Major depressive disorder (MDD) and bipolar spectrum disorders are associated with some symptoms of—and fully defined—posttraumatic stress disorder (PTSD). Many traumatic experiences can lead to this comorbidity, the most common being exposure to or witnessing combat for men and rape and sexual molestation for women.1

Trauma has major prognostic and treatment implications for affectively ill patients, including those whose symptoms do not meet PTSD’s full diagnostic criteria. This article aims to help clinicians by:

• presenting evidence characterizing the overlap between affective disorders and PTSD
• reviewing evidence that the bipolar spectrum may be broader than generally thought, an insight that affects PTSD treatment
• making a case for routine PTSD screening for all patients with affective illnesses
• recommending PTSD treatments tailored to the patient’s comorbid affective disorder.

Overlap of trauma and affective illness

PTSD is remarkably comorbid with mood disorders. Americans with MDD and bipolar disorder (BPD) are 7 and 9.4 times, respectively, more likely to meet criteria for PTSD than persons in the general population, according to odds ratios Kessler et al² calculated from the National Comorbidity Survey database.

I have never seen a patient with PTSD who did not also meet criteria for an affective disorder. The concurrence of PTSD and MDD is not the product of overlapping diagnostic criteria. Rather, evidence indicates these are distinct diagnostic entities.³ A review of diagnostic criteria for PTSD and hypomania/mania leads to the same conclusion.

Bipolar spectrum disorders

DSM-IV-TR assumes that mood disorders fall neatly into boxes. Other data (Table 1)^4–8 indicate that these disorders fall along a continuum or—more conservatively—that the scope of bipolarity is much wider than DSM-IV-TR recognizes. This is a controversial topic, and the individual clinician’s position could impact how one manages PTSD patients.

Table 1

Evidence of bipolar spectrum features in major depressive episodes

In this article, I include bipolar I disorder, bipolar II disorder, and mixed depression within the “bipolar spectrum disorders.” If one accepts this—and I do—it follows that 50% to 70% of all major depressive episodes (MDEs) are bipolar in nature.^4–9 Depending on your practice setting, you may see a higher or lower base rate of bipolar spectrum disorders.

Mixed depression is not recognized in DSM-IV-TR, and the purpose of this article is not to defend its inclusion as a bipolar spectrum phenomenon. A proposed definition of mixed depression⁹ requires the presence of an MDE contaminated by ≥3 features of hypomania or mania, without euphoria or inflated self-esteem/grandiosity (Table 2).¹⁰

Some experts believe episodes of hypomania and mania frequently occur in the illness course of persons with mixed depression; indeed, mixed depression is a predictor of a bipolar course. It is observed in outpatient⁹ and inpatient settings.¹¹ Common forms of mixed depression feature combinations of irritability, psychomotor agitation (mild to severe), increased talkativeness (which may fall short of frank pressured speech), racing or “crowded” thoughts (or “mental overactivity”), and distractibility. Other than increased self-esteem/grandiosity, any symptoms within DSM-IV-TR criterion B for a hypomanic or manic episode may be seen in mixed depression. Psychosis is an exclusion criterion for mixed depression.

Mixed depression responds poorly to antidepressant monotherapy. Validation studies suggest that mixed depression is a bipolar variant, as determined by its capacity to predict a bipolar course and its association with a family history of bipolar disorder and age of onset.⁹

Table 2

Diagnostic characteristics of a hypomanic episode, DSM-IV-TR criteria A and B

PTSD risk in affective illness

An adolescent sample. A preliminary cross-sectional study conducted by our group indicates that adolescents with affective disorders may have a much higher risk of developing PTSD than psychiatric comparison subjects.¹² We used modules from the Structured Clinical Interview for DSM-IV (SCID) to screen for intra-episode psychopathology (as opposed to lifetime prevalence of disorders) in 79 adolescents with MDD, 34 with BPD as defined in the DSM-IV-TR, and 26 with neither affective disorder (psychiatric controls). We found:

• 38.2% of subjects with BPD met criteria for PTSD, compared with 13.9% of those with MDD (OR 4.9; P =.001)
• 3.8% of adolescents without a mood disorder met criteria for PTSD.

We also found that comorbid PTSD was associated with a 4.5-fold higher risk of a suicide attempt, even after we controlled for BPD diagnosis. When we controlled for the presence of other concurrent anxiety disorders, the likelihood of an adolescent with PTSD having attempted suicide remained significant (OR 3.4; P=.023). This finding suggests that PTSD is an independent risk factor for a suicide attempt.

An adult sample. We then focused on adults meeting criteria for MDD or BPD. In a study of 187 consecutively presenting affectively ill patients, we used the SCID to screen for multiple anxiety disorders including PTSD.¹³ Lifetime—as opposed to intra-episode—PTSD prevalence was 23.8% among the 118 patients with MDD and 62.3% among the 69 patients with BPD. A patient with BPD was 5 times more likely to have PTSD than a patient with MDD (OR 5.3; P < .0001). The most common cause of trauma leading to PTSD was sexual molestation or rape as a child or adolescent in this predominantly female Latino population.

Populations at risk for PTSD

The prevalence of PTSD in clinical samples varies, depending on the population studied. For instance, women are at much higher risk for developing PTSD than men, even in comparisons where men are exposed to a greater number of traumatic events and analyses control for differences in the prevalence of sexual abuse. The gender difference is greater if the trauma occurs during childhood.¹⁴ Essentially all patients in our adolescent and adult studies developed PTSD in response to childhood or adolescent sexual trauma.^12,13

A population exposed to a high rate of violent crime would be expected to show a higher PTSD prevalence than one exposed to substantially less violence. The base rate of PTSD also is much higher in affectively ill patients than in the general population.

An analysis by Otto et al¹⁵ found a 16% lifetime prevalence of concomitant PTSD in 1,214 persons with BPD (not the manifold forms within the bipolar spectrum). Oquendo et al¹⁶ reported a 25.7% lifetime prevalence of PTSD in 230 patients with a history of MDD. Other epidemiologic² and clinical studies^12,13 suggest a considerably higher base rate of PTSD among persons with bipolar disorders than those with MDD.

The method of ascertaining the presence of this disorder may be another variable affecting the reported PTSD prevalence. Persistent avoidance—including “efforts to avoid thoughts, feelings, or conversations associated with the trauma”—is a diagnostic feature of PTSD.¹⁰ Researchers and clinicians who do not intentionally screen patients for PTSD are not likely to detect it. Determining the true prevalence of PTSD requires empathic inquiry about exposure to traumatic events.

PTSD screening

Humans are remarkably resilient, and most persons exposed to major trauma are thought not to develop PTSD. However, in my experience, because PTSD appears to be common among persons with affective illness, determining whether such patients have been traumatized is important for prognosis and treatment selection.

To get started, you could create a 1-page form to record traumatic events and identify features of PTSD according to DSM-IV-TR criteria (Checklist).¹⁰ PTSD screening without a form can become second nature with practice; an experienced clinician can screen a traumatized patient for the disorder within 3 to 5 minutes.

When screening for a history of trauma, ask patients in a straightforward manner if they have:

• been victims of violent crimes
• witnessed violent crimes
• been exposed to events in which people could have suffered grave injury
• experienced emotional, physical, or sexual abuse.

A person who has experienced emotional abuse but not physical or sexual abuse cannot meet DSM-IV-TR criterion A and therefore does not meet full criteria for PTSD. Many emotionally abused persons meet criteria B through F, however, and they are most reasonably managed similarly to persons who also meet criterion A. When formulating a treatment plan, I recommend using clinical judgment rather than rigid adherence to DSM-IV-TR.

Checklist

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Treating PTSD in depression

Pharmacotherapy and psychotherapeutic interventions are important to PTSD patients’ recovery. Limited resources often prevent these patients from receiving expert psychotherapeutic intervention, however, leaving pharmacotherapy as the mainstay of treatment. This is unfortunate, because psychological interventions may be sufficient and preferred in some instances (Box).^17–20

Pharmacotherapy for comorbid MDD. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are first-line interventions for PTSD in depressed patients who do not meet criteria for a bipolar spectrum disorder. Placebo-controlled studies suggest that sertraline,^21,22 fluoxetine,²³ and paroxetine,²⁴ are effective; doses higher than those used to treat depression may be required. Extended-release venlafaxine²⁵ in dosages similar to those needed for depressive disorders also can be effective. Bupropion does not appear to be beneficial in treating PTSD.

The monoamine oxidase inhibitor phenelzine was long used successfully in treating PTSD but for the most part has been replaced by SSRIs. Because of its associated dietary restrictions, risk of hypertensive crises, and other side effects, phenelzine probably is best reserved for patients who do not respond to treatment with SSRIs or venlafaxine.

Pharmacotherapy for comorbid bipolar spectrum. If one accepts that most patients meeting criteria for MDE have a bipolar spectrum disorder, then most affectively ill patients with PTSD would need to be treated as if they have bipolar disorder. Oddly enough, this creates difficulties for the use of not only antidepressants and benzodiazepines, but also mood stabilizers:

• Patients with BPD and comorbid anxiety disorders, including PTSD, may be resistant to mood stabilizers.^26,27
• Antidepressants can precipitate hypomanic or manic switches or onset of mixed hypomania, a mixed state, or rapid cycling in patients with a bipolar spectrum disorder.^28–30
• Benzodiazepines do not appear to relieve acute or chronic PTSD-related distress, and discontinuation could cause rebound symptoms.³¹

Because no outcome studies have addressed PTSD management in patients with bipolar spectrum disorders, clinicians must rely on their judgment when formulating treatment plans. One strategy is to treat patients with mood stabilizers, then leave well enough alone if both the mood and anxiety symptoms remit (which is possible but unlikely in my experience). I often start treatment for the bipolar spectrum disorder and co-existing PTSD using mood stabilizers (including atypical antipsychotics) and prazosin, an α-1antagonist originally used for treating hypertension.

Prazosin can help diminish nightmares, dreams, and other painful recollections of trauma.^32,33 The drug does not affect time to sleep onset. It also has been reported to reduce avoidance behavior and hyperarousal, such as irritability and anger.³⁴ This has been my experience.

Box

Prazosin to treat PTSD-related symptoms in children or adolescents has not been studied, but it can be useful in adults over a wide range of doses. As little as 1 mg at bedtime may confer benefit, although the mean prazosin dose in an 8-week, placebo-controlled study of 40 combat veterans was 13.3 mg in the evening.³³

I often initiate prazosin treatment as follows:

• 1 mg on the first night of treatment
• 2 mg on the second night
• 3 mg on the third night
• then, if tolerated, 1 mg upon waking, 1 mg 8 hours later, and 3 mg at bedtime. I then slowly adjust the dose schedule based on the patient’s needs, such as minimizing painful re-experiencing of the trauma. Reducing avoidance and hyperarousal also are reasonable targets. For example, when using prazosin to treat extremely angry men with PTSD stemming from exposure to violent crimes, I have observed that even “murderous” rage ceases with prazosin treatment, only to reappear when prazosin is discontinued.

In treating approximately 100 patients with prazosin, I have not exceeded 16 mg/d. Dosages used for treating hypertension usually are 5 to 20 mg/d. When using prazosin, I always:

• warn patients that faintness or fainting is a side effect and record this caveat in their chart
• obtain sitting and standing blood pressure and pulse before starting treatment and subsequently
• ask patients if they feel dizzy when changing posture before and after initiating treatment.

Most of my PTSD patients are suffering so much that they are willing to accept the risk of fainting associated with prazosin use. For PTSD comorbid with severe panic disorder,^12,13 I find that a benzodiazepine with antipanic properties such as alprazolam or clonazepam often works well in conjunction with prazosin.

Some patients with bipolar spectrum disorders might benefit from the addition of an SSRI after mood stabilizer treatment proves effective. However, I have never managed a patient in this manner, and like my own treatment strategy, this has not been subjected to rigorous empiric inquiry. In my view, psychological treatment is much preferred to antidepressant therapy.

Related resource

• Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet. 2007;369:935-945.

Drug brand names

• Alprazolam • Xanax
• Bupropion • Wellbutrin
• Clonazepam • Klonopin
• D-cycloserine • Seromycin
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Phenelzine • Nardil
• Prazosin • Minipress
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Dilsaver reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Major depressive disorder (MDD) and bipolar spectrum disorders are associated with some symptoms of—and fully defined—posttraumatic stress disorder (PTSD). Many traumatic experiences can lead to this comorbidity, the most common being exposure to or witnessing combat for men and rape and sexual molestation for women.1

Trauma has major prognostic and treatment implications for affectively ill patients, including those whose symptoms do not meet PTSD’s full diagnostic criteria. This article aims to help clinicians by:

• presenting evidence characterizing the overlap between affective disorders and PTSD
• reviewing evidence that the bipolar spectrum may be broader than generally thought, an insight that affects PTSD treatment
• making a case for routine PTSD screening for all patients with affective illnesses
• recommending PTSD treatments tailored to the patient’s comorbid affective disorder.

Overlap of trauma and affective illness

PTSD is remarkably comorbid with mood disorders. Americans with MDD and bipolar disorder (BPD) are 7 and 9.4 times, respectively, more likely to meet criteria for PTSD than persons in the general population, according to odds ratios Kessler et al² calculated from the National Comorbidity Survey database.

I have never seen a patient with PTSD who did not also meet criteria for an affective disorder. The concurrence of PTSD and MDD is not the product of overlapping diagnostic criteria. Rather, evidence indicates these are distinct diagnostic entities.³ A review of diagnostic criteria for PTSD and hypomania/mania leads to the same conclusion.

Bipolar spectrum disorders

DSM-IV-TR assumes that mood disorders fall neatly into boxes. Other data (Table 1)^4–8 indicate that these disorders fall along a continuum or—more conservatively—that the scope of bipolarity is much wider than DSM-IV-TR recognizes. This is a controversial topic, and the individual clinician’s position could impact how one manages PTSD patients.

Table 1

Evidence of bipolar spectrum features in major depressive episodes

In this article, I include bipolar I disorder, bipolar II disorder, and mixed depression within the “bipolar spectrum disorders.” If one accepts this—and I do—it follows that 50% to 70% of all major depressive episodes (MDEs) are bipolar in nature.^4–9 Depending on your practice setting, you may see a higher or lower base rate of bipolar spectrum disorders.

Mixed depression is not recognized in DSM-IV-TR, and the purpose of this article is not to defend its inclusion as a bipolar spectrum phenomenon. A proposed definition of mixed depression⁹ requires the presence of an MDE contaminated by ≥3 features of hypomania or mania, without euphoria or inflated self-esteem/grandiosity (Table 2).¹⁰

Some experts believe episodes of hypomania and mania frequently occur in the illness course of persons with mixed depression; indeed, mixed depression is a predictor of a bipolar course. It is observed in outpatient⁹ and inpatient settings.¹¹ Common forms of mixed depression feature combinations of irritability, psychomotor agitation (mild to severe), increased talkativeness (which may fall short of frank pressured speech), racing or “crowded” thoughts (or “mental overactivity”), and distractibility. Other than increased self-esteem/grandiosity, any symptoms within DSM-IV-TR criterion B for a hypomanic or manic episode may be seen in mixed depression. Psychosis is an exclusion criterion for mixed depression.

Mixed depression responds poorly to antidepressant monotherapy. Validation studies suggest that mixed depression is a bipolar variant, as determined by its capacity to predict a bipolar course and its association with a family history of bipolar disorder and age of onset.⁹

Table 2

Diagnostic characteristics of a hypomanic episode, DSM-IV-TR criteria A and B

PTSD risk in affective illness

An adolescent sample. A preliminary cross-sectional study conducted by our group indicates that adolescents with affective disorders may have a much higher risk of developing PTSD than psychiatric comparison subjects.¹² We used modules from the Structured Clinical Interview for DSM-IV (SCID) to screen for intra-episode psychopathology (as opposed to lifetime prevalence of disorders) in 79 adolescents with MDD, 34 with BPD as defined in the DSM-IV-TR, and 26 with neither affective disorder (psychiatric controls). We found:

• 38.2% of subjects with BPD met criteria for PTSD, compared with 13.9% of those with MDD (OR 4.9; P =.001)
• 3.8% of adolescents without a mood disorder met criteria for PTSD.

We also found that comorbid PTSD was associated with a 4.5-fold higher risk of a suicide attempt, even after we controlled for BPD diagnosis. When we controlled for the presence of other concurrent anxiety disorders, the likelihood of an adolescent with PTSD having attempted suicide remained significant (OR 3.4; P=.023). This finding suggests that PTSD is an independent risk factor for a suicide attempt.

An adult sample. We then focused on adults meeting criteria for MDD or BPD. In a study of 187 consecutively presenting affectively ill patients, we used the SCID to screen for multiple anxiety disorders including PTSD.¹³ Lifetime—as opposed to intra-episode—PTSD prevalence was 23.8% among the 118 patients with MDD and 62.3% among the 69 patients with BPD. A patient with BPD was 5 times more likely to have PTSD than a patient with MDD (OR 5.3; P < .0001). The most common cause of trauma leading to PTSD was sexual molestation or rape as a child or adolescent in this predominantly female Latino population.

