SAVANNAH, GA—Patients diagnosed with both anxiety disorder and autism spectrum disorder used almost tenfold more antipsychotic medications, and fewer SSRIs, than those diagnosed with anxiety disorder alone, reported Alya Reeve, MD, at the 19th Annual Meeting of the American Neuropsychiatric Association.

Dr. Reeve’s group determined the effect of autism spectrum disorder on medications prescribed for anxiety disorders. A retrospective review of 218 charts for nine years found that 98 patients (45%) had anxiety disorder; of these, 31 (32%) also had a diagnosis of autism spectrum disorder.

Additional comorbid psychiatric conditions included mood, impulse control, and attention disorders, as well as psychosis. Thirteen percent of those with anxiety disorder and autism spectrum disorder had mood disorder, compared with 51% of those without autism spectrum disorder. Rates for other psychiatric conditions were higher in the autism spectrum disorder group than in the non–autism spectrum disorder group for impulse control disorders (60% vs 46%, respectively) and attention disorders (6% vs 4%, respectively) and were the same for psychosis (13%). Thirty-five percent of those with anxiety disorder and autism spectrum disorder had hypothyroidism versus 23% of those without autism spectrum disorder; and 26% of those with anxiety disorder and autism spectrum disorder had seizures versus 33% of those without autism spectrum disorder. For patients with GERD, the rates were 16% versus 18%, respectively.

“Psychotropic medications and their indication for usage were derived from chart notes and forms,” said Dr. Reeve, an Associate Professor in the Department of Psychiatry at the University of New Mexico Health Sciences Center in Albuquerque. Psychotropic medications used for anxiety included SSRIs, antipsychotics, tricyclic antidepressants, and heterocyclics. Each medication was classified as “current use,” “used > 50% duration of service,” or “ever used.”

Despite similar psychotropic medication prescribing rates, 48% of patients with anxiety disorder and autism spectrum disorder were currently using an SSRI, compared with 70% of those without autism spectrum disorder. Conversely, 1.5% of patients without autism spectrum disorder were using an antipsychotic, compared with 13% of those with autism spectrum disorder.

Psychotropic medications prescribed but not used for anxiety included antipsychotics for psychotic symptoms such as impulse control, aggression, agitation, sleep, or self-injurious behaviors. These medications were used by 84% of patients with anxiety disorder and autism spectrum disorder, compared with 69% of those without autism spectrum disorder. Other psychotropics, such as antiepileptics, anxiolytics, antidepressants, sedatives, and antihypertensives prescribed for impulse control, sleep attention, agitation, aggression, or self-injurious behaviors, were used by more patients with anxiety disorder and autism spectrum disorder than those without (87% vs 63%, respectively). Medications used as needed (eg, for anxiety prior to a dentist visit) or for nonanxiety symptoms (eg, trazodone for sleep) were excluded.

“Patients with autism spectrum disorder used SSRIs less successfully, and antipsychotics more successfully, than those without autism spectrum disorder,” Dr. Reeve concluded. “This may reflect a population with higher behavior challenges compounding anxiety disorder.”

SAVANNAH, GA—Patients diagnosed with both anxiety disorder and autism spectrum disorder used almost tenfold more antipsychotic medications, and fewer SSRIs, than those diagnosed with anxiety disorder alone, reported Alya Reeve, MD, at the 19th Annual Meeting of the American Neuropsychiatric Association.

Dr. Reeve’s group determined the effect of autism spectrum disorder on medications prescribed for anxiety disorders. A retrospective review of 218 charts for nine years found that 98 patients (45%) had anxiety disorder; of these, 31 (32%) also had a diagnosis of autism spectrum disorder.

Additional comorbid psychiatric conditions included mood, impulse control, and attention disorders, as well as psychosis. Thirteen percent of those with anxiety disorder and autism spectrum disorder had mood disorder, compared with 51% of those without autism spectrum disorder. Rates for other psychiatric conditions were higher in the autism spectrum disorder group than in the non–autism spectrum disorder group for impulse control disorders (60% vs 46%, respectively) and attention disorders (6% vs 4%, respectively) and were the same for psychosis (13%). Thirty-five percent of those with anxiety disorder and autism spectrum disorder had hypothyroidism versus 23% of those without autism spectrum disorder; and 26% of those with anxiety disorder and autism spectrum disorder had seizures versus 33% of those without autism spectrum disorder. For patients with GERD, the rates were 16% versus 18%, respectively.

“Psychotropic medications and their indication for usage were derived from chart notes and forms,” said Dr. Reeve, an Associate Professor in the Department of Psychiatry at the University of New Mexico Health Sciences Center in Albuquerque. Psychotropic medications used for anxiety included SSRIs, antipsychotics, tricyclic antidepressants, and heterocyclics. Each medication was classified as “current use,” “used > 50% duration of service,” or “ever used.”

Despite similar psychotropic medication prescribing rates, 48% of patients with anxiety disorder and autism spectrum disorder were currently using an SSRI, compared with 70% of those without autism spectrum disorder. Conversely, 1.5% of patients without autism spectrum disorder were using an antipsychotic, compared with 13% of those with autism spectrum disorder.

