IC/BPS, including pentosoan polysulfate sodium (PPS; Elmiron, Janssen Pharmaceuticals, Titusville, New Jersey) and botulinum toxin (Botox, Allergan, Irvine, California) with hydrodistension.

Evaluation and treatment algorithms for IC/BPS: AUA guidelines

Hanno PM, Erickson D, Moldwin R, Faraday MM; American Urological Association. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545−1553.

The diagnosis of IC/BPS can be challenging due to a wide spectrum of symptoms, physical examination findings, and clinical test responses. The AUA developed its diagnostic and treatment guidelines mostly based on expert opinion, but they do provide a framework to help clinicians determine whether or not treatment for IC/BPS is warranted. The primary principles for evaluation are presented in FIGURE 1.

 

7,8

It is important to establish baseline voiding symptoms and pain levels with objective, validated instruments, including a voiding diary (FIGURE 2)⁹ and such patient questionnaires as the O’Leary Sant Interstitial Cystitis Index (ICSI; FIGURE 3).¹⁰ Characteristic IC/BPS voiding frequency is 10 or more times per day (to relieve pain, not to relieve a fear of wetting, which would be expected in a patient with overactive bladder).⁸ The ICSI questionnaire
should be used primarily to establish baseline symptoms, not as a diagnostic tool. A score higher than 8 has been used as inclusion criteria for therapeutic trials, however.¹¹

 

FIGURE 2 Voiding diary9

FIGURE 3 O’Leary Sant Interstitial Cystitis Index10

It is unnecessary to primarily perform cystoscopy or urodynamics, as there are no agreed-upon diagnostic criteria for these modalities for IC/BPS. They may be considered, however, if the patient does not respond to first- and second-line therapies. Additionally, potassium sensitivity testing is painful and, in view of the paucity of benefits, the risk/benefit ratio is too high to recommend for clinical care.

Treatment: Conservative first
The treatment for IC/BPS should start with more conservative therapy (including behavioral management and physical therapy). If symptom control is inadequate, other modalities should be employed. Behavioral modifications should include:

 

• local heat/cold over the bladder and perineum
• avoidance of foods and fluids that are known to be common irritants (such as coffee and citrus)
• trial of elimination diet
• bladder training with urge suppression techniques.

As noted in FIGURE 1, first make sure that patients do not have a urinary tract infection. If culture results are negative and other criteria fit, consider the diagnosis of IC/BPS and offer therapies as outlined in the ­treat‑
ment algorithm (FIGURE 4).⁷ Repeated 
treatment for negative results of urine cultures in patients with frequency, urgency, and bladder pain can lead to unnecessary antibiotics and delayed treatment of IC/BPS.

 

7

Treatments in FIGURE 4 are ordered from most to least conservative, and initial treatment depends on symptom severity, 
clinician judgment, and patient preference. If at any point in the patient’s care the diagnosis is questioned or treatments have been ineffective, referral to a specialist, including urogynecology or urology, may be appropriate.

Managing pain
Pain management is an important component at all levels of therapy, and pharmacologic pain management principles for 
IC/BPS should be similar to those for management of other chronic pain states. Options primarily include nonsteroidal anti-
inflammatory drugs (NSAIDs) and urinary analgesics (pyridium). The use of narcotics presents the risks of tolerance and dependence. If their use is necessary, all narcotic prescriptions must come from a single source and should be used as a component of multimodality therapy to minimize narcotic use.

Hysterectomy for benign disease is a very effective operation to treat moderate to severe uterine bleeding or pain caused by uterine problems. There are 3 main surgical approaches to performing a hysterectomy: vaginal, laparoscopic, and abdominal.

“Abdominal hysterectomy” is a term that indicates the procedure was performed using a relatively large incision in the abdominal wall. It also is possible for 2 surgical routes to be combined into one operation, such as a laparoscopically assisted vaginal hysterectomy or a laparoscopic hysterectomy with a mini-laparotomy incision to remove the uterus.

Substantial evidence indicates that vaginal and laparoscopic approaches to hysterectomy result in superior outcomes when compared with abdominal hysterectomy. In this editorial I highlight that data, as well as offer concrete ways in which we can increase the use of vaginal and laparoscopic hysterectomy while reducing the current reliance on an abdominal approach.

Vaginal and laparoscopic hysterectomy are associated with more rapid recoveryAuthors of a meta-analysis of 
47 randomized trials involving 
5,102 women concluded that women who underwent vaginal and laparoscopic hysterectomy had faster return to full activity, compared with women who had an abdominal hysterectomy. Compared with vaginal hysterectomy, the abdominal 
 approach required an additional 
12 days of postoperative recovery before return to normal activities and 
1 additional day of postoperative hospitalization.¹

In the same meta-analysis, when compared with the laparoscopic approach, abdominal hysterectomy required 15 additional days to return to normal activity and 2.6 more days of postoperative hospitalization.¹ The evidence indicates that to maximize rapid return of the patient to full activity, we should reduce the use of abdominal hysterectomy for benign disease.