Populations at risk for PTSD

The prevalence of PTSD in clinical samples varies, depending on the population studied. For instance, women are at much higher risk for developing PTSD than men, even in comparisons where men are exposed to a greater number of traumatic events and analyses control for differences in the prevalence of sexual abuse. The gender difference is greater if the trauma occurs during childhood.¹⁴ Essentially all patients in our adolescent and adult studies developed PTSD in response to childhood or adolescent sexual trauma.^12,13

A population exposed to a high rate of violent crime would be expected to show a higher PTSD prevalence than one exposed to substantially less violence. The base rate of PTSD also is much higher in affectively ill patients than in the general population.

An analysis by Otto et al¹⁵ found a 16% lifetime prevalence of concomitant PTSD in 1,214 persons with BPD (not the manifold forms within the bipolar spectrum). Oquendo et al¹⁶ reported a 25.7% lifetime prevalence of PTSD in 230 patients with a history of MDD. Other epidemiologic² and clinical studies^12,13 suggest a considerably higher base rate of PTSD among persons with bipolar disorders than those with MDD.

The method of ascertaining the presence of this disorder may be another variable affecting the reported PTSD prevalence. Persistent avoidance—including “efforts to avoid thoughts, feelings, or conversations associated with the trauma”—is a diagnostic feature of PTSD.¹⁰ Researchers and clinicians who do not intentionally screen patients for PTSD are not likely to detect it. Determining the true prevalence of PTSD requires empathic inquiry about exposure to traumatic events.

PTSD screening

Humans are remarkably resilient, and most persons exposed to major trauma are thought not to develop PTSD. However, in my experience, because PTSD appears to be common among persons with affective illness, determining whether such patients have been traumatized is important for prognosis and treatment selection.

To get started, you could create a 1-page form to record traumatic events and identify features of PTSD according to DSM-IV-TR criteria (Checklist).¹⁰ PTSD screening without a form can become second nature with practice; an experienced clinician can screen a traumatized patient for the disorder within 3 to 5 minutes.

When screening for a history of trauma, ask patients in a straightforward manner if they have:

• been victims of violent crimes
• witnessed violent crimes
• been exposed to events in which people could have suffered grave injury
• experienced emotional, physical, or sexual abuse.

A person who has experienced emotional abuse but not physical or sexual abuse cannot meet DSM-IV-TR criterion A and therefore does not meet full criteria for PTSD. Many emotionally abused persons meet criteria B through F, however, and they are most reasonably managed similarly to persons who also meet criterion A. When formulating a treatment plan, I recommend using clinical judgment rather than rigid adherence to DSM-IV-TR.

Checklist

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Treating PTSD in depression

Pharmacotherapy and psychotherapeutic interventions are important to PTSD patients’ recovery. Limited resources often prevent these patients from receiving expert psychotherapeutic intervention, however, leaving pharmacotherapy as the mainstay of treatment. This is unfortunate, because psychological interventions may be sufficient and preferred in some instances (Box).^17–20

Pharmacotherapy for comorbid MDD. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are first-line interventions for PTSD in depressed patients who do not meet criteria for a bipolar spectrum disorder. Placebo-controlled studies suggest that sertraline,^21,22 fluoxetine,²³ and paroxetine,²⁴ are effective; doses higher than those used to treat depression may be required. Extended-release venlafaxine²⁵ in dosages similar to those needed for depressive disorders also can be effective. Bupropion does not appear to be beneficial in treating PTSD.

The monoamine oxidase inhibitor phenelzine was long used successfully in treating PTSD but for the most part has been replaced by SSRIs. Because of its associated dietary restrictions, risk of hypertensive crises, and other side effects, phenelzine probably is best reserved for patients who do not respond to treatment with SSRIs or venlafaxine.

Pharmacotherapy for comorbid bipolar spectrum. If one accepts that most patients meeting criteria for MDE have a bipolar spectrum disorder, then most affectively ill patients with PTSD would need to be treated as if they have bipolar disorder. Oddly enough, this creates difficulties for the use of not only antidepressants and benzodiazepines, but also mood stabilizers:

• Patients with BPD and comorbid anxiety disorders, including PTSD, may be resistant to mood stabilizers.^26,27
• Antidepressants can precipitate hypomanic or manic switches or onset of mixed hypomania, a mixed state, or rapid cycling in patients with a bipolar spectrum disorder.^28–30
• Benzodiazepines do not appear to relieve acute or chronic PTSD-related distress, and discontinuation could cause rebound symptoms.³¹

Because no outcome studies have addressed PTSD management in patients with bipolar spectrum disorders, clinicians must rely on their judgment when formulating treatment plans. One strategy is to treat patients with mood stabilizers, then leave well enough alone if both the mood and anxiety symptoms remit (which is possible but unlikely in my experience). I often start treatment for the bipolar spectrum disorder and co-existing PTSD using mood stabilizers (including atypical antipsychotics) and prazosin, an α-1antagonist originally used for treating hypertension.

Prazosin can help diminish nightmares, dreams, and other painful recollections of trauma.^32,33 The drug does not affect time to sleep onset. It also has been reported to reduce avoidance behavior and hyperarousal, such as irritability and anger.³⁴ This has been my experience.

Box

Prazosin to treat PTSD-related symptoms in children or adolescents has not been studied, but it can be useful in adults over a wide range of doses. As little as 1 mg at bedtime may confer benefit, although the mean prazosin dose in an 8-week, placebo-controlled study of 40 combat veterans was 13.3 mg in the evening.³³

I often initiate prazosin treatment as follows:

• 1 mg on the first night of treatment
• 2 mg on the second night
• 3 mg on the third night
• then, if tolerated, 1 mg upon waking, 1 mg 8 hours later, and 3 mg at bedtime. I then slowly adjust the dose schedule based on the patient’s needs, such as minimizing painful re-experiencing of the trauma. Reducing avoidance and hyperarousal also are reasonable targets. For example, when using prazosin to treat extremely angry men with PTSD stemming from exposure to violent crimes, I have observed that even “murderous” rage ceases with prazosin treatment, only to reappear when prazosin is discontinued.

In treating approximately 100 patients with prazosin, I have not exceeded 16 mg/d. Dosages used for treating hypertension usually are 5 to 20 mg/d. When using prazosin, I always:

• warn patients that faintness or fainting is a side effect and record this caveat in their chart
• obtain sitting and standing blood pressure and pulse before starting treatment and subsequently
• ask patients if they feel dizzy when changing posture before and after initiating treatment.

Most of my PTSD patients are suffering so much that they are willing to accept the risk of fainting associated with prazosin use. For PTSD comorbid with severe panic disorder,^12,13 I find that a benzodiazepine with antipanic properties such as alprazolam or clonazepam often works well in conjunction with prazosin.

Some patients with bipolar spectrum disorders might benefit from the addition of an SSRI after mood stabilizer treatment proves effective. However, I have never managed a patient in this manner, and like my own treatment strategy, this has not been subjected to rigorous empiric inquiry. In my view, psychological treatment is much preferred to antidepressant therapy.

Related resource

• Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet. 2007;369:935-945.

Drug brand names

• Alprazolam • Xanax
• Bupropion • Wellbutrin
• Clonazepam • Klonopin
• D-cycloserine • Seromycin
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Phenelzine • Nardil
• Prazosin • Minipress
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Dilsaver reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Major depressive disorder (MDD) and bipolar spectrum disorders are associated with some symptoms of—and fully defined—posttraumatic stress disorder (PTSD). Many traumatic experiences can lead to this comorbidity, the most common being exposure to or witnessing combat for men and rape and sexual molestation for women.1

Trauma has major prognostic and treatment implications for affectively ill patients, including those whose symptoms do not meet PTSD’s full diagnostic criteria. This article aims to help clinicians by:

• presenting evidence characterizing the overlap between affective disorders and PTSD
• reviewing evidence that the bipolar spectrum may be broader than generally thought, an insight that affects PTSD treatment
• making a case for routine PTSD screening for all patients with affective illnesses
• recommending PTSD treatments tailored to the patient’s comorbid affective disorder.

Overlap of trauma and affective illness

PTSD is remarkably comorbid with mood disorders. Americans with MDD and bipolar disorder (BPD) are 7 and 9.4 times, respectively, more likely to meet criteria for PTSD than persons in the general population, according to odds ratios Kessler et al² calculated from the National Comorbidity Survey database.

I have never seen a patient with PTSD who did not also meet criteria for an affective disorder. The concurrence of PTSD and MDD is not the product of overlapping diagnostic criteria. Rather, evidence indicates these are distinct diagnostic entities.³ A review of diagnostic criteria for PTSD and hypomania/mania leads to the same conclusion.

Bipolar spectrum disorders

DSM-IV-TR assumes that mood disorders fall neatly into boxes. Other data (Table 1)^4–8 indicate that these disorders fall along a continuum or—more conservatively—that the scope of bipolarity is much wider than DSM-IV-TR recognizes. This is a controversial topic, and the individual clinician’s position could impact how one manages PTSD patients.

Table 1

Evidence of bipolar spectrum features in major depressive episodes

In this article, I include bipolar I disorder, bipolar II disorder, and mixed depression within the “bipolar spectrum disorders.” If one accepts this—and I do—it follows that 50% to 70% of all major depressive episodes (MDEs) are bipolar in nature.^4–9 Depending on your practice setting, you may see a higher or lower base rate of bipolar spectrum disorders.

Mixed depression is not recognized in DSM-IV-TR, and the purpose of this article is not to defend its inclusion as a bipolar spectrum phenomenon. A proposed definition of mixed depression⁹ requires the presence of an MDE contaminated by ≥3 features of hypomania or mania, without euphoria or inflated self-esteem/grandiosity (Table 2).¹⁰

Some experts believe episodes of hypomania and mania frequently occur in the illness course of persons with mixed depression; indeed, mixed depression is a predictor of a bipolar course. It is observed in outpatient⁹ and inpatient settings.¹¹ Common forms of mixed depression feature combinations of irritability, psychomotor agitation (mild to severe), increased talkativeness (which may fall short of frank pressured speech), racing or “crowded” thoughts (or “mental overactivity”), and distractibility. Other than increased self-esteem/grandiosity, any symptoms within DSM-IV-TR criterion B for a hypomanic or manic episode may be seen in mixed depression. Psychosis is an exclusion criterion for mixed depression.

Mixed depression responds poorly to antidepressant monotherapy. Validation studies suggest that mixed depression is a bipolar variant, as determined by its capacity to predict a bipolar course and its association with a family history of bipolar disorder and age of onset.⁹

Table 2

Diagnostic characteristics of a hypomanic episode, DSM-IV-TR criteria A and B

PTSD risk in affective illness

An adolescent sample. A preliminary cross-sectional study conducted by our group indicates that adolescents with affective disorders may have a much higher risk of developing PTSD than psychiatric comparison subjects.¹² We used modules from the Structured Clinical Interview for DSM-IV (SCID) to screen for intra-episode psychopathology (as opposed to lifetime prevalence of disorders) in 79 adolescents with MDD, 34 with BPD as defined in the DSM-IV-TR, and 26 with neither affective disorder (psychiatric controls). We found:

• 38.2% of subjects with BPD met criteria for PTSD, compared with 13.9% of those with MDD (OR 4.9; P =.001)
• 3.8% of adolescents without a mood disorder met criteria for PTSD.

We also found that comorbid PTSD was associated with a 4.5-fold higher risk of a suicide attempt, even after we controlled for BPD diagnosis. When we controlled for the presence of other concurrent anxiety disorders, the likelihood of an adolescent with PTSD having attempted suicide remained significant (OR 3.4; P=.023). This finding suggests that PTSD is an independent risk factor for a suicide attempt.

An adult sample. We then focused on adults meeting criteria for MDD or BPD. In a study of 187 consecutively presenting affectively ill patients, we used the SCID to screen for multiple anxiety disorders including PTSD.¹³ Lifetime—as opposed to intra-episode—PTSD prevalence was 23.8% among the 118 patients with MDD and 62.3% among the 69 patients with BPD. A patient with BPD was 5 times more likely to have PTSD than a patient with MDD (OR 5.3; P < .0001). The most common cause of trauma leading to PTSD was sexual molestation or rape as a child or adolescent in this predominantly female Latino population.

Populations at risk for PTSD

The prevalence of PTSD in clinical samples varies, depending on the population studied. For instance, women are at much higher risk for developing PTSD than men, even in comparisons where men are exposed to a greater number of traumatic events and analyses control for differences in the prevalence of sexual abuse. The gender difference is greater if the trauma occurs during childhood.¹⁴ Essentially all patients in our adolescent and adult studies developed PTSD in response to childhood or adolescent sexual trauma.^12,13

A population exposed to a high rate of violent crime would be expected to show a higher PTSD prevalence than one exposed to substantially less violence. The base rate of PTSD also is much higher in affectively ill patients than in the general population.

An analysis by Otto et al¹⁵ found a 16% lifetime prevalence of concomitant PTSD in 1,214 persons with BPD (not the manifold forms within the bipolar spectrum). Oquendo et al¹⁶ reported a 25.7% lifetime prevalence of PTSD in 230 patients with a history of MDD. Other epidemiologic² and clinical studies^12,13 suggest a considerably higher base rate of PTSD among persons with bipolar disorders than those with MDD.

The method of ascertaining the presence of this disorder may be another variable affecting the reported PTSD prevalence. Persistent avoidance—including “efforts to avoid thoughts, feelings, or conversations associated with the trauma”—is a diagnostic feature of PTSD.¹⁰ Researchers and clinicians who do not intentionally screen patients for PTSD are not likely to detect it. Determining the true prevalence of PTSD requires empathic inquiry about exposure to traumatic events.

PTSD screening

Humans are remarkably resilient, and most persons exposed to major trauma are thought not to develop PTSD. However, in my experience, because PTSD appears to be common among persons with affective illness, determining whether such patients have been traumatized is important for prognosis and treatment selection.

To get started, you could create a 1-page form to record traumatic events and identify features of PTSD according to DSM-IV-TR criteria (Checklist).¹⁰ PTSD screening without a form can become second nature with practice; an experienced clinician can screen a traumatized patient for the disorder within 3 to 5 minutes.

When screening for a history of trauma, ask patients in a straightforward manner if they have:

• been victims of violent crimes
• witnessed violent crimes
• been exposed to events in which people could have suffered grave injury
• experienced emotional, physical, or sexual abuse.

A person who has experienced emotional abuse but not physical or sexual abuse cannot meet DSM-IV-TR criterion A and therefore does not meet full criteria for PTSD. Many emotionally abused persons meet criteria B through F, however, and they are most reasonably managed similarly to persons who also meet criterion A. When formulating a treatment plan, I recommend using clinical judgment rather than rigid adherence to DSM-IV-TR.

Checklist

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Treating PTSD in depression

Pharmacotherapy and psychotherapeutic interventions are important to PTSD patients’ recovery. Limited resources often prevent these patients from receiving expert psychotherapeutic intervention, however, leaving pharmacotherapy as the mainstay of treatment. This is unfortunate, because psychological interventions may be sufficient and preferred in some instances (Box).^17–20

Pharmacotherapy for comorbid MDD. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine are first-line interventions for PTSD in depressed patients who do not meet criteria for a bipolar spectrum disorder. Placebo-controlled studies suggest that sertraline,^21,22 fluoxetine,²³ and paroxetine,²⁴ are effective; doses higher than those used to treat depression may be required. Extended-release venlafaxine²⁵ in dosages similar to those needed for depressive disorders also can be effective. Bupropion does not appear to be beneficial in treating PTSD.

The monoamine oxidase inhibitor phenelzine was long used successfully in treating PTSD but for the most part has been replaced by SSRIs. Because of its associated dietary restrictions, risk of hypertensive crises, and other side effects, phenelzine probably is best reserved for patients who do not respond to treatment with SSRIs or venlafaxine.

Pharmacotherapy for comorbid bipolar spectrum. If one accepts that most patients meeting criteria for MDE have a bipolar spectrum disorder, then most affectively ill patients with PTSD would need to be treated as if they have bipolar disorder. Oddly enough, this creates difficulties for the use of not only antidepressants and benzodiazepines, but also mood stabilizers:

• Patients with BPD and comorbid anxiety disorders, including PTSD, may be resistant to mood stabilizers.^26,27
• Antidepressants can precipitate hypomanic or manic switches or onset of mixed hypomania, a mixed state, or rapid cycling in patients with a bipolar spectrum disorder.^28–30
• Benzodiazepines do not appear to relieve acute or chronic PTSD-related distress, and discontinuation could cause rebound symptoms.³¹

Because no outcome studies have addressed PTSD management in patients with bipolar spectrum disorders, clinicians must rely on their judgment when formulating treatment plans. One strategy is to treat patients with mood stabilizers, then leave well enough alone if both the mood and anxiety symptoms remit (which is possible but unlikely in my experience). I often start treatment for the bipolar spectrum disorder and co-existing PTSD using mood stabilizers (including atypical antipsychotics) and prazosin, an α-1antagonist originally used for treating hypertension.