Psychotropic medications prescribed but not used for anxiety included antipsychotics for psychotic symptoms such as impulse control, aggression, agitation, sleep, or self-injurious behaviors. These medications were used by 84% of patients with anxiety disorder and autism spectrum disorder, compared with 69% of those without autism spectrum disorder. Other psychotropics, such as antiepileptics, anxiolytics, antidepressants, sedatives, and antihypertensives prescribed for impulse control, sleep attention, agitation, aggression, or self-injurious behaviors, were used by more patients with anxiety disorder and autism spectrum disorder than those without (87% vs 63%, respectively). Medications used as needed (eg, for anxiety prior to a dentist visit) or for nonanxiety symptoms (eg, trazodone for sleep) were excluded.

“Patients with autism spectrum disorder used SSRIs less successfully, and antipsychotics more successfully, than those without autism spectrum disorder,” Dr. Reeve concluded. “This may reflect a population with higher behavior challenges compounding anxiety disorder.”

SAVANNAH, GA—Patients diagnosed with both anxiety disorder and autism spectrum disorder used almost tenfold more antipsychotic medications, and fewer SSRIs, than those diagnosed with anxiety disorder alone, reported Alya Reeve, MD, at the 19th Annual Meeting of the American Neuropsychiatric Association.

Dr. Reeve’s group determined the effect of autism spectrum disorder on medications prescribed for anxiety disorders. A retrospective review of 218 charts for nine years found that 98 patients (45%) had anxiety disorder; of these, 31 (32%) also had a diagnosis of autism spectrum disorder.

Additional comorbid psychiatric conditions included mood, impulse control, and attention disorders, as well as psychosis. Thirteen percent of those with anxiety disorder and autism spectrum disorder had mood disorder, compared with 51% of those without autism spectrum disorder. Rates for other psychiatric conditions were higher in the autism spectrum disorder group than in the non–autism spectrum disorder group for impulse control disorders (60% vs 46%, respectively) and attention disorders (6% vs 4%, respectively) and were the same for psychosis (13%). Thirty-five percent of those with anxiety disorder and autism spectrum disorder had hypothyroidism versus 23% of those without autism spectrum disorder; and 26% of those with anxiety disorder and autism spectrum disorder had seizures versus 33% of those without autism spectrum disorder. For patients with GERD, the rates were 16% versus 18%, respectively.

“Psychotropic medications and their indication for usage were derived from chart notes and forms,” said Dr. Reeve, an Associate Professor in the Department of Psychiatry at the University of New Mexico Health Sciences Center in Albuquerque. Psychotropic medications used for anxiety included SSRIs, antipsychotics, tricyclic antidepressants, and heterocyclics. Each medication was classified as “current use,” “used > 50% duration of service,” or “ever used.”

Despite similar psychotropic medication prescribing rates, 48% of patients with anxiety disorder and autism spectrum disorder were currently using an SSRI, compared with 70% of those without autism spectrum disorder. Conversely, 1.5% of patients without autism spectrum disorder were using an antipsychotic, compared with 13% of those with autism spectrum disorder.

Psychotropic medications prescribed but not used for anxiety included antipsychotics for psychotic symptoms such as impulse control, aggression, agitation, sleep, or self-injurious behaviors. These medications were used by 84% of patients with anxiety disorder and autism spectrum disorder, compared with 69% of those without autism spectrum disorder. Other psychotropics, such as antiepileptics, anxiolytics, antidepressants, sedatives, and antihypertensives prescribed for impulse control, sleep attention, agitation, aggression, or self-injurious behaviors, were used by more patients with anxiety disorder and autism spectrum disorder than those without (87% vs 63%, respectively). Medications used as needed (eg, for anxiety prior to a dentist visit) or for nonanxiety symptoms (eg, trazodone for sleep) were excluded.

“Patients with autism spectrum disorder used SSRIs less successfully, and antipsychotics more successfully, than those without autism spectrum disorder,” Dr. Reeve concluded. “This may reflect a population with higher behavior challenges compounding anxiety disorder.”

ILLUSTRATIVE CASE

A 52-year-old man presents to your office for follow-up 2 days after he was seen in the ED and diagnosed with a distal ureteral calculus, his first. His pain is reasonably well controlled, but he has not yet passed the stone. Is there anything you can do to help him pass the stone?

Yes. Patients who are candidates for observation should be offered a trial of “medical expulsive therapy” using an α-antagonist or a calcium channel blocker. Until now, medical therapy for kidney stones consisted of pain relief only.

The ordeal of a first stone is all too common—the lifetime prevalence of kidney stones is 5.2%—and the probability of recurrence is about 50%.^2,3

NHANES data show increasing prevalence between the periods 1976-1980 and 1988-1996.³ One fifth to one third of kidney stones require surgical intervention.⁴ In a cohort of 245 patients presenting to an ED in Canada, 50 (20%) required further procedures, including lithotripsy. Stones ≥ 6 mm in size were much less likely to pass (OR=10.7, 95% CI 4.6-24.8).⁵ The burden on the healthcare system is significant; there are approximately 2 million out-patient visits annually for this problem, and diagnosis and treatment costs about $2 billion annually.⁶

Watch and wait

The standard approach is a period of watchful waiting and pain control, with urgent urological referral for patients with evidence of upper urinary tract infection, high grade obstruction, inadequate pain or nausea control, or insufficient renal reserve.^2,4 Most patients treated with watchful waiting pass their stone within 4 weeks. Any stones that don’t pass within 8 weeks are unlikely to pass spontaneously.^2,7

Medical therapy has been proposed for decades

Medications that relax ureteral smooth muscle to help pass ureteral stones have been proposed for decades.⁸ Prior to 2000, however, only 1 randomized controlled trial (RCT) of medical therapy for ureteral stones had been published.⁹ A subsequent meta-analysis found 9 studies and showed that medical therapy did increase the chances that a stone would pass.¹⁰ The Singh meta-analysis found 13 subsequently published studies and nearly tripled the number of patients evaluated.