Abdominal hysterectomy is the most frequent US surgical approach In the United States in 2010, the rates of hysterectomy by route were 56% abdominal, 25% laparoscopic, and 19% vaginal.² In contrast to US practice, French, German, and Australian gynecologists prioritize the vaginal route. In France in 2004, the rates of hysterectomy by route were 48% vaginal, 27% laparoscopic, and 25% abdominal.³ In Australia and Germany, vaginal hysterectomy is performed in 39% and 55% of all hysterectomy cases, respectively—a greater rate of vaginal hysterectomy than observed in the United States (TABLE 1).^4,5

Our goal should be 40% or less 
for abdominal hysterectomy. 
Based on the experience of French,³ 
Australian,⁴ and German⁵ surgeons, a realistic goal is to reduce the use of abdominal hysterectomy in the United States to a rate of 40% or less and to increase the use of vaginal and laparoscopic hysterectomy to a combined rate of 60% or more.

How will we increase vaginal and laparoscopic hysterectomy for benign disease?In order to reduce the use of abdominal hysterectomy, a multipronged effort is needed:

AAGL launches comprehensive video cooperative. A major new educational video offering on vaginal hysterectomy recently was released by the AAGL (TABLE 2).
 Produced by the AAGL and cosponsored by the American College 
of Obstetricians and Gynecologists 
and the Society of Gynecologic 
Surgeons, this resource includes detailed videos focused on basic instrumentation and technique, techniques for adnexal surgery at vaginal hysterectomy, and managing
 complications. I believe this resource will be of great value as momentum builds to increase the use of vaginal hysterectomy. In addition, OBG Management will continue to publish major articles by 
leading surgeons focused on vaginal hysterectomy.

Are you a champion of vaginal and laparoscopic hysterectomy? Every hospital should identify champions of these approaches. These master surgeons could help advance the capability of the hospital staff to confidently and safely prioritize the use of vaginal and laparoscopic hysterectomy for benign disease by mentoring other surgeons. If we reduce the use of abdominal hysterectomy we will improve outcomes and significantly advance women’s health.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Hysterectomy for benign disease is a very effective operation to treat moderate to severe uterine bleeding or pain caused by uterine problems. There are 3 main surgical approaches to performing a hysterectomy: vaginal, laparoscopic, and abdominal.

“Abdominal hysterectomy” is a term that indicates the procedure was performed using a relatively large incision in the abdominal wall. It also is possible for 2 surgical routes to be combined into one operation, such as a laparoscopically assisted vaginal hysterectomy or a laparoscopic hysterectomy with a mini-laparotomy incision to remove the uterus.

Substantial evidence indicates that vaginal and laparoscopic approaches to hysterectomy result in superior outcomes when compared with abdominal hysterectomy. In this editorial I highlight that data, as well as offer concrete ways in which we can increase the use of vaginal and laparoscopic hysterectomy while reducing the current reliance on an abdominal approach.

Vaginal and laparoscopic hysterectomy are associated with more rapid recoveryAuthors of a meta-analysis of 
47 randomized trials involving 
5,102 women concluded that women who underwent vaginal and laparoscopic hysterectomy had faster return to full activity, compared with women who had an abdominal hysterectomy. Compared with vaginal hysterectomy, the abdominal 
 approach required an additional 
12 days of postoperative recovery before return to normal activities and 
1 additional day of postoperative hospitalization.¹

In the same meta-analysis, when compared with the laparoscopic approach, abdominal hysterectomy required 15 additional days to return to normal activity and 2.6 more days of postoperative hospitalization.¹ The evidence indicates that to maximize rapid return of the patient to full activity, we should reduce the use of abdominal hysterectomy for benign disease.

Abdominal hysterectomy is the most frequent US surgical approach In the United States in 2010, the rates of hysterectomy by route were 56% abdominal, 25% laparoscopic, and 19% vaginal.² In contrast to US practice, French, German, and Australian gynecologists prioritize the vaginal route. In France in 2004, the rates of hysterectomy by route were 48% vaginal, 27% laparoscopic, and 25% abdominal.³ In Australia and Germany, vaginal hysterectomy is performed in 39% and 55% of all hysterectomy cases, respectively—a greater rate of vaginal hysterectomy than observed in the United States (TABLE 1).^4,5

Our goal should be 40% or less 
for abdominal hysterectomy. 
Based on the experience of French,³ 
Australian,⁴ and German⁵ surgeons, a realistic goal is to reduce the use of abdominal hysterectomy in the United States to a rate of 40% or less and to increase the use of vaginal and laparoscopic hysterectomy to a combined rate of 60% or more.