Prazosin can help diminish nightmares, dreams, and other painful recollections of trauma.^32,33 The drug does not affect time to sleep onset. It also has been reported to reduce avoidance behavior and hyperarousal, such as irritability and anger.³⁴ This has been my experience.

Box

Prazosin to treat PTSD-related symptoms in children or adolescents has not been studied, but it can be useful in adults over a wide range of doses. As little as 1 mg at bedtime may confer benefit, although the mean prazosin dose in an 8-week, placebo-controlled study of 40 combat veterans was 13.3 mg in the evening.³³

I often initiate prazosin treatment as follows:

• 1 mg on the first night of treatment
• 2 mg on the second night
• 3 mg on the third night
• then, if tolerated, 1 mg upon waking, 1 mg 8 hours later, and 3 mg at bedtime. I then slowly adjust the dose schedule based on the patient’s needs, such as minimizing painful re-experiencing of the trauma. Reducing avoidance and hyperarousal also are reasonable targets. For example, when using prazosin to treat extremely angry men with PTSD stemming from exposure to violent crimes, I have observed that even “murderous” rage ceases with prazosin treatment, only to reappear when prazosin is discontinued.

In treating approximately 100 patients with prazosin, I have not exceeded 16 mg/d. Dosages used for treating hypertension usually are 5 to 20 mg/d. When using prazosin, I always:

• warn patients that faintness or fainting is a side effect and record this caveat in their chart
• obtain sitting and standing blood pressure and pulse before starting treatment and subsequently
• ask patients if they feel dizzy when changing posture before and after initiating treatment.

Most of my PTSD patients are suffering so much that they are willing to accept the risk of fainting associated with prazosin use. For PTSD comorbid with severe panic disorder,^12,13 I find that a benzodiazepine with antipanic properties such as alprazolam or clonazepam often works well in conjunction with prazosin.

Some patients with bipolar spectrum disorders might benefit from the addition of an SSRI after mood stabilizer treatment proves effective. However, I have never managed a patient in this manner, and like my own treatment strategy, this has not been subjected to rigorous empiric inquiry. In my view, psychological treatment is much preferred to antidepressant therapy.

Related resource

• Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet. 2007;369:935-945.

Drug brand names

• Alprazolam • Xanax
• Bupropion • Wellbutrin
• Clonazepam • Klonopin
• D-cycloserine • Seromycin
• Fluoxetine • Prozac
• Paroxetine • Paxil
• Phenelzine • Nardil
• Prazosin • Minipress
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosure

Dr. Dilsaver reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Stubborn pneumonia turns out to be cancer

AFTER RECEIVING ANTIBIOTICS FOR PNEUMONIA, a 37-year-old man improved but didn’t fully recover; his radiographs didn’t return to normal. He’d never smoked cigarettes.

During the several months after the pneumonia, the patient’s doctor ordered repeat radiographs and prescribed antibiotics and pain medication. When the patient’s spine collapsed, the doctor diagnosed metastatic lung cancer. The patient received palliative treatment and ultimately died.

PLAINTIFF’S CLAIM The doctor was negligent in failing to change the patient’s treatment after 2 or 3 months and failing to order a computed tomography (CT) scan or refer the patient to a pulmonologist.

THE DEFENSE No information about the doctor’s defense is available.

VERDICT $1.25 million Washington settlement.

COMMENT I’d like a nickel for every case of delayed diagnosis of lung cancer based on clearly abnormal chest radiographs. We can argue about whether diagnosis would make a difference, but we need to follow up assiduously on abnormal radiographs and document our actions.

Rapidly raised serum sodium leads to osmotic demyelination

A 60-YEAR-OLD WOMAN went to her local medical center complaining of a cough for the previous 2 weeks, decreased appetite and oral intake, and generalized body aches. She first went to urgent care, where laboratory studies showed critically low levels of sodium and potassium. Based on these results, the woman was told to go to the facility’s emergency department (ED).

In the ED, she reported feeling very weak and tired and having body aches and pain. When laboratory tests showed that her sodium and potassium levels had fallen further, she was admitted to the intensive care unit (ICU).

The doctor who saw the patient in the ICU ordered intravenous fluids with normal saline and potassium supplements. He then had the patient admitted to the ICU at another hospital. The physician at that hospital continued to prescribe IV sodium and potassium until the patient was discharged with diagnoses that included hyponatremia and hypokalemia.

Ten days later, the patient returned to the ED complaining of slurred speech for the previous 2 days. A CT scan of her head showed a possible basilar tip aneurysm. Subsequent magnetic resonance imaging with and without contrast and intracranial magnetic resonance angiography confirmed a basilar tip aneurysm and showed findings suggestive of osmotic demyelination. Neurologic examination revealed dysarthria, right upper extremity weakness without spasticity, and periods of confusion interspersed with lucid intervals.

A subsequent neurologic consultation confirmed osmotic demyelination syndrome (formerly known as central pontine myelinolysis). Neurologic examination at that time found continued mild dysarthria, problems standing, inability to walk unsupported, mild oral and pharyngeal dysphagia, and language and writing deficits.

PLAINTIFF’S CLAIM The patient’s sodium level was increased at an inappropriately rapid rate, which caused neurologically devastating osmotic demyelination. Serum sodium should have been monitored every 4 hours during the first 24 hours of treatment. The plaintiff also alleged negligence in continuing normal saline after the patient’s serum sodium was measured at 112 mEq/L.

THE DEFENSE The treatment provided was appropriate.

VERDICT $550,000 California settlement.

COMMENT Avoiding osmotic demyelination syndrome requires careful treatment and monitoring. I have independently reviewed several allegations of malpractice involving this uncommon, but devastating condition. Two recent articles summarize the treatment of this disorder: Sterns RH, Silver S, Klein-schmidt-DeMasters BK, et al. Current perspectives in the management of hyponatremia: prevention of CPM. Expert Rev Neurother. 2007;7:1791-1797; and Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120:653-658.

Iodine contrast media kills man with known shellfish allergy

A 41-YEAR-OLD MAN WITH CHEST PAIN was admitted to his local hospital, where he received a diagnosis of acute coronary syndrome. After treatment in the emergency department, the patient was admitted to the telemetry unit by an internist, the partner of the patient’s primary care physician. The patient’s admission records noted that he had an allergy to shellfish.

The next morning, a cardiologist was called in. The cardiologist then called in an interventional cardiologist, who scheduled a cardiac catheterization. The interventional cardiologist ordered 1 dose of steroids, followed a few minutes later by contrast iodine. The patient immediately suffered a severe allergic reaction and died.

PLAINTIFF’S CLAIM The internist who admitted the patient to the telemetry unit took an incomplete history regarding the patient’s allergies (although the admission records contained that information). No information about the claims against the 2 cardiologists is available.

THE DEFENSE No information about the defense is available.

VERDICT $4.7 million gross verdict in Florida.

COMMENT In addition to considering the risk of dye loads and carefully checking renal function, remember to assess for allergy when administering contrast agents. Failure to do so in this case led to the death of the patient and a multimillion-dollar verdict.

Stubborn pneumonia turns out to be cancer

AFTER RECEIVING ANTIBIOTICS FOR PNEUMONIA, a 37-year-old man improved but didn’t fully recover; his radiographs didn’t return to normal. He’d never smoked cigarettes.

During the several months after the pneumonia, the patient’s doctor ordered repeat radiographs and prescribed antibiotics and pain medication. When the patient’s spine collapsed, the doctor diagnosed metastatic lung cancer. The patient received palliative treatment and ultimately died.

PLAINTIFF’S CLAIM The doctor was negligent in failing to change the patient’s treatment after 2 or 3 months and failing to order a computed tomography (CT) scan or refer the patient to a pulmonologist.

THE DEFENSE No information about the doctor’s defense is available.

VERDICT $1.25 million Washington settlement.

COMMENT I’d like a nickel for every case of delayed diagnosis of lung cancer based on clearly abnormal chest radiographs. We can argue about whether diagnosis would make a difference, but we need to follow up assiduously on abnormal radiographs and document our actions.

Rapidly raised serum sodium leads to osmotic demyelination

A 60-YEAR-OLD WOMAN went to her local medical center complaining of a cough for the previous 2 weeks, decreased appetite and oral intake, and generalized body aches. She first went to urgent care, where laboratory studies showed critically low levels of sodium and potassium. Based on these results, the woman was told to go to the facility’s emergency department (ED).

In the ED, she reported feeling very weak and tired and having body aches and pain. When laboratory tests showed that her sodium and potassium levels had fallen further, she was admitted to the intensive care unit (ICU).

The doctor who saw the patient in the ICU ordered intravenous fluids with normal saline and potassium supplements. He then had the patient admitted to the ICU at another hospital. The physician at that hospital continued to prescribe IV sodium and potassium until the patient was discharged with diagnoses that included hyponatremia and hypokalemia.

Ten days later, the patient returned to the ED complaining of slurred speech for the previous 2 days. A CT scan of her head showed a possible basilar tip aneurysm. Subsequent magnetic resonance imaging with and without contrast and intracranial magnetic resonance angiography confirmed a basilar tip aneurysm and showed findings suggestive of osmotic demyelination. Neurologic examination revealed dysarthria, right upper extremity weakness without spasticity, and periods of confusion interspersed with lucid intervals.

A subsequent neurologic consultation confirmed osmotic demyelination syndrome (formerly known as central pontine myelinolysis). Neurologic examination at that time found continued mild dysarthria, problems standing, inability to walk unsupported, mild oral and pharyngeal dysphagia, and language and writing deficits.

PLAINTIFF’S CLAIM The patient’s sodium level was increased at an inappropriately rapid rate, which caused neurologically devastating osmotic demyelination. Serum sodium should have been monitored every 4 hours during the first 24 hours of treatment. The plaintiff also alleged negligence in continuing normal saline after the patient’s serum sodium was measured at 112 mEq/L.

THE DEFENSE The treatment provided was appropriate.

VERDICT $550,000 California settlement.

COMMENT Avoiding osmotic demyelination syndrome requires careful treatment and monitoring. I have independently reviewed several allegations of malpractice involving this uncommon, but devastating condition. Two recent articles summarize the treatment of this disorder: Sterns RH, Silver S, Klein-schmidt-DeMasters BK, et al. Current perspectives in the management of hyponatremia: prevention of CPM. Expert Rev Neurother. 2007;7:1791-1797; and Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120:653-658.

Iodine contrast media kills man with known shellfish allergy

A 41-YEAR-OLD MAN WITH CHEST PAIN was admitted to his local hospital, where he received a diagnosis of acute coronary syndrome. After treatment in the emergency department, the patient was admitted to the telemetry unit by an internist, the partner of the patient’s primary care physician. The patient’s admission records noted that he had an allergy to shellfish.

The next morning, a cardiologist was called in. The cardiologist then called in an interventional cardiologist, who scheduled a cardiac catheterization. The interventional cardiologist ordered 1 dose of steroids, followed a few minutes later by contrast iodine. The patient immediately suffered a severe allergic reaction and died.

PLAINTIFF’S CLAIM The internist who admitted the patient to the telemetry unit took an incomplete history regarding the patient’s allergies (although the admission records contained that information). No information about the claims against the 2 cardiologists is available.

THE DEFENSE No information about the defense is available.

VERDICT $4.7 million gross verdict in Florida.

COMMENT In addition to considering the risk of dye loads and carefully checking renal function, remember to assess for allergy when administering contrast agents. Failure to do so in this case led to the death of the patient and a multimillion-dollar verdict.

Stubborn pneumonia turns out to be cancer

AFTER RECEIVING ANTIBIOTICS FOR PNEUMONIA, a 37-year-old man improved but didn’t fully recover; his radiographs didn’t return to normal. He’d never smoked cigarettes.

During the several months after the pneumonia, the patient’s doctor ordered repeat radiographs and prescribed antibiotics and pain medication. When the patient’s spine collapsed, the doctor diagnosed metastatic lung cancer. The patient received palliative treatment and ultimately died.

PLAINTIFF’S CLAIM The doctor was negligent in failing to change the patient’s treatment after 2 or 3 months and failing to order a computed tomography (CT) scan or refer the patient to a pulmonologist.

THE DEFENSE No information about the doctor’s defense is available.

VERDICT $1.25 million Washington settlement.

COMMENT I’d like a nickel for every case of delayed diagnosis of lung cancer based on clearly abnormal chest radiographs. We can argue about whether diagnosis would make a difference, but we need to follow up assiduously on abnormal radiographs and document our actions.

Rapidly raised serum sodium leads to osmotic demyelination

A 60-YEAR-OLD WOMAN went to her local medical center complaining of a cough for the previous 2 weeks, decreased appetite and oral intake, and generalized body aches. She first went to urgent care, where laboratory studies showed critically low levels of sodium and potassium. Based on these results, the woman was told to go to the facility’s emergency department (ED).

In the ED, she reported feeling very weak and tired and having body aches and pain. When laboratory tests showed that her sodium and potassium levels had fallen further, she was admitted to the intensive care unit (ICU).

The doctor who saw the patient in the ICU ordered intravenous fluids with normal saline and potassium supplements. He then had the patient admitted to the ICU at another hospital. The physician at that hospital continued to prescribe IV sodium and potassium until the patient was discharged with diagnoses that included hyponatremia and hypokalemia.

Ten days later, the patient returned to the ED complaining of slurred speech for the previous 2 days. A CT scan of her head showed a possible basilar tip aneurysm. Subsequent magnetic resonance imaging with and without contrast and intracranial magnetic resonance angiography confirmed a basilar tip aneurysm and showed findings suggestive of osmotic demyelination. Neurologic examination revealed dysarthria, right upper extremity weakness without spasticity, and periods of confusion interspersed with lucid intervals.

A subsequent neurologic consultation confirmed osmotic demyelination syndrome (formerly known as central pontine myelinolysis). Neurologic examination at that time found continued mild dysarthria, problems standing, inability to walk unsupported, mild oral and pharyngeal dysphagia, and language and writing deficits.

PLAINTIFF’S CLAIM The patient’s sodium level was increased at an inappropriately rapid rate, which caused neurologically devastating osmotic demyelination. Serum sodium should have been monitored every 4 hours during the first 24 hours of treatment. The plaintiff also alleged negligence in continuing normal saline after the patient’s serum sodium was measured at 112 mEq/L.

THE DEFENSE The treatment provided was appropriate.

VERDICT $550,000 California settlement.

COMMENT Avoiding osmotic demyelination syndrome requires careful treatment and monitoring. I have independently reviewed several allegations of malpractice involving this uncommon, but devastating condition. Two recent articles summarize the treatment of this disorder: Sterns RH, Silver S, Klein-schmidt-DeMasters BK, et al. Current perspectives in the management of hyponatremia: prevention of CPM. Expert Rev Neurother. 2007;7:1791-1797; and Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120:653-658.

Iodine contrast media kills man with known shellfish allergy

A 41-YEAR-OLD MAN WITH CHEST PAIN was admitted to his local hospital, where he received a diagnosis of acute coronary syndrome. After treatment in the emergency department, the patient was admitted to the telemetry unit by an internist, the partner of the patient’s primary care physician. The patient’s admission records noted that he had an allergy to shellfish.

The next morning, a cardiologist was called in. The cardiologist then called in an interventional cardiologist, who scheduled a cardiac catheterization. The interventional cardiologist ordered 1 dose of steroids, followed a few minutes later by contrast iodine. The patient immediately suffered a severe allergic reaction and died.

PLAINTIFF’S CLAIM The internist who admitted the patient to the telemetry unit took an incomplete history regarding the patient’s allergies (although the admission records contained that information). No information about the claims against the 2 cardiologists is available.

THE DEFENSE No information about the defense is available.

VERDICT $4.7 million gross verdict in Florida.

COMMENT In addition to considering the risk of dye loads and carefully checking renal function, remember to assess for allergy when administering contrast agents. Failure to do so in this case led to the death of the patient and a multimillion-dollar verdict.

Over the last decade, the prevalence of chronic kidney disease (CKD) has grown approximately 20% to 25%, and current estimates are that the disease affects about 15% of the general population.¹ All-cause hospitalization rates are almost 3 times higher among CKD patients than in those without the disease, and costs associated with CKD account for as much as 28% of the Medicare budget.¹ Most disturbingly, the incidence at which patients diagnosed with CKD progress to end-stage renal disease (ESRD) continues to increase annually, reaching 354 cases per million population in 2007.¹ By 2020, estimates are that more than 750,000 people in the United States will need dialysis for kidney failure.¹

Guidelines exist, but awareness falls short
Several initiatives to increase awareness of CKD have been publicized. They include the Kidney Disease Outcome Quality Initiative (KDOQI) of the National Kidney Foundation (NKF), which issued clinical practice guidelines for treating chronic kidney disease in 2002, and Healthy People 2010, which includes specific measures to reduce the number of new cases and the complications, disability, economic costs, and mortality associated with the disease.^2,3 Despite these efforts, studies show that many primary care providers are still unaware of these guidelines.^4,5

Patients go undiagnosed until they reach the later stages of the disease, and many receive suboptimal care—even when they are identified—including lack of timely referral to a nephrologist and inadequate management of CKD comorbidities.^6-13 (More on comorbidities, in a bit.)