STUDY SUMMARY: A well-done meta-analysis

This meta-analysis is based on 16 studies of α-antagonists (most used tamsulosin) and 9 studies of nifedipine, a calcium channel blocker.¹ The studies were identified by a comprehensive search strategy that included Medline, EMBASE, and the Cochrane Controlled Trials Register from January 1980 to January 2007. The authors included all randomized trials or controlled clinical trials of medical therapy for adults with acute ureteral colic.

The authors assessed the studies for quality using the Jadad scale, a validated scale of study quality. Higher scores represent better quality, including better documentation of randomization, blinding, and follow-up. The authors specified their planned sensitivity analyses, and used the random effects model to synthesize the results, which tends to provide a more conservative estimate of the effect.

In other words, this was a very well done meta-analysis.

Twenty-two studies met the inclusion criteria: 13 of α-antagonists, 6 of nifedipine, and 3 of both. In 13 of the 16 studies of α-antagonists, tamsulosin (Flomax) was the study drug. The results from the terazosin (Hytrin) and doxazosin (Cardura) studies were included with the tamsulosin studies. The Jadad quality scores of the 22 studies were fairly low, with a median of 2 (range of 0 to 3) on the 5-point scale. The most common deduction was because the study was not double-blinded.

Medical therapy makes sense

“Therapy using either α-antagonists or calcium channel blockers augments the stone expulsion rate compared to standard therapy for moderately sized distal ureteral stones.” ¹ CT showing distal ureteral stone

 

α-Antagonist studies

These 16 studies enrolled 1235 patients with distal ureteral stones. Mean stone size ranged from 4.3 to 7.8 mm. α-Antagonists improved the stone expulsion rate (RR= 1.59, 95% CI 1.44-1.75; NNT=3.3).

The mean time to expulsion of the stone ranged from 2.7 to 14.2 days and duration of therapy ranged from 1 to 7 weeks. In the 9 trials that reported the time to stone expulsion, the stone came out between 2 and 6 days earlier than the control groups.

Adverse effects were reported in 4% of patients receiving the active medication; most were mild.

Nifedipine studies

There were 686 patients in the 9 trials of nifedipine. The mean stone size was 3.9 to 12.8 mm. Some studies included stones in the more proximal as well as the distal ureter.

Nifedipine treatment increased the rate of stone expulsion (RR=1.5, 95% CI 1.34-1.68; NNT=3.9). Time to stone expulsion was shorter in 7 of the 9 studies.

Adverse effects were reported in 15% of the patients. Most of these were mild— nausea, vomiting, asthenia, and dyspepsia.

WHAT’S NEW: Strong evidence for use of medical therapy

The new findings from the Singh meta-analysis reviewed in this PURL supports physicians who have already adopted this practice and should encourage usage by those who have not yet done so.

Inpatients in academic medical centers

There is a growing trend to use tamsulosin to facilitate passage of ureteral stones. The University Health System Consortium (www.uhc.org) has complete clinical data on inpatients with ureteral stones, from 64 academic medical centers and teaching hospitals, between 2003 and 2007. We used this database to analyze trends in the use of tamsulosin in 4300 inpatients with ureteral stones (ICD 9 code 5921).

In 2003, only 3.3% of patients with a discharge diagnosis of ureteral stone received tamsulosin. In 2007, 34.1% of patients with ureteral stones discharged from these hospitals received tamsulosin, with similar rates of use when stratified by the specialty of the attending physician at discharge (family medicine, emergency medicine, internal medicine, urology) (FIGURE 1). We noted a wide range in the rate of adoption of this practice among academic medical centers: 48% in the centers with the highest rate of usage and 4.4% in the centers with the lowest rate.

FIGURE 1
% of inpatients in academic medical centers who received tamsulosin for ureteral stones, by year

Source: Unpublished data from the University Health System Consortium

Outpatients from a sample of US practices

The use of tamsulosin or nifedipine in outpatient practice was infrequent even 2 or 3 years ago. We used the National Ambulatory Medical Care Survey data (www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm) from 2004 and 2005 (the most recent available), which provides a sample of all US outpatient practices. Only 7% of an estimated 1,345,000 patients diagnosed with ureteral stones were prescribed either tamsulosin or nifedipine, and urologists cared for most of those.

These unpublished data show that physicians in academic medical centers are increasingly adopting the practice of using tamsulosin or nifedipine for expulsion of ureteral stones, that urologists appear to be the first to begin using these medications in outpatients several years ago, and that this practice is being adopted actively in selected academic medical centers.

 

CAVEATS: Is either drug better? Too little data to tell

Our conclusion is that the strengths of this meta-analysis outweigh the weaknesses, the findings across studies are consistent, and the use of smooth-muscle relaxants for this indication makes sense from a mechanistic point of view.