How will we increase vaginal and laparoscopic hysterectomy for benign disease?In order to reduce the use of abdominal hysterectomy, a multipronged effort is needed:

AAGL launches comprehensive video cooperative. A major new educational video offering on vaginal hysterectomy recently was released by the AAGL (TABLE 2).
 Produced by the AAGL and cosponsored by the American College 
of Obstetricians and Gynecologists 
and the Society of Gynecologic 
Surgeons, this resource includes detailed videos focused on basic instrumentation and technique, techniques for adnexal surgery at vaginal hysterectomy, and managing
 complications. I believe this resource will be of great value as momentum builds to increase the use of vaginal hysterectomy. In addition, OBG Management will continue to publish major articles by 
leading surgeons focused on vaginal hysterectomy.

Are you a champion of vaginal and laparoscopic hysterectomy? Every hospital should identify champions of these approaches. These master surgeons could help advance the capability of the hospital staff to confidently and safely prioritize the use of vaginal and laparoscopic hysterectomy for benign disease by mentoring other surgeons. If we reduce the use of abdominal hysterectomy we will improve outcomes and significantly advance women’s health.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Hysterectomy for benign disease is a very effective operation to treat moderate to severe uterine bleeding or pain caused by uterine problems. There are 3 main surgical approaches to performing a hysterectomy: vaginal, laparoscopic, and abdominal.

“Abdominal hysterectomy” is a term that indicates the procedure was performed using a relatively large incision in the abdominal wall. It also is possible for 2 surgical routes to be combined into one operation, such as a laparoscopically assisted vaginal hysterectomy or a laparoscopic hysterectomy with a mini-laparotomy incision to remove the uterus.

Substantial evidence indicates that vaginal and laparoscopic approaches to hysterectomy result in superior outcomes when compared with abdominal hysterectomy. In this editorial I highlight that data, as well as offer concrete ways in which we can increase the use of vaginal and laparoscopic hysterectomy while reducing the current reliance on an abdominal approach.

Vaginal and laparoscopic hysterectomy are associated with more rapid recoveryAuthors of a meta-analysis of 
47 randomized trials involving 
5,102 women concluded that women who underwent vaginal and laparoscopic hysterectomy had faster return to full activity, compared with women who had an abdominal hysterectomy. Compared with vaginal hysterectomy, the abdominal 
 approach required an additional 
12 days of postoperative recovery before return to normal activities and 
1 additional day of postoperative hospitalization.¹

In the same meta-analysis, when compared with the laparoscopic approach, abdominal hysterectomy required 15 additional days to return to normal activity and 2.6 more days of postoperative hospitalization.¹ The evidence indicates that to maximize rapid return of the patient to full activity, we should reduce the use of abdominal hysterectomy for benign disease.

Abdominal hysterectomy is the most frequent US surgical approach In the United States in 2010, the rates of hysterectomy by route were 56% abdominal, 25% laparoscopic, and 19% vaginal.² In contrast to US practice, French, German, and Australian gynecologists prioritize the vaginal route. In France in 2004, the rates of hysterectomy by route were 48% vaginal, 27% laparoscopic, and 25% abdominal.³ In Australia and Germany, vaginal hysterectomy is performed in 39% and 55% of all hysterectomy cases, respectively—a greater rate of vaginal hysterectomy than observed in the United States (TABLE 1).^4,5

Our goal should be 40% or less 
for abdominal hysterectomy. 
Based on the experience of French,³ 
Australian,⁴ and German⁵ surgeons, a realistic goal is to reduce the use of abdominal hysterectomy in the United States to a rate of 40% or less and to increase the use of vaginal and laparoscopic hysterectomy to a combined rate of 60% or more.

How will we increase vaginal and laparoscopic hysterectomy for benign disease?In order to reduce the use of abdominal hysterectomy, a multipronged effort is needed:

AAGL launches comprehensive video cooperative. A major new educational video offering on vaginal hysterectomy recently was released by the AAGL (TABLE 2).
 Produced by the AAGL and cosponsored by the American College 
of Obstetricians and Gynecologists 
and the Society of Gynecologic 
Surgeons, this resource includes detailed videos focused on basic instrumentation and technique, techniques for adnexal surgery at vaginal hysterectomy, and managing
 complications. I believe this resource will be of great value as momentum builds to increase the use of vaginal hysterectomy. In addition, OBG Management will continue to publish major articles by 
leading surgeons focused on vaginal hysterectomy.

Are you a champion of vaginal and laparoscopic hysterectomy? Every hospital should identify champions of these approaches. These master surgeons could help advance the capability of the hospital staff to confidently and safely prioritize the use of vaginal and laparoscopic hysterectomy for benign disease by mentoring other surgeons. If we reduce the use of abdominal hysterectomy we will improve outcomes and significantly advance women’s health.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.