Plus, there’s a lack of support … Care for these conditions is complex and difficult, and consultation or referral to a nephrologist may not be readily available, as the current pool of specialists is barely adequate to meet the needs of a growing population of CKD patients and the number of physicians-in-training entering the specialty is not adequate to meet the need.¹⁴ In this situation, primary care providers will have to assume an ever-enlarging share of the responsibility for care of CKD patients, including some clinical activities that are currently performed by specialists.

The first step: Screen all patients for CKD

Incorporating CKD screening into routine blood work for all patients facilitates earlier detection, evaluation, and treatment of the disease. Screening tests include the estimated glomerular filtration rate (GFR) based on serum creatinine as well as measurements of urine albumin and proteinuria. The persistence of proteinuria must be confirmed by 2 of 3 abnormal readings over a minimum of 3 months, because factors such as fever or exercise may affect test results. Measurement of albumin or total protein concentration in a spot sample avoids the need for timed collections. Factoring the concentration of total protein or albumin by urine creatinine concentration and using age/sex-specific thresholds eliminates most variations in measurement.¹⁵

Keep these comorbidities on your radar screen

Diabetes and hypertension are 2 of the most common causes of CKD in the United States, and the number of kidney failure cases due to these problems is increasing. The most important adverse outcomes of CKD are not only progression to ESRD, but also increased risk for cardiovascular disease (CVD). Studies show that the presence of albuminuria and a decreased estimated GFR consistently and incrementally increase the risk for CVD.¹⁶ Decreased GFR is an independent risk factor for CVD outcomes and for all-cause mortality, including sudden death in patients with existing coronary artery disease. Moreover, patients with CKD are 100 times more likely to die from CVD than to develop kidney failure.¹⁶

Depression is another prevalent, yet commonly overlooked, comorbid condition. Patients with any chronic disease are at risk for depression, with the incidence rising with the severity of the medical condition.¹⁷ CKD is no exception. Rates of depression as high as 29%, as well as rates of anxiety disorders as high as 46%, have been documented in patients on dialysis.¹⁸ Patients with depression are impaired in overall functioning and less able to follow medical regimens.¹⁷ In addition, low quality of life and depression predict higher morbidity and mortality rates in patients with ESRD.¹⁹ Because the diagnosis of depression is frequently missed in primary care settings, screening for depression should be a basic element in CKD management.²⁰

Clinical management of kidney disease

The treatment goal for early-stage kidney disease is to address the risk factors that contribute to the progression of kidney disease: hypertension, heart disease, stroke, diabetes, and dyslipidemia. The TABLE reviews clinical management areas by disease stage.

Prescribe angiotensin antagonists. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors antagonize the toxic effects of increases in circulating angiotensin II and are therefore a key component of a therapeutic strategy to halt progressive kidney disease.^2,21

Review medications, promote a healthier lifestyle. In addition to prescribing ARBs or ACE inhibitors, the family physician should review the CKD patient’s current medications to eliminate nephrotoxic drugs and adjust other medications on the basis of the patient’s creatinine clearance. Other measures include making sure vaccinations for influenza, pneumococcal pneumonia, and hepatitis B are up to date and emphasizing the importance of smoking cessation and exercise.

Treat comorbid conditions. Hypertension and diabetes must be treated aggressively. Patients with dyslipidemia should be managed with statins.² Certain complications of progressive kidney disease, such as anemia, bone/mineral metabolic disease, and metabolic disorders, are typically treated by a nephrologist. Nevertheless, primary care providers need to understand these conditions in order to work together with the nephrologist in managing the CKD patient.

Check thyroid hormone and vitamin D levels. Understanding which factors predict disease progression or poor outcome is particularly useful. Most patients with CKD have low T3 syndrome, that is, low serum triiodothyronine levels in the absence of a thyroidal illness. In a recent paper, Song and colleagues showed that low T3 syndrome was common in early CKD and that estimated GFR was positively related with T3, independent of age and serum albumin.²²

In another recent study, Ravani et al showed that plasma 25-hydroxyvitamin D is an independent, inverse predictor of disease progression and death in patients with stage 2 to 5 CKD.²³ Vitamin D deficiency has been linked to CVD and early mortality in patients on hemodialysis.²³ Checking for these 2 markers—low T3 syndrome and vitamin D deficiency—should therefore be part of your screening process for early stage CKD.

Refer to a dietitian. Dietary modification is another important component of the treatment plan. Dietary modifications are often needed to protect against CVD, help control blood pressure, reduce proteinuria, and improve metabolic control in patients with diabetes.^2,24 Dietary modifications for CKD patients may go well beyond standard recommendations for a heart-healthy diet.^2,24 Calcium, sodium, phosphorus, and potassium may need to be restricted according to laboratory values and stage of the disease.²⁵ The KDOQI guidelines recommend referring CKD patients to a registered dietitian with experience in CKD for a complete nutritional assessment, comprehensive education on dietary restrictions and guidelines, and detailed dietary instruction.²

Manage CKD-associated anemia. Current guidelines do not propose normalizing hemoglobin in patients with renal disease, because lower levels of hemoglobin probably represent an adaptive response and correction to a “normal” level may disturb that response and lead to worse outcomes.²⁶ For a discussion of management of anemia associated with CKD, see “Anemia and chronic kidney disease: What’s the connection?” in the January 2010 issue of this journal.²⁷

Refer to a nephrologist early. A recent study by Chan et al demonstrates the beneficial effects of early referral to a nephrologist.²⁸ There is no clear definition of early vs late referral and, at times, the only criterion is how much time elapsed before the patient was put on dialysis. Referral is considered “late” when management could have been improved by earlier contact with a specialist. It is probably prudent to refer stage 3 and 4 patients, at least for initial consultation. Chan’s meta-analysis found that patients referred late had nearly a 2-fold risk of death compared with those with early referrals. This risk persists at least up to 1 year after the initiation of renal replacement therapy.

Prepare patients for dialysis. It is very important that new hemodialysis patients present for initial treatment with an arteriovenous fistula in place, as first access for hemodialysis. Fistula placement is one of the most important reasons for timely referral to a nephrologist. Later referral is associated with a significantly prolonged hospital stay for initial renal replacement therapy. Late-referred patients are sicker, and many of the complications discussed here have not been optimally treated.

The optimal time to start preparing your patient for dialysis is when GFR measures between 15 and 29 mL/min/1.73 m². Preparation includes counseling on nutrition and exercise, hepatitis B vaccination if needed, and scheduling for fistula placement.²⁹

The hardest part: Changing habits
Effective CKD treatment must emphasize lifestyle management. You need to persuade smokers to quit and “couch potatoes” to start exercising regularly. Eating habits need to change, as well: This means fewer calories and restrictions on intake of salt and certain minerals. Medications for high blood pressure, diabetes, and kidney disease need to be taken consistently, as prescribed. The TABLE reviews the lifestyle issues that are particularly salient at each stage of CKD.

TABLE
Keying interventions to CKD stages

Lifestyle modifications like these are very difficult, and helping patients make them involves much more than simple patient education. In 1 study, Durose et al found that patients on hemodialysis failed to stay on their diets even when they knew which dietary restrictions they should follow and what the consequences of going off their diets would be.³⁰

Update your persuasive techniques: take on the role of coach

Newer theories of behavior change no longer rely on simply providing information and advice, but rather address the complex interaction of motivations involved in attempts to change. These include cues to action, perception of benefits and consequences, environmental and cultural influences, sense of self-efficacy, ambivalence, and the intention to change.³¹

Unfortunately, health care providers are rarely trained in motivational techniques. Often, their approach to inducing change is authoritarian, confrontational, overly forceful, or guilt inducing. Such attitudes not only limit progress, but are actually correlated with negative behavioral and clinical outcomes.^32,33 Recent research has verified the power of the patient–provider interaction in influencing treatment adherence and lifestyle change.³³

To be successful in getting patients to adopt new behaviors, physicians need to move away from authoritarian modes and take on some of the attributes of a coach urging on the team.

How this coaching technique works
Motivational Interviewing is a health coaching technique that has been shown to be causally and independently associated with positive behavioral outcomes.³⁴ The techniques used in the motivational interviewing approach are summarized in “The motivational interviewing tool kit”. Motivational interviewing is a goal-oriented, patient-centered counseling style for helping patients explore and resolve their ambivalence about behavior change.³⁵ The approach has been used in diverse populations, settings, and medical conditions. Its efficacy was first demonstrated in the treatment of addictions to illegal drugs and alcohol.³⁶ Continued research and 2 recent meta-analyses using rigorous methodology have validated the usefulness of this approach.^37,38

Motivational interviewing has been shown to be effective in improving general health status and sense of well-being, promoting physical activity, improving nutritional habits, encouraging medication adherence, and managing chronic conditions such as hypertension, hypercholesterolemia, obesity, and diabetes.³⁵ A review of the literature on health behavior change demonstrates that motivational interviewing outperforms traditional advice-giving in the treatment of a broad range of behavioral problems and diseases.³⁸

Motivational interviewing is focused on helping patients explore their ambivalence and identify individual barriers that are preventing change. The skill set that motivational interviewing provides can be modified for use in the brief patient encounters typically found in the primary care setting. For an example of how you might use motivational interviewing techniques with your CKD patients, see “Talking about change: A motivational interviewing conversation”.

Your crucial role
CKD is well on its way to becoming a full-blown epidemic in the United States. Primary care providers carry the brunt of responsibility for the care of these patients, and with an increasing shortage of nephrologists, the scope of those activities will likely grow. Physicians in solo or small group practice must be prepared to deliver both the clinical and behavioral/lifestyle components of care themselves. While this is a challenging endeavor, we believe the framework outlined here will improve your ability to meet the complex needs of CKD patients.

CORRESPONDENCE Ariel Linden, DrPH, MS, Linden Consulting Group, 6208 NE Chestnut Street, Hillsboro, OR 97124; [email protected]

Over the last decade, the prevalence of chronic kidney disease (CKD) has grown approximately 20% to 25%, and current estimates are that the disease affects about 15% of the general population.¹ All-cause hospitalization rates are almost 3 times higher among CKD patients than in those without the disease, and costs associated with CKD account for as much as 28% of the Medicare budget.¹ Most disturbingly, the incidence at which patients diagnosed with CKD progress to end-stage renal disease (ESRD) continues to increase annually, reaching 354 cases per million population in 2007.¹ By 2020, estimates are that more than 750,000 people in the United States will need dialysis for kidney failure.¹

Guidelines exist, but awareness falls short
Several initiatives to increase awareness of CKD have been publicized. They include the Kidney Disease Outcome Quality Initiative (KDOQI) of the National Kidney Foundation (NKF), which issued clinical practice guidelines for treating chronic kidney disease in 2002, and Healthy People 2010, which includes specific measures to reduce the number of new cases and the complications, disability, economic costs, and mortality associated with the disease.^2,3 Despite these efforts, studies show that many primary care providers are still unaware of these guidelines.^4,5

Patients go undiagnosed until they reach the later stages of the disease, and many receive suboptimal care—even when they are identified—including lack of timely referral to a nephrologist and inadequate management of CKD comorbidities.^6-13 (More on comorbidities, in a bit.)

Plus, there’s a lack of support … Care for these conditions is complex and difficult, and consultation or referral to a nephrologist may not be readily available, as the current pool of specialists is barely adequate to meet the needs of a growing population of CKD patients and the number of physicians-in-training entering the specialty is not adequate to meet the need.¹⁴ In this situation, primary care providers will have to assume an ever-enlarging share of the responsibility for care of CKD patients, including some clinical activities that are currently performed by specialists.

The first step: Screen all patients for CKD

Incorporating CKD screening into routine blood work for all patients facilitates earlier detection, evaluation, and treatment of the disease. Screening tests include the estimated glomerular filtration rate (GFR) based on serum creatinine as well as measurements of urine albumin and proteinuria. The persistence of proteinuria must be confirmed by 2 of 3 abnormal readings over a minimum of 3 months, because factors such as fever or exercise may affect test results. Measurement of albumin or total protein concentration in a spot sample avoids the need for timed collections. Factoring the concentration of total protein or albumin by urine creatinine concentration and using age/sex-specific thresholds eliminates most variations in measurement.¹⁵

Keep these comorbidities on your radar screen

Diabetes and hypertension are 2 of the most common causes of CKD in the United States, and the number of kidney failure cases due to these problems is increasing. The most important adverse outcomes of CKD are not only progression to ESRD, but also increased risk for cardiovascular disease (CVD). Studies show that the presence of albuminuria and a decreased estimated GFR consistently and incrementally increase the risk for CVD.¹⁶ Decreased GFR is an independent risk factor for CVD outcomes and for all-cause mortality, including sudden death in patients with existing coronary artery disease. Moreover, patients with CKD are 100 times more likely to die from CVD than to develop kidney failure.¹⁶

Depression is another prevalent, yet commonly overlooked, comorbid condition. Patients with any chronic disease are at risk for depression, with the incidence rising with the severity of the medical condition.¹⁷ CKD is no exception. Rates of depression as high as 29%, as well as rates of anxiety disorders as high as 46%, have been documented in patients on dialysis.¹⁸ Patients with depression are impaired in overall functioning and less able to follow medical regimens.¹⁷ In addition, low quality of life and depression predict higher morbidity and mortality rates in patients with ESRD.¹⁹ Because the diagnosis of depression is frequently missed in primary care settings, screening for depression should be a basic element in CKD management.²⁰

Clinical management of kidney disease

The treatment goal for early-stage kidney disease is to address the risk factors that contribute to the progression of kidney disease: hypertension, heart disease, stroke, diabetes, and dyslipidemia. The TABLE reviews clinical management areas by disease stage.

Prescribe angiotensin antagonists. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors antagonize the toxic effects of increases in circulating angiotensin II and are therefore a key component of a therapeutic strategy to halt progressive kidney disease.^2,21

Review medications, promote a healthier lifestyle. In addition to prescribing ARBs or ACE inhibitors, the family physician should review the CKD patient’s current medications to eliminate nephrotoxic drugs and adjust other medications on the basis of the patient’s creatinine clearance. Other measures include making sure vaccinations for influenza, pneumococcal pneumonia, and hepatitis B are up to date and emphasizing the importance of smoking cessation and exercise.

Treat comorbid conditions. Hypertension and diabetes must be treated aggressively. Patients with dyslipidemia should be managed with statins.² Certain complications of progressive kidney disease, such as anemia, bone/mineral metabolic disease, and metabolic disorders, are typically treated by a nephrologist. Nevertheless, primary care providers need to understand these conditions in order to work together with the nephrologist in managing the CKD patient.

Check thyroid hormone and vitamin D levels. Understanding which factors predict disease progression or poor outcome is particularly useful. Most patients with CKD have low T3 syndrome, that is, low serum triiodothyronine levels in the absence of a thyroidal illness. In a recent paper, Song and colleagues showed that low T3 syndrome was common in early CKD and that estimated GFR was positively related with T3, independent of age and serum albumin.²²

In another recent study, Ravani et al showed that plasma 25-hydroxyvitamin D is an independent, inverse predictor of disease progression and death in patients with stage 2 to 5 CKD.²³ Vitamin D deficiency has been linked to CVD and early mortality in patients on hemodialysis.²³ Checking for these 2 markers—low T3 syndrome and vitamin D deficiency—should therefore be part of your screening process for early stage CKD.

Refer to a dietitian. Dietary modification is another important component of the treatment plan. Dietary modifications are often needed to protect against CVD, help control blood pressure, reduce proteinuria, and improve metabolic control in patients with diabetes.^2,24 Dietary modifications for CKD patients may go well beyond standard recommendations for a heart-healthy diet.^2,24 Calcium, sodium, phosphorus, and potassium may need to be restricted according to laboratory values and stage of the disease.²⁵ The KDOQI guidelines recommend referring CKD patients to a registered dietitian with experience in CKD for a complete nutritional assessment, comprehensive education on dietary restrictions and guidelines, and detailed dietary instruction.²

Manage CKD-associated anemia. Current guidelines do not propose normalizing hemoglobin in patients with renal disease, because lower levels of hemoglobin probably represent an adaptive response and correction to a “normal” level may disturb that response and lead to worse outcomes.²⁶ For a discussion of management of anemia associated with CKD, see “Anemia and chronic kidney disease: What’s the connection?” in the January 2010 issue of this journal.²⁷

Refer to a nephrologist early. A recent study by Chan et al demonstrates the beneficial effects of early referral to a nephrologist.²⁸ There is no clear definition of early vs late referral and, at times, the only criterion is how much time elapsed before the patient was put on dialysis. Referral is considered “late” when management could have been improved by earlier contact with a specialist. It is probably prudent to refer stage 3 and 4 patients, at least for initial consultation. Chan’s meta-analysis found that patients referred late had nearly a 2-fold risk of death compared with those with early referrals. This risk persists at least up to 1 year after the initiation of renal replacement therapy.