The quality of a meta-analysis is only as good as the quality of the included studies, and, in this case, the overall quality of studies was not uniformly high. Median Jadad score, a summary measure of study quality, was 2, and the highest score was 3 (of a maximum of 5). The most common problem was lack of blinding, which can be critical in studies with subjective outcomes such as pain. We doubt that the lack of blinding led to any significant misclassification of outcome in this study, however.

Patients either passed the stone or they didn’t, or had a surgical intervention or not. It is reassuring that, when the best quality studies (Jadad score= 3) were analyzed separately, the results were equally good.

There have not been sufficient head-to-head trials to know if one is better than the other. We prefer α-antagonists because of the lower apparent side-effect profile. Our analysis of the UHC data shows that most of the physicians who are using medical therapy are using tamsulosin primarily for this diagnosis.

The majority of the patients in the studies included in the meta-analysis had been referred to a urologist. This raises the possibility that this treatment may not be as effective in patients with less severe symptoms for whom urological consultation is not necessary.

CHALLENGES TO IMPLEMENTATION: This change should be easy to put into practice

Tamsulosin is the best studied of the drugs, but also the most expensive. Based on the estimated number need to treat (NNT) of between 3 and 4 to prevent a surgical intervention and an estimated cost of around $90 for 1 month (www. drugstore.com, February 16, 2008), tamsulosin seems like a good investment to avoid surgical intervention.

The evidence for the other α-antagonists is consistent with that of tamsulosin, but there are fewer data, so it is not clear that the other agents will work as well.

Many people with renal colic are diagnosed and treated in the emergency department; they may not see their family physician until some time after the stone is diagnosed. It is unclear what effect this delay might have on medication effectiveness.

Neither tamsulosin nor nifedipine have an FDA indication for ureterolithiasis. However, they are prescribed commonly, and most physicians are familiar with their use and adverse-effect profiles.

Drugs used in the meta-analysis studies

α-Antagonists

Tamsulosin (Flomax)
Terazosin (Hytrin)
Doxazosin (Cardura)

Calcium channel blockers

Nifedipine (Adalat, Nifedical, Procardia)

Acknowledgement

We acknowledge Sofia Medvedev, PhD of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the UHC Clinical Database and the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 52-year-old man presents to your office for follow-up 2 days after he was seen in the ED and diagnosed with a distal ureteral calculus, his first. His pain is reasonably well controlled, but he has not yet passed the stone. Is there anything you can do to help him pass the stone?

Yes. Patients who are candidates for observation should be offered a trial of “medical expulsive therapy” using an α-antagonist or a calcium channel blocker. Until now, medical therapy for kidney stones consisted of pain relief only.

The ordeal of a first stone is all too common—the lifetime prevalence of kidney stones is 5.2%—and the probability of recurrence is about 50%.^2,3

NHANES data show increasing prevalence between the periods 1976-1980 and 1988-1996.³ One fifth to one third of kidney stones require surgical intervention.⁴ In a cohort of 245 patients presenting to an ED in Canada, 50 (20%) required further procedures, including lithotripsy. Stones ≥ 6 mm in size were much less likely to pass (OR=10.7, 95% CI 4.6-24.8).⁵ The burden on the healthcare system is significant; there are approximately 2 million out-patient visits annually for this problem, and diagnosis and treatment costs about $2 billion annually.⁶

Watch and wait

The standard approach is a period of watchful waiting and pain control, with urgent urological referral for patients with evidence of upper urinary tract infection, high grade obstruction, inadequate pain or nausea control, or insufficient renal reserve.^2,4 Most patients treated with watchful waiting pass their stone within 4 weeks. Any stones that don’t pass within 8 weeks are unlikely to pass spontaneously.^2,7

Medical therapy has been proposed for decades

Medications that relax ureteral smooth muscle to help pass ureteral stones have been proposed for decades.⁸ Prior to 2000, however, only 1 randomized controlled trial (RCT) of medical therapy for ureteral stones had been published.⁹ A subsequent meta-analysis found 9 studies and showed that medical therapy did increase the chances that a stone would pass.¹⁰ The Singh meta-analysis found 13 subsequently published studies and nearly tripled the number of patients evaluated.

STUDY SUMMARY: A well-done meta-analysis

This meta-analysis is based on 16 studies of α-antagonists (most used tamsulosin) and 9 studies of nifedipine, a calcium channel blocker.¹ The studies were identified by a comprehensive search strategy that included Medline, EMBASE, and the Cochrane Controlled Trials Register from January 1980 to January 2007. The authors included all randomized trials or controlled clinical trials of medical therapy for adults with acute ureteral colic.

The authors assessed the studies for quality using the Jadad scale, a validated scale of study quality. Higher scores represent better quality, including better documentation of randomization, blinding, and follow-up. The authors specified their planned sensitivity analyses, and used the random effects model to synthesize the results, which tends to provide a more conservative estimate of the effect.

In other words, this was a very well done meta-analysis.

Twenty-two studies met the inclusion criteria: 13 of α-antagonists, 6 of nifedipine, and 3 of both. In 13 of the 16 studies of α-antagonists, tamsulosin (Flomax) was the study drug. The results from the terazosin (Hytrin) and doxazosin (Cardura) studies were included with the tamsulosin studies. The Jadad quality scores of the 22 studies were fairly low, with a median of 2 (range of 0 to 3) on the 5-point scale. The most common deduction was because the study was not double-blinded.

Medical therapy makes sense

“Therapy using either α-antagonists or calcium channel blockers augments the stone expulsion rate compared to standard therapy for moderately sized distal ureteral stones.” ¹ CT showing distal ureteral stone

 

α-Antagonist studies

These 16 studies enrolled 1235 patients with distal ureteral stones. Mean stone size ranged from 4.3 to 7.8 mm. α-Antagonists improved the stone expulsion rate (RR= 1.59, 95% CI 1.44-1.75; NNT=3.3).

The mean time to expulsion of the stone ranged from 2.7 to 14.2 days and duration of therapy ranged from 1 to 7 weeks. In the 9 trials that reported the time to stone expulsion, the stone came out between 2 and 6 days earlier than the control groups.

Adverse effects were reported in 4% of patients receiving the active medication; most were mild.

Nifedipine studies

There were 686 patients in the 9 trials of nifedipine. The mean stone size was 3.9 to 12.8 mm. Some studies included stones in the more proximal as well as the distal ureter.

Nifedipine treatment increased the rate of stone expulsion (RR=1.5, 95% CI 1.34-1.68; NNT=3.9). Time to stone expulsion was shorter in 7 of the 9 studies.

Adverse effects were reported in 15% of the patients. Most of these were mild— nausea, vomiting, asthenia, and dyspepsia.

WHAT’S NEW: Strong evidence for use of medical therapy

The new findings from the Singh meta-analysis reviewed in this PURL supports physicians who have already adopted this practice and should encourage usage by those who have not yet done so.

Inpatients in academic medical centers

There is a growing trend to use tamsulosin to facilitate passage of ureteral stones. The University Health System Consortium (www.uhc.org) has complete clinical data on inpatients with ureteral stones, from 64 academic medical centers and teaching hospitals, between 2003 and 2007. We used this database to analyze trends in the use of tamsulosin in 4300 inpatients with ureteral stones (ICD 9 code 5921).

In 2003, only 3.3% of patients with a discharge diagnosis of ureteral stone received tamsulosin. In 2007, 34.1% of patients with ureteral stones discharged from these hospitals received tamsulosin, with similar rates of use when stratified by the specialty of the attending physician at discharge (family medicine, emergency medicine, internal medicine, urology) (FIGURE 1). We noted a wide range in the rate of adoption of this practice among academic medical centers: 48% in the centers with the highest rate of usage and 4.4% in the centers with the lowest rate.

FIGURE 1
% of inpatients in academic medical centers who received tamsulosin for ureteral stones, by year

Source: Unpublished data from the University Health System Consortium

Outpatients from a sample of US practices

The use of tamsulosin or nifedipine in outpatient practice was infrequent even 2 or 3 years ago. We used the National Ambulatory Medical Care Survey data (www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm) from 2004 and 2005 (the most recent available), which provides a sample of all US outpatient practices. Only 7% of an estimated 1,345,000 patients diagnosed with ureteral stones were prescribed either tamsulosin or nifedipine, and urologists cared for most of those.

These unpublished data show that physicians in academic medical centers are increasingly adopting the practice of using tamsulosin or nifedipine for expulsion of ureteral stones, that urologists appear to be the first to begin using these medications in outpatients several years ago, and that this practice is being adopted actively in selected academic medical centers.

 

CAVEATS: Is either drug better? Too little data to tell

Our conclusion is that the strengths of this meta-analysis outweigh the weaknesses, the findings across studies are consistent, and the use of smooth-muscle relaxants for this indication makes sense from a mechanistic point of view.

The quality of a meta-analysis is only as good as the quality of the included studies, and, in this case, the overall quality of studies was not uniformly high. Median Jadad score, a summary measure of study quality, was 2, and the highest score was 3 (of a maximum of 5). The most common problem was lack of blinding, which can be critical in studies with subjective outcomes such as pain. We doubt that the lack of blinding led to any significant misclassification of outcome in this study, however.

Patients either passed the stone or they didn’t, or had a surgical intervention or not. It is reassuring that, when the best quality studies (Jadad score= 3) were analyzed separately, the results were equally good.

There have not been sufficient head-to-head trials to know if one is better than the other. We prefer α-antagonists because of the lower apparent side-effect profile. Our analysis of the UHC data shows that most of the physicians who are using medical therapy are using tamsulosin primarily for this diagnosis.

The majority of the patients in the studies included in the meta-analysis had been referred to a urologist. This raises the possibility that this treatment may not be as effective in patients with less severe symptoms for whom urological consultation is not necessary.

CHALLENGES TO IMPLEMENTATION: This change should be easy to put into practice

Tamsulosin is the best studied of the drugs, but also the most expensive. Based on the estimated number need to treat (NNT) of between 3 and 4 to prevent a surgical intervention and an estimated cost of around $90 for 1 month (www. drugstore.com, February 16, 2008), tamsulosin seems like a good investment to avoid surgical intervention.

The evidence for the other α-antagonists is consistent with that of tamsulosin, but there are fewer data, so it is not clear that the other agents will work as well.