Prepare patients for dialysis. It is very important that new hemodialysis patients present for initial treatment with an arteriovenous fistula in place, as first access for hemodialysis. Fistula placement is one of the most important reasons for timely referral to a nephrologist. Later referral is associated with a significantly prolonged hospital stay for initial renal replacement therapy. Late-referred patients are sicker, and many of the complications discussed here have not been optimally treated.

The optimal time to start preparing your patient for dialysis is when GFR measures between 15 and 29 mL/min/1.73 m². Preparation includes counseling on nutrition and exercise, hepatitis B vaccination if needed, and scheduling for fistula placement.²⁹

The hardest part: Changing habits
Effective CKD treatment must emphasize lifestyle management. You need to persuade smokers to quit and “couch potatoes” to start exercising regularly. Eating habits need to change, as well: This means fewer calories and restrictions on intake of salt and certain minerals. Medications for high blood pressure, diabetes, and kidney disease need to be taken consistently, as prescribed. The TABLE reviews the lifestyle issues that are particularly salient at each stage of CKD.

TABLE
Keying interventions to CKD stages

Lifestyle modifications like these are very difficult, and helping patients make them involves much more than simple patient education. In 1 study, Durose et al found that patients on hemodialysis failed to stay on their diets even when they knew which dietary restrictions they should follow and what the consequences of going off their diets would be.³⁰

Update your persuasive techniques: take on the role of coach

Newer theories of behavior change no longer rely on simply providing information and advice, but rather address the complex interaction of motivations involved in attempts to change. These include cues to action, perception of benefits and consequences, environmental and cultural influences, sense of self-efficacy, ambivalence, and the intention to change.³¹

Unfortunately, health care providers are rarely trained in motivational techniques. Often, their approach to inducing change is authoritarian, confrontational, overly forceful, or guilt inducing. Such attitudes not only limit progress, but are actually correlated with negative behavioral and clinical outcomes.^32,33 Recent research has verified the power of the patient–provider interaction in influencing treatment adherence and lifestyle change.³³

To be successful in getting patients to adopt new behaviors, physicians need to move away from authoritarian modes and take on some of the attributes of a coach urging on the team.

How this coaching technique works
Motivational Interviewing is a health coaching technique that has been shown to be causally and independently associated with positive behavioral outcomes.³⁴ The techniques used in the motivational interviewing approach are summarized in “The motivational interviewing tool kit”. Motivational interviewing is a goal-oriented, patient-centered counseling style for helping patients explore and resolve their ambivalence about behavior change.³⁵ The approach has been used in diverse populations, settings, and medical conditions. Its efficacy was first demonstrated in the treatment of addictions to illegal drugs and alcohol.³⁶ Continued research and 2 recent meta-analyses using rigorous methodology have validated the usefulness of this approach.^37,38

Motivational interviewing has been shown to be effective in improving general health status and sense of well-being, promoting physical activity, improving nutritional habits, encouraging medication adherence, and managing chronic conditions such as hypertension, hypercholesterolemia, obesity, and diabetes.³⁵ A review of the literature on health behavior change demonstrates that motivational interviewing outperforms traditional advice-giving in the treatment of a broad range of behavioral problems and diseases.³⁸

Motivational interviewing is focused on helping patients explore their ambivalence and identify individual barriers that are preventing change. The skill set that motivational interviewing provides can be modified for use in the brief patient encounters typically found in the primary care setting. For an example of how you might use motivational interviewing techniques with your CKD patients, see “Talking about change: A motivational interviewing conversation”.

Your crucial role
CKD is well on its way to becoming a full-blown epidemic in the United States. Primary care providers carry the brunt of responsibility for the care of these patients, and with an increasing shortage of nephrologists, the scope of those activities will likely grow. Physicians in solo or small group practice must be prepared to deliver both the clinical and behavioral/lifestyle components of care themselves. While this is a challenging endeavor, we believe the framework outlined here will improve your ability to meet the complex needs of CKD patients.

CORRESPONDENCE Ariel Linden, DrPH, MS, Linden Consulting Group, 6208 NE Chestnut Street, Hillsboro, OR 97124; [email protected]

Over the last decade, the prevalence of chronic kidney disease (CKD) has grown approximately 20% to 25%, and current estimates are that the disease affects about 15% of the general population.¹ All-cause hospitalization rates are almost 3 times higher among CKD patients than in those without the disease, and costs associated with CKD account for as much as 28% of the Medicare budget.¹ Most disturbingly, the incidence at which patients diagnosed with CKD progress to end-stage renal disease (ESRD) continues to increase annually, reaching 354 cases per million population in 2007.¹ By 2020, estimates are that more than 750,000 people in the United States will need dialysis for kidney failure.¹

Guidelines exist, but awareness falls short
Several initiatives to increase awareness of CKD have been publicized. They include the Kidney Disease Outcome Quality Initiative (KDOQI) of the National Kidney Foundation (NKF), which issued clinical practice guidelines for treating chronic kidney disease in 2002, and Healthy People 2010, which includes specific measures to reduce the number of new cases and the complications, disability, economic costs, and mortality associated with the disease.^2,3 Despite these efforts, studies show that many primary care providers are still unaware of these guidelines.^4,5

Patients go undiagnosed until they reach the later stages of the disease, and many receive suboptimal care—even when they are identified—including lack of timely referral to a nephrologist and inadequate management of CKD comorbidities.^6-13 (More on comorbidities, in a bit.)

Plus, there’s a lack of support … Care for these conditions is complex and difficult, and consultation or referral to a nephrologist may not be readily available, as the current pool of specialists is barely adequate to meet the needs of a growing population of CKD patients and the number of physicians-in-training entering the specialty is not adequate to meet the need.¹⁴ In this situation, primary care providers will have to assume an ever-enlarging share of the responsibility for care of CKD patients, including some clinical activities that are currently performed by specialists.

The first step: Screen all patients for CKD

Incorporating CKD screening into routine blood work for all patients facilitates earlier detection, evaluation, and treatment of the disease. Screening tests include the estimated glomerular filtration rate (GFR) based on serum creatinine as well as measurements of urine albumin and proteinuria. The persistence of proteinuria must be confirmed by 2 of 3 abnormal readings over a minimum of 3 months, because factors such as fever or exercise may affect test results. Measurement of albumin or total protein concentration in a spot sample avoids the need for timed collections. Factoring the concentration of total protein or albumin by urine creatinine concentration and using age/sex-specific thresholds eliminates most variations in measurement.¹⁵

Keep these comorbidities on your radar screen

Diabetes and hypertension are 2 of the most common causes of CKD in the United States, and the number of kidney failure cases due to these problems is increasing. The most important adverse outcomes of CKD are not only progression to ESRD, but also increased risk for cardiovascular disease (CVD). Studies show that the presence of albuminuria and a decreased estimated GFR consistently and incrementally increase the risk for CVD.¹⁶ Decreased GFR is an independent risk factor for CVD outcomes and for all-cause mortality, including sudden death in patients with existing coronary artery disease. Moreover, patients with CKD are 100 times more likely to die from CVD than to develop kidney failure.¹⁶

Depression is another prevalent, yet commonly overlooked, comorbid condition. Patients with any chronic disease are at risk for depression, with the incidence rising with the severity of the medical condition.¹⁷ CKD is no exception. Rates of depression as high as 29%, as well as rates of anxiety disorders as high as 46%, have been documented in patients on dialysis.¹⁸ Patients with depression are impaired in overall functioning and less able to follow medical regimens.¹⁷ In addition, low quality of life and depression predict higher morbidity and mortality rates in patients with ESRD.¹⁹ Because the diagnosis of depression is frequently missed in primary care settings, screening for depression should be a basic element in CKD management.²⁰

Clinical management of kidney disease

The treatment goal for early-stage kidney disease is to address the risk factors that contribute to the progression of kidney disease: hypertension, heart disease, stroke, diabetes, and dyslipidemia. The TABLE reviews clinical management areas by disease stage.

Prescribe angiotensin antagonists. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors antagonize the toxic effects of increases in circulating angiotensin II and are therefore a key component of a therapeutic strategy to halt progressive kidney disease.^2,21

Review medications, promote a healthier lifestyle. In addition to prescribing ARBs or ACE inhibitors, the family physician should review the CKD patient’s current medications to eliminate nephrotoxic drugs and adjust other medications on the basis of the patient’s creatinine clearance. Other measures include making sure vaccinations for influenza, pneumococcal pneumonia, and hepatitis B are up to date and emphasizing the importance of smoking cessation and exercise.

Treat comorbid conditions. Hypertension and diabetes must be treated aggressively. Patients with dyslipidemia should be managed with statins.² Certain complications of progressive kidney disease, such as anemia, bone/mineral metabolic disease, and metabolic disorders, are typically treated by a nephrologist. Nevertheless, primary care providers need to understand these conditions in order to work together with the nephrologist in managing the CKD patient.

Check thyroid hormone and vitamin D levels. Understanding which factors predict disease progression or poor outcome is particularly useful. Most patients with CKD have low T3 syndrome, that is, low serum triiodothyronine levels in the absence of a thyroidal illness. In a recent paper, Song and colleagues showed that low T3 syndrome was common in early CKD and that estimated GFR was positively related with T3, independent of age and serum albumin.²²

In another recent study, Ravani et al showed that plasma 25-hydroxyvitamin D is an independent, inverse predictor of disease progression and death in patients with stage 2 to 5 CKD.²³ Vitamin D deficiency has been linked to CVD and early mortality in patients on hemodialysis.²³ Checking for these 2 markers—low T3 syndrome and vitamin D deficiency—should therefore be part of your screening process for early stage CKD.

Refer to a dietitian. Dietary modification is another important component of the treatment plan. Dietary modifications are often needed to protect against CVD, help control blood pressure, reduce proteinuria, and improve metabolic control in patients with diabetes.^2,24 Dietary modifications for CKD patients may go well beyond standard recommendations for a heart-healthy diet.^2,24 Calcium, sodium, phosphorus, and potassium may need to be restricted according to laboratory values and stage of the disease.²⁵ The KDOQI guidelines recommend referring CKD patients to a registered dietitian with experience in CKD for a complete nutritional assessment, comprehensive education on dietary restrictions and guidelines, and detailed dietary instruction.²

Manage CKD-associated anemia. Current guidelines do not propose normalizing hemoglobin in patients with renal disease, because lower levels of hemoglobin probably represent an adaptive response and correction to a “normal” level may disturb that response and lead to worse outcomes.²⁶ For a discussion of management of anemia associated with CKD, see “Anemia and chronic kidney disease: What’s the connection?” in the January 2010 issue of this journal.²⁷

Refer to a nephrologist early. A recent study by Chan et al demonstrates the beneficial effects of early referral to a nephrologist.²⁸ There is no clear definition of early vs late referral and, at times, the only criterion is how much time elapsed before the patient was put on dialysis. Referral is considered “late” when management could have been improved by earlier contact with a specialist. It is probably prudent to refer stage 3 and 4 patients, at least for initial consultation. Chan’s meta-analysis found that patients referred late had nearly a 2-fold risk of death compared with those with early referrals. This risk persists at least up to 1 year after the initiation of renal replacement therapy.

Prepare patients for dialysis. It is very important that new hemodialysis patients present for initial treatment with an arteriovenous fistula in place, as first access for hemodialysis. Fistula placement is one of the most important reasons for timely referral to a nephrologist. Later referral is associated with a significantly prolonged hospital stay for initial renal replacement therapy. Late-referred patients are sicker, and many of the complications discussed here have not been optimally treated.

The optimal time to start preparing your patient for dialysis is when GFR measures between 15 and 29 mL/min/1.73 m². Preparation includes counseling on nutrition and exercise, hepatitis B vaccination if needed, and scheduling for fistula placement.²⁹

The hardest part: Changing habits
Effective CKD treatment must emphasize lifestyle management. You need to persuade smokers to quit and “couch potatoes” to start exercising regularly. Eating habits need to change, as well: This means fewer calories and restrictions on intake of salt and certain minerals. Medications for high blood pressure, diabetes, and kidney disease need to be taken consistently, as prescribed. The TABLE reviews the lifestyle issues that are particularly salient at each stage of CKD.

TABLE
Keying interventions to CKD stages

Lifestyle modifications like these are very difficult, and helping patients make them involves much more than simple patient education. In 1 study, Durose et al found that patients on hemodialysis failed to stay on their diets even when they knew which dietary restrictions they should follow and what the consequences of going off their diets would be.³⁰

Update your persuasive techniques: take on the role of coach

Newer theories of behavior change no longer rely on simply providing information and advice, but rather address the complex interaction of motivations involved in attempts to change. These include cues to action, perception of benefits and consequences, environmental and cultural influences, sense of self-efficacy, ambivalence, and the intention to change.³¹

Unfortunately, health care providers are rarely trained in motivational techniques. Often, their approach to inducing change is authoritarian, confrontational, overly forceful, or guilt inducing. Such attitudes not only limit progress, but are actually correlated with negative behavioral and clinical outcomes.^32,33 Recent research has verified the power of the patient–provider interaction in influencing treatment adherence and lifestyle change.³³

To be successful in getting patients to adopt new behaviors, physicians need to move away from authoritarian modes and take on some of the attributes of a coach urging on the team.

How this coaching technique works
Motivational Interviewing is a health coaching technique that has been shown to be causally and independently associated with positive behavioral outcomes.³⁴ The techniques used in the motivational interviewing approach are summarized in “The motivational interviewing tool kit”. Motivational interviewing is a goal-oriented, patient-centered counseling style for helping patients explore and resolve their ambivalence about behavior change.³⁵ The approach has been used in diverse populations, settings, and medical conditions. Its efficacy was first demonstrated in the treatment of addictions to illegal drugs and alcohol.³⁶ Continued research and 2 recent meta-analyses using rigorous methodology have validated the usefulness of this approach.^37,38

Motivational interviewing has been shown to be effective in improving general health status and sense of well-being, promoting physical activity, improving nutritional habits, encouraging medication adherence, and managing chronic conditions such as hypertension, hypercholesterolemia, obesity, and diabetes.³⁵ A review of the literature on health behavior change demonstrates that motivational interviewing outperforms traditional advice-giving in the treatment of a broad range of behavioral problems and diseases.³⁸

Motivational interviewing is focused on helping patients explore their ambivalence and identify individual barriers that are preventing change. The skill set that motivational interviewing provides can be modified for use in the brief patient encounters typically found in the primary care setting. For an example of how you might use motivational interviewing techniques with your CKD patients, see “Talking about change: A motivational interviewing conversation”.

Your crucial role
CKD is well on its way to becoming a full-blown epidemic in the United States. Primary care providers carry the brunt of responsibility for the care of these patients, and with an increasing shortage of nephrologists, the scope of those activities will likely grow. Physicians in solo or small group practice must be prepared to deliver both the clinical and behavioral/lifestyle components of care themselves. While this is a challenging endeavor, we believe the framework outlined here will improve your ability to meet the complex needs of CKD patients.

CORRESPONDENCE Ariel Linden, DrPH, MS, Linden Consulting Group, 6208 NE Chestnut Street, Hillsboro, OR 97124; [email protected]

[email protected]

Acanthosis nigricans is one of the most common skin signs of obesity and hyperinsulinism and is a valuable predictor of insulin resistance in obese children. Patients with both obesity and acanthosis nigricans, compared with those with obesity alone, tend to have higher body mass indexes and increased fasting and evening insulin levels.

Early recognition and intervention are crucial to avoid complications of insulin resistance. The general pediatrician is in the best position to perform the initial assessment. Begin with measuring body mass index (BMI). Then evaluate the patient for the associated risk factors. If you diagnose acanthosis nigricans, screen the patient for associated conditions such as Cushing's syndrome; hypothyroidism; coexisting syndromes (including Prader-Willi, Bardet-Biedl, and leprechaunism); lipodystrophy; or psychiatric disorders including depression or eating disorders.

Children with a BMI under the 85th percentile and no complications can be managed well by their pediatrician. Early intervention is key. Focus on healthful living, increased physical activity, and education of the family regarding associated conditions and the adverse effects that obesity can have on the child's health and quality of life.

The best strategy is to treat the underlying cause of acanthosis nigricans. Address obesity and any secondary insulin resistance because obesity is the No. 1 cause of acanthosis nigricans. Although topical keratolytic lotions or other topical therapies may be of some benefit, results are often disappointing.

It is also important to involve the entire family in the treatment plan. If everyone is not ready for change, success will be limited. Because much embarrassment and stigma are often associated with obesity, discuss treatment, diet, and weight loss in an objective, nonjudgmental, and nonaccusatory fashion. Consider the family's schedule, financial situation, and lifestyle.