Many people with renal colic are diagnosed and treated in the emergency department; they may not see their family physician until some time after the stone is diagnosed. It is unclear what effect this delay might have on medication effectiveness.

Neither tamsulosin nor nifedipine have an FDA indication for ureterolithiasis. However, they are prescribed commonly, and most physicians are familiar with their use and adverse-effect profiles.

Drugs used in the meta-analysis studies

α-Antagonists

Tamsulosin (Flomax)
Terazosin (Hytrin)
Doxazosin (Cardura)

Calcium channel blockers

Nifedipine (Adalat, Nifedical, Procardia)

Acknowledgement

We acknowledge Sofia Medvedev, PhD of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the UHC Clinical Database and the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 52-year-old man presents to your office for follow-up 2 days after he was seen in the ED and diagnosed with a distal ureteral calculus, his first. His pain is reasonably well controlled, but he has not yet passed the stone. Is there anything you can do to help him pass the stone?

Yes. Patients who are candidates for observation should be offered a trial of “medical expulsive therapy” using an α-antagonist or a calcium channel blocker. Until now, medical therapy for kidney stones consisted of pain relief only.

The ordeal of a first stone is all too common—the lifetime prevalence of kidney stones is 5.2%—and the probability of recurrence is about 50%.^2,3

NHANES data show increasing prevalence between the periods 1976-1980 and 1988-1996.³ One fifth to one third of kidney stones require surgical intervention.⁴ In a cohort of 245 patients presenting to an ED in Canada, 50 (20%) required further procedures, including lithotripsy. Stones ≥ 6 mm in size were much less likely to pass (OR=10.7, 95% CI 4.6-24.8).⁵ The burden on the healthcare system is significant; there are approximately 2 million out-patient visits annually for this problem, and diagnosis and treatment costs about $2 billion annually.⁶

Watch and wait

The standard approach is a period of watchful waiting and pain control, with urgent urological referral for patients with evidence of upper urinary tract infection, high grade obstruction, inadequate pain or nausea control, or insufficient renal reserve.^2,4 Most patients treated with watchful waiting pass their stone within 4 weeks. Any stones that don’t pass within 8 weeks are unlikely to pass spontaneously.^2,7

Medical therapy has been proposed for decades

Medications that relax ureteral smooth muscle to help pass ureteral stones have been proposed for decades.⁸ Prior to 2000, however, only 1 randomized controlled trial (RCT) of medical therapy for ureteral stones had been published.⁹ A subsequent meta-analysis found 9 studies and showed that medical therapy did increase the chances that a stone would pass.¹⁰ The Singh meta-analysis found 13 subsequently published studies and nearly tripled the number of patients evaluated.

STUDY SUMMARY: A well-done meta-analysis

This meta-analysis is based on 16 studies of α-antagonists (most used tamsulosin) and 9 studies of nifedipine, a calcium channel blocker.¹ The studies were identified by a comprehensive search strategy that included Medline, EMBASE, and the Cochrane Controlled Trials Register from January 1980 to January 2007. The authors included all randomized trials or controlled clinical trials of medical therapy for adults with acute ureteral colic.

The authors assessed the studies for quality using the Jadad scale, a validated scale of study quality. Higher scores represent better quality, including better documentation of randomization, blinding, and follow-up. The authors specified their planned sensitivity analyses, and used the random effects model to synthesize the results, which tends to provide a more conservative estimate of the effect.

In other words, this was a very well done meta-analysis.

Twenty-two studies met the inclusion criteria: 13 of α-antagonists, 6 of nifedipine, and 3 of both. In 13 of the 16 studies of α-antagonists, tamsulosin (Flomax) was the study drug. The results from the terazosin (Hytrin) and doxazosin (Cardura) studies were included with the tamsulosin studies. The Jadad quality scores of the 22 studies were fairly low, with a median of 2 (range of 0 to 3) on the 5-point scale. The most common deduction was because the study was not double-blinded.

Medical therapy makes sense

“Therapy using either α-antagonists or calcium channel blockers augments the stone expulsion rate compared to standard therapy for moderately sized distal ureteral stones.” ¹ CT showing distal ureteral stone

 

α-Antagonist studies

These 16 studies enrolled 1235 patients with distal ureteral stones. Mean stone size ranged from 4.3 to 7.8 mm. α-Antagonists improved the stone expulsion rate (RR= 1.59, 95% CI 1.44-1.75; NNT=3.3).

The mean time to expulsion of the stone ranged from 2.7 to 14.2 days and duration of therapy ranged from 1 to 7 weeks. In the 9 trials that reported the time to stone expulsion, the stone came out between 2 and 6 days earlier than the control groups.

Adverse effects were reported in 4% of patients receiving the active medication; most were mild.

Nifedipine studies

There were 686 patients in the 9 trials of nifedipine. The mean stone size was 3.9 to 12.8 mm. Some studies included stones in the more proximal as well as the distal ureter.

Nifedipine treatment increased the rate of stone expulsion (RR=1.5, 95% CI 1.34-1.68; NNT=3.9). Time to stone expulsion was shorter in 7 of the 9 studies.

Adverse effects were reported in 15% of the patients. Most of these were mild— nausea, vomiting, asthenia, and dyspepsia.

WHAT’S NEW: Strong evidence for use of medical therapy

The new findings from the Singh meta-analysis reviewed in this PURL supports physicians who have already adopted this practice and should encourage usage by those who have not yet done so.

Inpatients in academic medical centers

There is a growing trend to use tamsulosin to facilitate passage of ureteral stones. The University Health System Consortium (www.uhc.org) has complete clinical data on inpatients with ureteral stones, from 64 academic medical centers and teaching hospitals, between 2003 and 2007. We used this database to analyze trends in the use of tamsulosin in 4300 inpatients with ureteral stones (ICD 9 code 5921).

In 2003, only 3.3% of patients with a discharge diagnosis of ureteral stone received tamsulosin. In 2007, 34.1% of patients with ureteral stones discharged from these hospitals received tamsulosin, with similar rates of use when stratified by the specialty of the attending physician at discharge (family medicine, emergency medicine, internal medicine, urology) (FIGURE 1). We noted a wide range in the rate of adoption of this practice among academic medical centers: 48% in the centers with the highest rate of usage and 4.4% in the centers with the lowest rate.

FIGURE 1
% of inpatients in academic medical centers who received tamsulosin for ureteral stones, by year

Source: Unpublished data from the University Health System Consortium

Outpatients from a sample of US practices

The use of tamsulosin or nifedipine in outpatient practice was infrequent even 2 or 3 years ago. We used the National Ambulatory Medical Care Survey data (www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm) from 2004 and 2005 (the most recent available), which provides a sample of all US outpatient practices. Only 7% of an estimated 1,345,000 patients diagnosed with ureteral stones were prescribed either tamsulosin or nifedipine, and urologists cared for most of those.

These unpublished data show that physicians in academic medical centers are increasingly adopting the practice of using tamsulosin or nifedipine for expulsion of ureteral stones, that urologists appear to be the first to begin using these medications in outpatients several years ago, and that this practice is being adopted actively in selected academic medical centers.

 

CAVEATS: Is either drug better? Too little data to tell

Our conclusion is that the strengths of this meta-analysis outweigh the weaknesses, the findings across studies are consistent, and the use of smooth-muscle relaxants for this indication makes sense from a mechanistic point of view.

The quality of a meta-analysis is only as good as the quality of the included studies, and, in this case, the overall quality of studies was not uniformly high. Median Jadad score, a summary measure of study quality, was 2, and the highest score was 3 (of a maximum of 5). The most common problem was lack of blinding, which can be critical in studies with subjective outcomes such as pain. We doubt that the lack of blinding led to any significant misclassification of outcome in this study, however.

Patients either passed the stone or they didn’t, or had a surgical intervention or not. It is reassuring that, when the best quality studies (Jadad score= 3) were analyzed separately, the results were equally good.

There have not been sufficient head-to-head trials to know if one is better than the other. We prefer α-antagonists because of the lower apparent side-effect profile. Our analysis of the UHC data shows that most of the physicians who are using medical therapy are using tamsulosin primarily for this diagnosis.

The majority of the patients in the studies included in the meta-analysis had been referred to a urologist. This raises the possibility that this treatment may not be as effective in patients with less severe symptoms for whom urological consultation is not necessary.

CHALLENGES TO IMPLEMENTATION: This change should be easy to put into practice

Tamsulosin is the best studied of the drugs, but also the most expensive. Based on the estimated number need to treat (NNT) of between 3 and 4 to prevent a surgical intervention and an estimated cost of around $90 for 1 month (www. drugstore.com, February 16, 2008), tamsulosin seems like a good investment to avoid surgical intervention.

The evidence for the other α-antagonists is consistent with that of tamsulosin, but there are fewer data, so it is not clear that the other agents will work as well.

Many people with renal colic are diagnosed and treated in the emergency department; they may not see their family physician until some time after the stone is diagnosed. It is unclear what effect this delay might have on medication effectiveness.

Neither tamsulosin nor nifedipine have an FDA indication for ureterolithiasis. However, they are prescribed commonly, and most physicians are familiar with their use and adverse-effect profiles.

Drugs used in the meta-analysis studies

α-Antagonists

Tamsulosin (Flomax)
Terazosin (Hytrin)
Doxazosin (Cardura)

Calcium channel blockers

Nifedipine (Adalat, Nifedical, Procardia)

Acknowledgement

We acknowledge Sofia Medvedev, PhD of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the UHC Clinical Database and the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

 

Measles is still a threat. Endemic transmission of measles no longer occurs in the United States (or any of the Americas), yet this highly infectious disease is still a threat from importation by visitors from other countries and from US residents who have traveled abroad. Two recent outbreaks (described at left) illustrate these risks.

 

 

3 infants too young to be vaccinated contracted measles in their doctor’s office in San Diego, in January 2008. (An infant with measles rash [above] is for illustration only, and does not depict any of the 3.)

What the CDC discovered

The 2 outbreaks of import-linked measles brought home—literally—the sobering facts about vulnerability among US residents. The CDC report ^1,2 of its investigation observed:

US travelers can be exposed almost anywhere, developed countries included. The California outbreak started with a visit to Switzerland.

Measles spreads rapidly in susceptible subgroups, unless effective control strategies are used. In California, on 2 consecutive days, 5 school children and 4 children in a doctor’s office were infected; all were unvaccinated.