Educate patients and family members about appropriate weight for age and height, self-management skills, and a healthy, balanced diet with lower levels of carbohydrates and fats. It is easy for patients and parents to become discouraged, so institute changes gradually.

If a patient presents with obesity and acanthosis nigricans, evaluate the child for other insulin risk factors. These include a BMI above the 85th percentile for age and sex, polycystic ovarian syndrome, hypertension, dyslipidemia, a history of small size for gestational age at birth, premature pubarche, allergic diathesis, and/or a family history of these conditions. Also note that children of certain ethnicities are at higher risk as well, including African, Indian subcontinent, American Indian, and Hispanic populations.

Children with obesity and insulin resistance are at increased future risk for associated complications including orthopedic problems, fatty liver or gallbladder disease, infertility, hyperandrogenism, coronary artery disease and stroke, type 2 diabetes, predisposition to certain cancers, and Alzheimer's disease.

In addition to measurements of blood pressure, height, weight, and BMI, helpful laboratory studies include nonfasting lipid, hemoglobin A_1c, and insulin and glucose levels. Fasting glucose, insulin, and lipid tests are especially recommended for a child whose BMI is at the 85th percentile or greater.

Conditions that can mimic acanthosis nigricans include postinflammatory hyperpigmentation; chronic eczema (especially in children with darker skin and secondary hyperpigmentation or lichenification); and confluent and reticulated papillomatosis of Gougerot and Carteaud (the plaques in this condition are very similar to acanthosis nigricans, but are more reticulated and located on the chest and back). Other conditions to consider in your differential diagnosis include linear epidermal nevi and retained keratin (which presents as brownish patches on the neck or postauricular areas that are easily removed with alcohol, but not with water).

If the diagnosis of acanthosis nigricans is uncertain, referral to a pediatric dermatologist is recommended. Also refer a girl with suspected PCOS or hyperandrogenism and associated acne, which can be difficult to manage, as well as a girl with male-pattern hair loss.

The following criteria can warrant referral of the patient to a specialist other than a pediatric dermatologist:

▸ A child with a BMI at the 85th percentile or greater and any associated complications or any child with a BMI greater than the 95th percentile should be referred to a pediatric obesity treatment specialist, if available.

▸ Referral to a pediatric cardiologist may be needed if hypertension or dyslipidemia is present.

▸ Referral for a sleep study or for evaluation by a pediatric otolaryngologist may be indicated if signs of sleep disturbance suggest sleep apnea or obesity hypoventilation syndrome.

▸ Persistent headaches could indicate pseudotumor cerebri requiring neurologic evaluation.

▸ Referral to an endocrinologist would be indicated if Cushing's syndrome, type 2 diabetes, or hypothyroidism is suspected, or for girls with signs of PCOS or hyperandrogenism. The guidance of a pediatric endocrinologist may be required with certain medications, such as metformin, to decrease insulin resistance and hyperglycemia.

▸ Children with knee or hip pain and x-ray findings suggestive of slipped capital femoral epiphysis or Blount's disease (tibia vara) may need orthopedic evaluation.

▸ Children with abdominal pain may require referral to a pediatric gastroenterologist for evaluation of obesity-associated liver or gallbladder disease.

Regular monitoring of the overweight child with acanthosis nigricans is recommended. If initial screening is negative for type 2 diabetes or insulin resistance, the American Diabetes Association recommends repeating the screening every 2 years for at-risk children. Follow-up screening can also include thyroid studies to evaluate for hypothyroidism and dehydroepiandrosterone sulfate, free testosterone, and a luteinizing hormone to follicle-stimulating hormone (LH:FSH) ratio to screen for hyperandrogenism.

[email protected]

Acanthosis nigricans is one of the most common skin signs of obesity and hyperinsulinism and is a valuable predictor of insulin resistance in obese children. Patients with both obesity and acanthosis nigricans, compared with those with obesity alone, tend to have higher body mass indexes and increased fasting and evening insulin levels.

Early recognition and intervention are crucial to avoid complications of insulin resistance. The general pediatrician is in the best position to perform the initial assessment. Begin with measuring body mass index (BMI). Then evaluate the patient for the associated risk factors. If you diagnose acanthosis nigricans, screen the patient for associated conditions such as Cushing's syndrome; hypothyroidism; coexisting syndromes (including Prader-Willi, Bardet-Biedl, and leprechaunism); lipodystrophy; or psychiatric disorders including depression or eating disorders.

Children with a BMI under the 85th percentile and no complications can be managed well by their pediatrician. Early intervention is key. Focus on healthful living, increased physical activity, and education of the family regarding associated conditions and the adverse effects that obesity can have on the child's health and quality of life.

The best strategy is to treat the underlying cause of acanthosis nigricans. Address obesity and any secondary insulin resistance because obesity is the No. 1 cause of acanthosis nigricans. Although topical keratolytic lotions or other topical therapies may be of some benefit, results are often disappointing.

It is also important to involve the entire family in the treatment plan. If everyone is not ready for change, success will be limited. Because much embarrassment and stigma are often associated with obesity, discuss treatment, diet, and weight loss in an objective, nonjudgmental, and nonaccusatory fashion. Consider the family's schedule, financial situation, and lifestyle.

Educate patients and family members about appropriate weight for age and height, self-management skills, and a healthy, balanced diet with lower levels of carbohydrates and fats. It is easy for patients and parents to become discouraged, so institute changes gradually.

If a patient presents with obesity and acanthosis nigricans, evaluate the child for other insulin risk factors. These include a BMI above the 85th percentile for age and sex, polycystic ovarian syndrome, hypertension, dyslipidemia, a history of small size for gestational age at birth, premature pubarche, allergic diathesis, and/or a family history of these conditions. Also note that children of certain ethnicities are at higher risk as well, including African, Indian subcontinent, American Indian, and Hispanic populations.

Children with obesity and insulin resistance are at increased future risk for associated complications including orthopedic problems, fatty liver or gallbladder disease, infertility, hyperandrogenism, coronary artery disease and stroke, type 2 diabetes, predisposition to certain cancers, and Alzheimer's disease.

In addition to measurements of blood pressure, height, weight, and BMI, helpful laboratory studies include nonfasting lipid, hemoglobin A_1c, and insulin and glucose levels. Fasting glucose, insulin, and lipid tests are especially recommended for a child whose BMI is at the 85th percentile or greater.

Conditions that can mimic acanthosis nigricans include postinflammatory hyperpigmentation; chronic eczema (especially in children with darker skin and secondary hyperpigmentation or lichenification); and confluent and reticulated papillomatosis of Gougerot and Carteaud (the plaques in this condition are very similar to acanthosis nigricans, but are more reticulated and located on the chest and back). Other conditions to consider in your differential diagnosis include linear epidermal nevi and retained keratin (which presents as brownish patches on the neck or postauricular areas that are easily removed with alcohol, but not with water).

If the diagnosis of acanthosis nigricans is uncertain, referral to a pediatric dermatologist is recommended. Also refer a girl with suspected PCOS or hyperandrogenism and associated acne, which can be difficult to manage, as well as a girl with male-pattern hair loss.

The following criteria can warrant referral of the patient to a specialist other than a pediatric dermatologist:

▸ A child with a BMI at the 85th percentile or greater and any associated complications or any child with a BMI greater than the 95th percentile should be referred to a pediatric obesity treatment specialist, if available.

▸ Referral to a pediatric cardiologist may be needed if hypertension or dyslipidemia is present.

▸ Referral for a sleep study or for evaluation by a pediatric otolaryngologist may be indicated if signs of sleep disturbance suggest sleep apnea or obesity hypoventilation syndrome.

▸ Persistent headaches could indicate pseudotumor cerebri requiring neurologic evaluation.

▸ Referral to an endocrinologist would be indicated if Cushing's syndrome, type 2 diabetes, or hypothyroidism is suspected, or for girls with signs of PCOS or hyperandrogenism. The guidance of a pediatric endocrinologist may be required with certain medications, such as metformin, to decrease insulin resistance and hyperglycemia.

▸ Children with knee or hip pain and x-ray findings suggestive of slipped capital femoral epiphysis or Blount's disease (tibia vara) may need orthopedic evaluation.

▸ Children with abdominal pain may require referral to a pediatric gastroenterologist for evaluation of obesity-associated liver or gallbladder disease.

Regular monitoring of the overweight child with acanthosis nigricans is recommended. If initial screening is negative for type 2 diabetes or insulin resistance, the American Diabetes Association recommends repeating the screening every 2 years for at-risk children. Follow-up screening can also include thyroid studies to evaluate for hypothyroidism and dehydroepiandrosterone sulfate, free testosterone, and a luteinizing hormone to follicle-stimulating hormone (LH:FSH) ratio to screen for hyperandrogenism.

[email protected]

Acanthosis nigricans is one of the most common skin signs of obesity and hyperinsulinism and is a valuable predictor of insulin resistance in obese children. Patients with both obesity and acanthosis nigricans, compared with those with obesity alone, tend to have higher body mass indexes and increased fasting and evening insulin levels.

Early recognition and intervention are crucial to avoid complications of insulin resistance. The general pediatrician is in the best position to perform the initial assessment. Begin with measuring body mass index (BMI). Then evaluate the patient for the associated risk factors. If you diagnose acanthosis nigricans, screen the patient for associated conditions such as Cushing's syndrome; hypothyroidism; coexisting syndromes (including Prader-Willi, Bardet-Biedl, and leprechaunism); lipodystrophy; or psychiatric disorders including depression or eating disorders.

Children with a BMI under the 85th percentile and no complications can be managed well by their pediatrician. Early intervention is key. Focus on healthful living, increased physical activity, and education of the family regarding associated conditions and the adverse effects that obesity can have on the child's health and quality of life.

The best strategy is to treat the underlying cause of acanthosis nigricans. Address obesity and any secondary insulin resistance because obesity is the No. 1 cause of acanthosis nigricans. Although topical keratolytic lotions or other topical therapies may be of some benefit, results are often disappointing.

It is also important to involve the entire family in the treatment plan. If everyone is not ready for change, success will be limited. Because much embarrassment and stigma are often associated with obesity, discuss treatment, diet, and weight loss in an objective, nonjudgmental, and nonaccusatory fashion. Consider the family's schedule, financial situation, and lifestyle.

Educate patients and family members about appropriate weight for age and height, self-management skills, and a healthy, balanced diet with lower levels of carbohydrates and fats. It is easy for patients and parents to become discouraged, so institute changes gradually.

If a patient presents with obesity and acanthosis nigricans, evaluate the child for other insulin risk factors. These include a BMI above the 85th percentile for age and sex, polycystic ovarian syndrome, hypertension, dyslipidemia, a history of small size for gestational age at birth, premature pubarche, allergic diathesis, and/or a family history of these conditions. Also note that children of certain ethnicities are at higher risk as well, including African, Indian subcontinent, American Indian, and Hispanic populations.

Children with obesity and insulin resistance are at increased future risk for associated complications including orthopedic problems, fatty liver or gallbladder disease, infertility, hyperandrogenism, coronary artery disease and stroke, type 2 diabetes, predisposition to certain cancers, and Alzheimer's disease.

In addition to measurements of blood pressure, height, weight, and BMI, helpful laboratory studies include nonfasting lipid, hemoglobin A_1c, and insulin and glucose levels. Fasting glucose, insulin, and lipid tests are especially recommended for a child whose BMI is at the 85th percentile or greater.

Conditions that can mimic acanthosis nigricans include postinflammatory hyperpigmentation; chronic eczema (especially in children with darker skin and secondary hyperpigmentation or lichenification); and confluent and reticulated papillomatosis of Gougerot and Carteaud (the plaques in this condition are very similar to acanthosis nigricans, but are more reticulated and located on the chest and back). Other conditions to consider in your differential diagnosis include linear epidermal nevi and retained keratin (which presents as brownish patches on the neck or postauricular areas that are easily removed with alcohol, but not with water).

If the diagnosis of acanthosis nigricans is uncertain, referral to a pediatric dermatologist is recommended. Also refer a girl with suspected PCOS or hyperandrogenism and associated acne, which can be difficult to manage, as well as a girl with male-pattern hair loss.

The following criteria can warrant referral of the patient to a specialist other than a pediatric dermatologist:

▸ A child with a BMI at the 85th percentile or greater and any associated complications or any child with a BMI greater than the 95th percentile should be referred to a pediatric obesity treatment specialist, if available.

▸ Referral to a pediatric cardiologist may be needed if hypertension or dyslipidemia is present.

▸ Referral for a sleep study or for evaluation by a pediatric otolaryngologist may be indicated if signs of sleep disturbance suggest sleep apnea or obesity hypoventilation syndrome.

▸ Persistent headaches could indicate pseudotumor cerebri requiring neurologic evaluation.

▸ Referral to an endocrinologist would be indicated if Cushing's syndrome, type 2 diabetes, or hypothyroidism is suspected, or for girls with signs of PCOS or hyperandrogenism. The guidance of a pediatric endocrinologist may be required with certain medications, such as metformin, to decrease insulin resistance and hyperglycemia.

▸ Children with knee or hip pain and x-ray findings suggestive of slipped capital femoral epiphysis or Blount's disease (tibia vara) may need orthopedic evaluation.

▸ Children with abdominal pain may require referral to a pediatric gastroenterologist for evaluation of obesity-associated liver or gallbladder disease.

Regular monitoring of the overweight child with acanthosis nigricans is recommended. If initial screening is negative for type 2 diabetes or insulin resistance, the American Diabetes Association recommends repeating the screening every 2 years for at-risk children. Follow-up screening can also include thyroid studies to evaluate for hypothyroidism and dehydroepiandrosterone sulfate, free testosterone, and a luteinizing hormone to follicle-stimulating hormone (LH:FSH) ratio to screen for hyperandrogenism.

As for many solid tumors, major advances in the treatment of ovarian cancer are more likely to be made through the introduction of novel targeted approaches rather than by manipulating cytotoxic chemotherapy regimens. Farletuzumab is a monoclonal antibody that binds to and blocks the function of folate receptor alpha, which is expressed in at least 90% of ovarian cancer patients. In platinum-sensitive patients experiencing the first relapse of their disease, farletuzumab enhances CA-125 responses as well as tumor response, as determined by RECIST criteria, compared with historic controls. Farletuzumab therefore represents a promising candidate for evaluation in phase III trials. The FAR-131 study is a multicenter, double-blind, randomized, placebo-controlled trial examining the safety and efficacy of two dose levels of farletuzumab in combination with carboplatin and a taxane in patients with platinum-sensitive ovarian cancer in first relapse. The primary endpoint is progression-free survival; the effects of this combination on overall survival, CA-125 response, duration of second remission, and quality of life are among the secondary objectives of this study.

As for many solid tumors, major advances in the treatment of ovarian cancer are more likely to be made through the introduction of novel targeted approaches rather than by manipulating cytotoxic chemotherapy regimens. Farletuzumab is a monoclonal antibody that binds to and blocks the function of folate receptor alpha, which is expressed in at least 90% of ovarian cancer patients. In platinum-sensitive patients experiencing the first relapse of their disease, farletuzumab enhances CA-125 responses as well as tumor response, as determined by RECIST criteria, compared with historic controls. Farletuzumab therefore represents a promising candidate for evaluation in phase III trials. The FAR-131 study is a multicenter, double-blind, randomized, placebo-controlled trial examining the safety and efficacy of two dose levels of farletuzumab in combination with carboplatin and a taxane in patients with platinum-sensitive ovarian cancer in first relapse. The primary endpoint is progression-free survival; the effects of this combination on overall survival, CA-125 response, duration of second remission, and quality of life are among the secondary objectives of this study.

As for many solid tumors, major advances in the treatment of ovarian cancer are more likely to be made through the introduction of novel targeted approaches rather than by manipulating cytotoxic chemotherapy regimens. Farletuzumab is a monoclonal antibody that binds to and blocks the function of folate receptor alpha, which is expressed in at least 90% of ovarian cancer patients. In platinum-sensitive patients experiencing the first relapse of their disease, farletuzumab enhances CA-125 responses as well as tumor response, as determined by RECIST criteria, compared with historic controls. Farletuzumab therefore represents a promising candidate for evaluation in phase III trials. The FAR-131 study is a multicenter, double-blind, randomized, placebo-controlled trial examining the safety and efficacy of two dose levels of farletuzumab in combination with carboplatin and a taxane in patients with platinum-sensitive ovarian cancer in first relapse. The primary endpoint is progression-free survival; the effects of this combination on overall survival, CA-125 response, duration of second remission, and quality of life are among the secondary objectives of this study.

Major Finding: Among diabetes patients at high cardiovascular risk, those treated to a mean systolic blood pressure of 119.3 mm Hg had a 1.87%/year rate of nonfatal MI, nonfatal stroke, or cardiovascular death over 4.7 years, compared with 2.09%/year in patients treated to a mean systolic blood pressure of 133.5 mm Hg. The difference was not statistically significant.

Data Source: ACCORD blood pressure trial, a randomized, controlled study of 4,733 patients with type 2 diabetes.

Disclosures: Dr. Cushman has received consultant fees and honoraria from Novartis, Sanofi-Aventis, Theravance, and Takeda, and served on data and safety monitoring boards of Novartis and Gilead. Dr. Bakris reported financial relationships with Abbott, GlaxoSmithKline, Novartis, Merck, Gilead, and other companies. Dr. Cooper-DeHoff and Dr. Simons-Morton had no disclosures.

ATLANTA — The official U.S. guideline that patients with diabetes should receive treatment to a blood pressure target of less than 130/80 mm Hg became suspect following reports from a pair of large studies showing no benefit in these patients beyond a goal systolic pressure of less than 140 mm Hg.

In a controlled trial with more than 4,700 U.S. patients with type 2 diabetes randomized to an intensive antihypertensive regimen with a goal systolic pressure of less than 120 mm Hg or to a standard-therapy arm aiming for less than 140 mm Hg, “the results provided no conclusive evidence that the intensive blood pressure control strategy reduces the rate of a composite of major cardiovascular disease events,” Dr. William C. Cushman said at the annual meeting of the American College of Cardiology.

“We were surprised by the findings” from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial, said Dr. Cushman, chief of the preventive medicine section at the VA Medical Center in Memphis. “The evidence supports less than 140 mm Hg. There generally was thinking that if you're dealing with [high cardiovascular risk], such as patients with diabetes, it makes sense that their goal pressure should be more intense.” The results “clearly say that we can't think that way anymore” and should influence recommendations expected in about a year from the Eighth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), he said in an interview.

The existing hypertension treatment guidelines of the National Heart, Blood, and Lung Institute, JNC 7, have a blood pressure treatment target of less than 130/80 mm Hg for patients with diabetes (JAMA 2003;289:2560-71). Dr. Cushman was a member of the JNC 7 panel, and is a member of the group now working on JNC 8.

The JNC 7 blood pressure target for patients with diabetes “was an extrapolation based on observational data. The guidelines were beyond evidence from randomized, controlled trials,” said Dr. Denise Simons-Morton, project director for ACCORD and director of the NHLBI division responsible for the JNC guidelines. The new ACCORD findings show that this extrapolation was a mistake, and that current evidence cannot support a goal systolic pressure that is more aggressive than the target of less than 140 mm Hg, she said in an interview.

Because of the way that JNC 8 is being prepared, the ACCORD results may be too late for inclusion in the new guidelines, said Dr. George Bakris, professor of medicine at the University of Chicago, who was a member of the JNC 7 writing committee but is not a member of the JNC 8 panel. But, he added in an interview, “all other guidelines” on treating hypertension in patients with diabetes, including those from the American Diabetes Association and various international societies, “will have to revise their blood pressure goals” based on the ACCORD results. In an editorial last year, Dr. Bakris and an associate called the goal of a systolic pressure below 130 mm Hg in patients with chronic kidney disease “questionable” (J. Clin. Hypertension 2009;11:345-7).

The 2,362 patients in the intensive-treatment arm of the ACCORD blood pressure trial reached a mean systolic pressure of 119.3 mm Hg after the first year while receiving an average of 3.4 antihypertensive drugs; those patients had a 1.87%/year rate of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death during an average follow-up of 4.7 years. The 2,371 patients in the standard-therapy arm reached a mean systolic pressure of 133.5 mm Hg after the first year and received an average of 2.1 drugs; they had a 2.09%/year rate for the combined end point. The difference in rates between the two groups was not statistically significant. Concurrently with Dr. Cushman's report at the meeting, the results were posted online (N. Engl. J. Med. 2010 March 14 [doi:10.1056/NEJMoa1001286]).

“Less than 140 mm Hg is the message we need to put out, and less than 130 mm Hg is probably not necessary to achieve benefit and may be harmful in certain populations,” said Rhonda M. Cooper-DeHoff, Pharm.D., associate director of the cardiovascular clinical research program at the University of Florida, Gainesville.

Dr. DeHoff presented results from a second study that also called into question a systolic blood pressure goal of less than 130 mm Hg for patients with diabetes. Her study used long-term follow-up data from the 6,400 patients with diabetes who had participated in the International Verapamil SR-Trandolapril (INVEST) study, with an overall enrollment of more than 22,000 patients that compared two different antihypertensive regimens (JAMA 2003;290:2805-16).

Using data collected during the trial plus 5 years of follow-up, Dr. DeHoff and her associates showed that the 2,255 patients with diabetes maintained at a systolic blood pressure below 130 mm Hg had cardiovascular disease event rates similar to the 1,970 patients with diabetes maintained at a systolic blood pressure of 130-139 mm Hg; patients in both groups did significantly better than did a third group of 2,175 patients with diabetes whose systolic pressure consistently remained at 140 mm Hg or higher. Among the 5,077 U.S. patients with diabetes in INVEST, those kept at a systolic pressure of less than 130 mm Hg had a significant 15% increase in the rate of all-cause death, compared with the patients kept at a systolic pressure of 130-139 mm Hg.

“Based on the results from ACCORD and INVEST, is it time to rethink lower blood pressure goals in patients with diabetes and coronary artery disease?” Dr. DeHoff asked as she concluded her report at the meeting.

To apply the ACCORD results in practice, Dr. Cushman advises physicians to prescribe for patients with diabetes a “maximum” dosage of a renin-angiotensin-aldosterone system (RAAS) blocker drug, such as an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, plus a diuretic such as chlorthalidone. He also urges physicians to prescribe other drugs with antihypertensive effects, such as certain beta-blockers or calcium channel blockers, that patients with diabetes and a high risk for cardiovascular disease events might need for specific risk indications.

If a patient's systolic pressure remains above 140 mm Hg despite these treatments, then another agent should be added; if the indicated drugs bring the patient's systolic pressure below 140 mm Hg, then additional treatments should stop. However, if the indicated drugs bring the patient's pressure moderately below 130 mm Hg, “I wouldn't back off,” and withdraw drugs that the patient might otherwise need, he said.

In this way, practice should not fully mimic the ACCORD trial design. In that trial, patients in the standard-therapy arm came off one or more of their medications if their systolic pressure fell below 130 mm Hg, noted Dr. Cushman, who also is professor of medicine at the University of Tennessee in Memphis.

Intensive blood pressure control did not reduce the rate of major cardiovascular disease events in patients with diabetes, Dr. William C. Cushman reported.

Source Courtesy Memphis VAMC

If the indicated drugs bring a patient's pressure moderately below 130 mm Hg, 'I wouldn't back off.'

Source Dr. Cushman

This Month's Talk Back Question

How low do you try to get blood pressure in your patients with diabetes?

My Take

Study Findings Diverge From Observational Data

We would have predicted that the lower a patient's blood pressure the better the outcome, and we have therefore sought to get blood pressures lower.

Normal blood pressure is less than 120/80 mm Hg, but we had no data on treating patients to blood pressures that low. Nature says that high blood pressure is not good, and we try to simulate nature by using treatments that lower blood pressure by lifestyle and drugs. There is no question that lower blood pressure benefits patients, but where is the floor? Is a pressure of 140 mm Hg good enough?

For patients with diabetes, chronic kidney disease, or dyslipidemia the guidelines set a lower target pressure. But in this large trial we did not see a difference from bringing the pressure lower. We need to look at the results further to try to explain them.

ELIJAH SAUNDERS, M.D., is professor of medicine and head of the division of hypertension at the University of Maryland in Baltimore. He has been a consultant to, served on the speakers bureau for, and has received research support from Bristol-Myers Squibb, Forest, Novartis, Pfizer, and Sanofi-Aventis.

Major Finding: Among diabetes patients at high cardiovascular risk, those treated to a mean systolic blood pressure of 119.3 mm Hg had a 1.87%/year rate of nonfatal MI, nonfatal stroke, or cardiovascular death over 4.7 years, compared with 2.09%/year in patients treated to a mean systolic blood pressure of 133.5 mm Hg. The difference was not statistically significant.

Data Source: ACCORD blood pressure trial, a randomized, controlled study of 4,733 patients with type 2 diabetes.

Disclosures: Dr. Cushman has received consultant fees and honoraria from Novartis, Sanofi-Aventis, Theravance, and Takeda, and served on data and safety monitoring boards of Novartis and Gilead. Dr. Bakris reported financial relationships with Abbott, GlaxoSmithKline, Novartis, Merck, Gilead, and other companies. Dr. Cooper-DeHoff and Dr. Simons-Morton had no disclosures.

ATLANTA — The official U.S. guideline that patients with diabetes should receive treatment to a blood pressure target of less than 130/80 mm Hg became suspect following reports from a pair of large studies showing no benefit in these patients beyond a goal systolic pressure of less than 140 mm Hg.

In a controlled trial with more than 4,700 U.S. patients with type 2 diabetes randomized to an intensive antihypertensive regimen with a goal systolic pressure of less than 120 mm Hg or to a standard-therapy arm aiming for less than 140 mm Hg, “the results provided no conclusive evidence that the intensive blood pressure control strategy reduces the rate of a composite of major cardiovascular disease events,” Dr. William C. Cushman said at the annual meeting of the American College of Cardiology.

“We were surprised by the findings” from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial, said Dr. Cushman, chief of the preventive medicine section at the VA Medical Center in Memphis. “The evidence supports less than 140 mm Hg. There generally was thinking that if you're dealing with [high cardiovascular risk], such as patients with diabetes, it makes sense that their goal pressure should be more intense.” The results “clearly say that we can't think that way anymore” and should influence recommendations expected in about a year from the Eighth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), he said in an interview.

The existing hypertension treatment guidelines of the National Heart, Blood, and Lung Institute, JNC 7, have a blood pressure treatment target of less than 130/80 mm Hg for patients with diabetes (JAMA 2003;289:2560-71). Dr. Cushman was a member of the JNC 7 panel, and is a member of the group now working on JNC 8.

The JNC 7 blood pressure target for patients with diabetes “was an extrapolation based on observational data. The guidelines were beyond evidence from randomized, controlled trials,” said Dr. Denise Simons-Morton, project director for ACCORD and director of the NHLBI division responsible for the JNC guidelines. The new ACCORD findings show that this extrapolation was a mistake, and that current evidence cannot support a goal systolic pressure that is more aggressive than the target of less than 140 mm Hg, she said in an interview.

Because of the way that JNC 8 is being prepared, the ACCORD results may be too late for inclusion in the new guidelines, said Dr. George Bakris, professor of medicine at the University of Chicago, who was a member of the JNC 7 writing committee but is not a member of the JNC 8 panel. But, he added in an interview, “all other guidelines” on treating hypertension in patients with diabetes, including those from the American Diabetes Association and various international societies, “will have to revise their blood pressure goals” based on the ACCORD results. In an editorial last year, Dr. Bakris and an associate called the goal of a systolic pressure below 130 mm Hg in patients with chronic kidney disease “questionable” (J. Clin. Hypertension 2009;11:345-7).

The 2,362 patients in the intensive-treatment arm of the ACCORD blood pressure trial reached a mean systolic pressure of 119.3 mm Hg after the first year while receiving an average of 3.4 antihypertensive drugs; those patients had a 1.87%/year rate of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death during an average follow-up of 4.7 years. The 2,371 patients in the standard-therapy arm reached a mean systolic pressure of 133.5 mm Hg after the first year and received an average of 2.1 drugs; they had a 2.09%/year rate for the combined end point. The difference in rates between the two groups was not statistically significant. Concurrently with Dr. Cushman's report at the meeting, the results were posted online (N. Engl. J. Med. 2010 March 14 [doi:10.1056/NEJMoa1001286]).

“Less than 140 mm Hg is the message we need to put out, and less than 130 mm Hg is probably not necessary to achieve benefit and may be harmful in certain populations,” said Rhonda M. Cooper-DeHoff, Pharm.D., associate director of the cardiovascular clinical research program at the University of Florida, Gainesville.

Dr. DeHoff presented results from a second study that also called into question a systolic blood pressure goal of less than 130 mm Hg for patients with diabetes. Her study used long-term follow-up data from the 6,400 patients with diabetes who had participated in the International Verapamil SR-Trandolapril (INVEST) study, with an overall enrollment of more than 22,000 patients that compared two different antihypertensive regimens (JAMA 2003;290:2805-16).

Using data collected during the trial plus 5 years of follow-up, Dr. DeHoff and her associates showed that the 2,255 patients with diabetes maintained at a systolic blood pressure below 130 mm Hg had cardiovascular disease event rates similar to the 1,970 patients with diabetes maintained at a systolic blood pressure of 130-139 mm Hg; patients in both groups did significantly better than did a third group of 2,175 patients with diabetes whose systolic pressure consistently remained at 140 mm Hg or higher. Among the 5,077 U.S. patients with diabetes in INVEST, those kept at a systolic pressure of less than 130 mm Hg had a significant 15% increase in the rate of all-cause death, compared with the patients kept at a systolic pressure of 130-139 mm Hg.

“Based on the results from ACCORD and INVEST, is it time to rethink lower blood pressure goals in patients with diabetes and coronary artery disease?” Dr. DeHoff asked as she concluded her report at the meeting.

To apply the ACCORD results in practice, Dr. Cushman advises physicians to prescribe for patients with diabetes a “maximum” dosage of a renin-angiotensin-aldosterone system (RAAS) blocker drug, such as an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, plus a diuretic such as chlorthalidone. He also urges physicians to prescribe other drugs with antihypertensive effects, such as certain beta-blockers or calcium channel blockers, that patients with diabetes and a high risk for cardiovascular disease events might need for specific risk indications.

If a patient's systolic pressure remains above 140 mm Hg despite these treatments, then another agent should be added; if the indicated drugs bring the patient's systolic pressure below 140 mm Hg, then additional treatments should stop. However, if the indicated drugs bring the patient's pressure moderately below 130 mm Hg, “I wouldn't back off,” and withdraw drugs that the patient might otherwise need, he said.

In this way, practice should not fully mimic the ACCORD trial design. In that trial, patients in the standard-therapy arm came off one or more of their medications if their systolic pressure fell below 130 mm Hg, noted Dr. Cushman, who also is professor of medicine at the University of Tennessee in Memphis.

Intensive blood pressure control did not reduce the rate of major cardiovascular disease events in patients with diabetes, Dr. William C. Cushman reported.

Source Courtesy Memphis VAMC

If the indicated drugs bring a patient's pressure moderately below 130 mm Hg, 'I wouldn't back off.'

Source Dr. Cushman

This Month's Talk Back Question

How low do you try to get blood pressure in your patients with diabetes?

My Take

Study Findings Diverge From Observational Data

We would have predicted that the lower a patient's blood pressure the better the outcome, and we have therefore sought to get blood pressures lower.

Normal blood pressure is less than 120/80 mm Hg, but we had no data on treating patients to blood pressures that low. Nature says that high blood pressure is not good, and we try to simulate nature by using treatments that lower blood pressure by lifestyle and drugs. There is no question that lower blood pressure benefits patients, but where is the floor? Is a pressure of 140 mm Hg good enough?

For patients with diabetes, chronic kidney disease, or dyslipidemia the guidelines set a lower target pressure. But in this large trial we did not see a difference from bringing the pressure lower. We need to look at the results further to try to explain them.

ELIJAH SAUNDERS, M.D., is professor of medicine and head of the division of hypertension at the University of Maryland in Baltimore. He has been a consultant to, served on the speakers bureau for, and has received research support from Bristol-Myers Squibb, Forest, Novartis, Pfizer, and Sanofi-Aventis.

Major Finding: Among diabetes patients at high cardiovascular risk, those treated to a mean systolic blood pressure of 119.3 mm Hg had a 1.87%/year rate of nonfatal MI, nonfatal stroke, or cardiovascular death over 4.7 years, compared with 2.09%/year in patients treated to a mean systolic blood pressure of 133.5 mm Hg. The difference was not statistically significant.

Data Source: ACCORD blood pressure trial, a randomized, controlled study of 4,733 patients with type 2 diabetes.

Disclosures: Dr. Cushman has received consultant fees and honoraria from Novartis, Sanofi-Aventis, Theravance, and Takeda, and served on data and safety monitoring boards of Novartis and Gilead. Dr. Bakris reported financial relationships with Abbott, GlaxoSmithKline, Novartis, Merck, Gilead, and other companies. Dr. Cooper-DeHoff and Dr. Simons-Morton had no disclosures.

ATLANTA — The official U.S. guideline that patients with diabetes should receive treatment to a blood pressure target of less than 130/80 mm Hg became suspect following reports from a pair of large studies showing no benefit in these patients beyond a goal systolic pressure of less than 140 mm Hg.

In a controlled trial with more than 4,700 U.S. patients with type 2 diabetes randomized to an intensive antihypertensive regimen with a goal systolic pressure of less than 120 mm Hg or to a standard-therapy arm aiming for less than 140 mm Hg, “the results provided no conclusive evidence that the intensive blood pressure control strategy reduces the rate of a composite of major cardiovascular disease events,” Dr. William C. Cushman said at the annual meeting of the American College of Cardiology.

“We were surprised by the findings” from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial, said Dr. Cushman, chief of the preventive medicine section at the VA Medical Center in Memphis. “The evidence supports less than 140 mm Hg. There generally was thinking that if you're dealing with [high cardiovascular risk], such as patients with diabetes, it makes sense that their goal pressure should be more intense.” The results “clearly say that we can't think that way anymore” and should influence recommendations expected in about a year from the Eighth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), he said in an interview.

The existing hypertension treatment guidelines of the National Heart, Blood, and Lung Institute, JNC 7, have a blood pressure treatment target of less than 130/80 mm Hg for patients with diabetes (JAMA 2003;289:2560-71). Dr. Cushman was a member of the JNC 7 panel, and is a member of the group now working on JNC 8.

The JNC 7 blood pressure target for patients with diabetes “was an extrapolation based on observational data. The guidelines were beyond evidence from randomized, controlled trials,” said Dr. Denise Simons-Morton, project director for ACCORD and director of the NHLBI division responsible for the JNC guidelines. The new ACCORD findings show that this extrapolation was a mistake, and that current evidence cannot support a goal systolic pressure that is more aggressive than the target of less than 140 mm Hg, she said in an interview.

Because of the way that JNC 8 is being prepared, the ACCORD results may be too late for inclusion in the new guidelines, said Dr. George Bakris, professor of medicine at the University of Chicago, who was a member of the JNC 7 writing committee but is not a member of the JNC 8 panel. But, he added in an interview, “all other guidelines” on treating hypertension in patients with diabetes, including those from the American Diabetes Association and various international societies, “will have to revise their blood pressure goals” based on the ACCORD results. In an editorial last year, Dr. Bakris and an associate called the goal of a systolic pressure below 130 mm Hg in patients with chronic kidney disease “questionable” (J. Clin. Hypertension 2009;11:345-7).

The 2,362 patients in the intensive-treatment arm of the ACCORD blood pressure trial reached a mean systolic pressure of 119.3 mm Hg after the first year while receiving an average of 3.4 antihypertensive drugs; those patients had a 1.87%/year rate of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death during an average follow-up of 4.7 years. The 2,371 patients in the standard-therapy arm reached a mean systolic pressure of 133.5 mm Hg after the first year and received an average of 2.1 drugs; they had a 2.09%/year rate for the combined end point. The difference in rates between the two groups was not statistically significant. Concurrently with Dr. Cushman's report at the meeting, the results were posted online (N. Engl. J. Med. 2010 March 14 [doi:10.1056/NEJMoa1001286]).

“Less than 140 mm Hg is the message we need to put out, and less than 130 mm Hg is probably not necessary to achieve benefit and may be harmful in certain populations,” said Rhonda M. Cooper-DeHoff, Pharm.D., associate director of the cardiovascular clinical research program at the University of Florida, Gainesville.

Dr. DeHoff presented results from a second study that also called into question a systolic blood pressure goal of less than 130 mm Hg for patients with diabetes. Her study used long-term follow-up data from the 6,400 patients with diabetes who had participated in the International Verapamil SR-Trandolapril (INVEST) study, with an overall enrollment of more than 22,000 patients that compared two different antihypertensive regimens (JAMA 2003;290:2805-16).

Using data collected during the trial plus 5 years of follow-up, Dr. DeHoff and her associates showed that the 2,255 patients with diabetes maintained at a systolic blood pressure below 130 mm Hg had cardiovascular disease event rates similar to the 1,970 patients with diabetes maintained at a systolic blood pressure of 130-139 mm Hg; patients in both groups did significantly better than did a third group of 2,175 patients with diabetes whose systolic pressure consistently remained at 140 mm Hg or higher. Among the 5,077 U.S. patients with diabetes in INVEST, those kept at a systolic pressure of less than 130 mm Hg had a significant 15% increase in the rate of all-cause death, compared with the patients kept at a systolic pressure of 130-139 mm Hg.

“Based on the results from ACCORD and INVEST, is it time to rethink lower blood pressure goals in patients with diabetes and coronary artery disease?” Dr. DeHoff asked as she concluded her report at the meeting.

To apply the ACCORD results in practice, Dr. Cushman advises physicians to prescribe for patients with diabetes a “maximum” dosage of a renin-angiotensin-aldosterone system (RAAS) blocker drug, such as an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, plus a diuretic such as chlorthalidone. He also urges physicians to prescribe other drugs with antihypertensive effects, such as certain beta-blockers or calcium channel blockers, that patients with diabetes and a high risk for cardiovascular disease events might need for specific risk indications.

If a patient's systolic pressure remains above 140 mm Hg despite these treatments, then another agent should be added; if the indicated drugs bring the patient's systolic pressure below 140 mm Hg, then additional treatments should stop. However, if the indicated drugs bring the patient's pressure moderately below 130 mm Hg, “I wouldn't back off,” and withdraw drugs that the patient might otherwise need, he said.

In this way, practice should not fully mimic the ACCORD trial design. In that trial, patients in the standard-therapy arm came off one or more of their medications if their systolic pressure fell below 130 mm Hg, noted Dr. Cushman, who also is professor of medicine at the University of Tennessee in Memphis.

Intensive blood pressure control did not reduce the rate of major cardiovascular disease events in patients with diabetes, Dr. William C. Cushman reported.

Source Courtesy Memphis VAMC

If the indicated drugs bring a patient's pressure moderately below 130 mm Hg, 'I wouldn't back off.'

Source Dr. Cushman

This Month's Talk Back Question

How low do you try to get blood pressure in your patients with diabetes?

My Take

Study Findings Diverge From Observational Data

We would have predicted that the lower a patient's blood pressure the better the outcome, and we have therefore sought to get blood pressures lower.

Normal blood pressure is less than 120/80 mm Hg, but we had no data on treating patients to blood pressures that low. Nature says that high blood pressure is not good, and we try to simulate nature by using treatments that lower blood pressure by lifestyle and drugs. There is no question that lower blood pressure benefits patients, but where is the floor? Is a pressure of 140 mm Hg good enough?

For patients with diabetes, chronic kidney disease, or dyslipidemia the guidelines set a lower target pressure. But in this large trial we did not see a difference from bringing the pressure lower. We need to look at the results further to try to explain them.

ELIJAH SAUNDERS, M.D., is professor of medicine and head of the division of hypertension at the University of Maryland in Baltimore. He has been a consultant to, served on the speakers bureau for, and has received research support from Bristol-Myers Squibb, Forest, Novartis, Pfizer, and Sanofi-Aventis.

The cost of healthcare varies widely from hospital to hospital and doesn't appear to be inherently linked to the quality of patient care, according to a study in the Archives of Internal Medicine.

"It's particularly perplexing because the differences in cost are quite substantial," says Mitchell Katz, MD, director of San Francisco's public-health program and the author of an accompanying editorial calling for more research.

The Feb. 22 report found wide disparities in the costs of care but no strong correlation in the context of patient care or the risk of death within 30 days. The nationwide study by researchers at the University of Michigan reviewed some 3,150 hospitals that discharged Medicare patients admitted for congestive heart failure or pneumonia in 2006. Data were studied in association with variables including readmission rates and quality scores.

Compared with hospitals in the lowest-cost quartile for congestive heart failure care, the researchers found that hospitals in the highest-cost quartile had higher quality-of-care scores (89.9% vs. 85.5%) and lower mortality for congestive heart failure (9.8% vs. 10.8%). For pneumonia, however, the converse was true. Compared with lower-cost hospitals, high-cost hospitals had lower quality-of-care scores (85.7% vs. 86.6%) and higher mortality (11.7% vs. 10.9%).

Dr. Katz is heartened that the study found longer length-of-stay (LOS) at high-cost hospitals, suggesting that decreased LOS—a staple of HM's value-added services—will slash hospital costs. But he says more randomized, comparative-effectiveness studies need to be published. Hospitalists are in a natural position to author those examinations, he says. "One of the roles of a hospitalist can be to be advocates of 'Yes, we think it can be done,' " Dr. Katz says. "Because there are a lot of doctors who want to say, ‘No, it can’t be done.' "

The cost of healthcare varies widely from hospital to hospital and doesn't appear to be inherently linked to the quality of patient care, according to a study in the Archives of Internal Medicine.

"It's particularly perplexing because the differences in cost are quite substantial," says Mitchell Katz, MD, director of San Francisco's public-health program and the author of an accompanying editorial calling for more research.

The Feb. 22 report found wide disparities in the costs of care but no strong correlation in the context of patient care or the risk of death within 30 days. The nationwide study by researchers at the University of Michigan reviewed some 3,150 hospitals that discharged Medicare patients admitted for congestive heart failure or pneumonia in 2006. Data were studied in association with variables including readmission rates and quality scores.

Compared with hospitals in the lowest-cost quartile for congestive heart failure care, the researchers found that hospitals in the highest-cost quartile had higher quality-of-care scores (89.9% vs. 85.5%) and lower mortality for congestive heart failure (9.8% vs. 10.8%). For pneumonia, however, the converse was true. Compared with lower-cost hospitals, high-cost hospitals had lower quality-of-care scores (85.7% vs. 86.6%) and higher mortality (11.7% vs. 10.9%).

Dr. Katz is heartened that the study found longer length-of-stay (LOS) at high-cost hospitals, suggesting that decreased LOS—a staple of HM's value-added services—will slash hospital costs. But he says more randomized, comparative-effectiveness studies need to be published. Hospitalists are in a natural position to author those examinations, he says. "One of the roles of a hospitalist can be to be advocates of 'Yes, we think it can be done,' " Dr. Katz says. "Because there are a lot of doctors who want to say, ‘No, it can’t be done.' "

The cost of healthcare varies widely from hospital to hospital and doesn't appear to be inherently linked to the quality of patient care, according to a study in the Archives of Internal Medicine.

"It's particularly perplexing because the differences in cost are quite substantial," says Mitchell Katz, MD, director of San Francisco's public-health program and the author of an accompanying editorial calling for more research.

The Feb. 22 report found wide disparities in the costs of care but no strong correlation in the context of patient care or the risk of death within 30 days. The nationwide study by researchers at the University of Michigan reviewed some 3,150 hospitals that discharged Medicare patients admitted for congestive heart failure or pneumonia in 2006. Data were studied in association with variables including readmission rates and quality scores.

Compared with hospitals in the lowest-cost quartile for congestive heart failure care, the researchers found that hospitals in the highest-cost quartile had higher quality-of-care scores (89.9% vs. 85.5%) and lower mortality for congestive heart failure (9.8% vs. 10.8%). For pneumonia, however, the converse was true. Compared with lower-cost hospitals, high-cost hospitals had lower quality-of-care scores (85.7% vs. 86.6%) and higher mortality (11.7% vs. 10.9%).

Dr. Katz is heartened that the study found longer length-of-stay (LOS) at high-cost hospitals, suggesting that decreased LOS—a staple of HM's value-added services—will slash hospital costs. But he says more randomized, comparative-effectiveness studies need to be published. Hospitalists are in a natural position to author those examinations, he says. "One of the roles of a hospitalist can be to be advocates of 'Yes, we think it can be done,' " Dr. Katz says. "Because there are a lot of doctors who want to say, ‘No, it can’t be done.' "

Clinical question: Does the appropriateness of the initial empiric antimicrobial agents started at the onset of septic shock have an impact on outcomes in this clinical syndrome?

Background: Septic shock is a common cause of death among ICU patients. Prompt initiation of appropriate antimicrobial therapy is key to improving outcomes. This study evaluates the effects of initiating inappropriate empiric antimicrobial therapy.

Study design: Retrospective cohort study.

Setting: Twenty-two hospitals in the U.S., Canada, and Saudi Arabia.

Synopsis: Records of more than 5,700 patients with septic shock were reviewed. Appropriate antimicrobial therapy was defined as agents with in vitro activity for the isolated microorganism(s), or if the antimicrobial agents provided adequate empiric coverage for local community and nosocomial flora in culture-negative shock. The main outcome variable was survival to hospital discharge.

The overall survival-to-hospital discharge was 43.7%, and 80.1% of patients received appropriate empiric antimicrobial therapy. Of those who died, 4.8% did not receive appropriate therapy. Inappropriate antimicrobial regimens caused survival to fall to 10.3% from 52.0% (OR 9.45; 95% CI, 7.74 to 11.54; p<0.0001).

After adjusting for potential confounding variables, the inappropriateness of initial antimicrobial therapy remained strongly associated with risk of death (OR 8.99; 95% CI, 6.60 to 12.23; p<0.0001).

The primary weakness of the study is that it was observational.

Bottom line: The choice of an appropriate empiric antimicrobial agent is a critical determinant of survival in patients with septic shock.

Citation: Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009;136(5):1237-1248.

Reviewed for TH eWire by Sameer Badlani, MD, Stacy S. Banerjee, MD, Alan J. Jung, MD, Elizabeth Marlow, MD, MPP, Valerie G. Press, MD, MPH, Milda R. Saunders, MD, MPH, Nilam J. Soni, MD, Srilaxmi Tumuluri, MD, Section of Hospital Medicine, University of Chicago

For more reviews of HM-related literature, visit our Web site.

Clinical question: Does the appropriateness of the initial empiric antimicrobial agents started at the onset of septic shock have an impact on outcomes in this clinical syndrome?

Background: Septic shock is a common cause of death among ICU patients. Prompt initiation of appropriate antimicrobial therapy is key to improving outcomes. This study evaluates the effects of initiating inappropriate empiric antimicrobial therapy.

Study design: Retrospective cohort study.

Setting: Twenty-two hospitals in the U.S., Canada, and Saudi Arabia.

Synopsis: Records of more than 5,700 patients with septic shock were reviewed. Appropriate antimicrobial therapy was defined as agents with in vitro activity for the isolated microorganism(s), or if the antimicrobial agents provided adequate empiric coverage for local community and nosocomial flora in culture-negative shock. The main outcome variable was survival to hospital discharge.

The overall survival-to-hospital discharge was 43.7%, and 80.1% of patients received appropriate empiric antimicrobial therapy. Of those who died, 4.8% did not receive appropriate therapy. Inappropriate antimicrobial regimens caused survival to fall to 10.3% from 52.0% (OR 9.45; 95% CI, 7.74 to 11.54; p<0.0001).

After adjusting for potential confounding variables, the inappropriateness of initial antimicrobial therapy remained strongly associated with risk of death (OR 8.99; 95% CI, 6.60 to 12.23; p<0.0001).

The primary weakness of the study is that it was observational.

Bottom line: The choice of an appropriate empiric antimicrobial agent is a critical determinant of survival in patients with septic shock.

Citation: Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009;136(5):1237-1248.

Reviewed for TH eWire by Sameer Badlani, MD, Stacy S. Banerjee, MD, Alan J. Jung, MD, Elizabeth Marlow, MD, MPP, Valerie G. Press, MD, MPH, Milda R. Saunders, MD, MPH, Nilam J. Soni, MD, Srilaxmi Tumuluri, MD, Section of Hospital Medicine, University of Chicago

For more reviews of HM-related literature, visit our Web site.

Clinical question: Does the appropriateness of the initial empiric antimicrobial agents started at the onset of septic shock have an impact on outcomes in this clinical syndrome?

Background: Septic shock is a common cause of death among ICU patients. Prompt initiation of appropriate antimicrobial therapy is key to improving outcomes. This study evaluates the effects of initiating inappropriate empiric antimicrobial therapy.

Study design: Retrospective cohort study.

Setting: Twenty-two hospitals in the U.S., Canada, and Saudi Arabia.

Synopsis: Records of more than 5,700 patients with septic shock were reviewed. Appropriate antimicrobial therapy was defined as agents with in vitro activity for the isolated microorganism(s), or if the antimicrobial agents provided adequate empiric coverage for local community and nosocomial flora in culture-negative shock. The main outcome variable was survival to hospital discharge.

The overall survival-to-hospital discharge was 43.7%, and 80.1% of patients received appropriate empiric antimicrobial therapy. Of those who died, 4.8% did not receive appropriate therapy. Inappropriate antimicrobial regimens caused survival to fall to 10.3% from 52.0% (OR 9.45; 95% CI, 7.74 to 11.54; p<0.0001).

After adjusting for potential confounding variables, the inappropriateness of initial antimicrobial therapy remained strongly associated with risk of death (OR 8.99; 95% CI, 6.60 to 12.23; p<0.0001).

The primary weakness of the study is that it was observational.

Bottom line: The choice of an appropriate empiric antimicrobial agent is a critical determinant of survival in patients with septic shock.

Citation: Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009;136(5):1237-1248.

Reviewed for TH eWire by Sameer Badlani, MD, Stacy S. Banerjee, MD, Alan J. Jung, MD, Elizabeth Marlow, MD, MPP, Valerie G. Press, MD, MPH, Milda R. Saunders, MD, MPH, Nilam J. Soni, MD, Srilaxmi Tumuluri, MD, Section of Hospital Medicine, University of Chicago

For more reviews of HM-related literature, visit our Web site.