People not considered at risk can contract measles. Although 2 doses of vaccine are 99% effective, vaccinated individuals, such as the college students, can contract measles. Likewise, people born before 1957 may not be immune, in contrast to the general definition of immunity (see Measles Basics. Case in point: the airline passenger, born in 1954.

Disease can be severe. The 40-year-old salesperson (no documented vaccination) was hospitalized with seizure, 105ºF fever, and pneumonia. One of the infants was hospitalized due to dehydration.

People in routine contact with travelers entering the United States can be exposed to measles—like the airline worker.

 

Take-home lessons for family physicians

Include measles in the differential diagnosis of patients who have fever and rash, especially if they have traveled to another country within the past 3 to 4 weeks. Any patient who meets the definition of measles (fever 101ºF or higher; rash; and at least 1 of the 3 Cs—cough, coryza, conjunctivitis) should be immediately reported to the local health department. The health department will provide instructions for collecting laboratory samples for confirmation; instructions on patient isolation; and assistance with notification and disease control measures for exposed individuals.

Immunize patients and staff. These recurring cases of imported measles underscore the importance of maintaining a high level of immunity. Outbreaks can happen even where immunity is 90% to 95%. When vaccination rates dip below 90%, sustained outbreaks can occur.⁶

Ensure that staff and patients are all immunized against vaccine-preventable diseases, and inform concerned parents about the safety and effectiveness of vaccines. Parents who refuse to have their children vaccinated place their children at risk and contribute to higher community risk. Communities that have higher rates of non-adherence to vaccine recommendations are more likely to have outbreaks.^7,8

 

Use strict infection control in the office. The recent outbreak in California where 4 children were infected in their physician’s office reinforces the need for strict infection-control practices. Do not allow patients with rash and fever to remain in a common waiting area. Move them to an examination room, preferably an airborne infection isolation room. Keep the door to the examination room closed, and be sure that all health care personnel who come in contact with such patients are immune. Do not use triage rooms for 2 hours after the patient suspected of having measles leaves. Do not send these patients to other health care facilities, such as laboratories, unless infection control measures can be adhered to at those locations. Guidelines on infection control practices in health care settings are available.^9,10

Quick response

Quick control of these outbreaks shows the value of the public health infrastructure. Disease surveillance and outbreak response is vital to the public health system, and its value is frequently under-appreciated by physicians and the public.

 

 

Measles is still a threat. Endemic transmission of measles no longer occurs in the United States (or any of the Americas), yet this highly infectious disease is still a threat from importation by visitors from other countries and from US residents who have traveled abroad. Two recent outbreaks (described at left) illustrate these risks.

 

 

3 infants too young to be vaccinated contracted measles in their doctor’s office in San Diego, in January 2008. (An infant with measles rash [above] is for illustration only, and does not depict any of the 3.)

What the CDC discovered

The 2 outbreaks of import-linked measles brought home—literally—the sobering facts about vulnerability among US residents. The CDC report ^1,2 of its investigation observed:

US travelers can be exposed almost anywhere, developed countries included. The California outbreak started with a visit to Switzerland.

Measles spreads rapidly in susceptible subgroups, unless effective control strategies are used. In California, on 2 consecutive days, 5 school children and 4 children in a doctor’s office were infected; all were unvaccinated.

People not considered at risk can contract measles. Although 2 doses of vaccine are 99% effective, vaccinated individuals, such as the college students, can contract measles. Likewise, people born before 1957 may not be immune, in contrast to the general definition of immunity (see Measles Basics. Case in point: the airline passenger, born in 1954.

Disease can be severe. The 40-year-old salesperson (no documented vaccination) was hospitalized with seizure, 105ºF fever, and pneumonia. One of the infants was hospitalized due to dehydration.

People in routine contact with travelers entering the United States can be exposed to measles—like the airline worker.

 

Take-home lessons for family physicians

Include measles in the differential diagnosis of patients who have fever and rash, especially if they have traveled to another country within the past 3 to 4 weeks. Any patient who meets the definition of measles (fever 101ºF or higher; rash; and at least 1 of the 3 Cs—cough, coryza, conjunctivitis) should be immediately reported to the local health department. The health department will provide instructions for collecting laboratory samples for confirmation; instructions on patient isolation; and assistance with notification and disease control measures for exposed individuals.

Immunize patients and staff. These recurring cases of imported measles underscore the importance of maintaining a high level of immunity. Outbreaks can happen even where immunity is 90% to 95%. When vaccination rates dip below 90%, sustained outbreaks can occur.⁶

Ensure that staff and patients are all immunized against vaccine-preventable diseases, and inform concerned parents about the safety and effectiveness of vaccines. Parents who refuse to have their children vaccinated place their children at risk and contribute to higher community risk. Communities that have higher rates of non-adherence to vaccine recommendations are more likely to have outbreaks.^7,8

 

Use strict infection control in the office. The recent outbreak in California where 4 children were infected in their physician’s office reinforces the need for strict infection-control practices. Do not allow patients with rash and fever to remain in a common waiting area. Move them to an examination room, preferably an airborne infection isolation room. Keep the door to the examination room closed, and be sure that all health care personnel who come in contact with such patients are immune. Do not use triage rooms for 2 hours after the patient suspected of having measles leaves. Do not send these patients to other health care facilities, such as laboratories, unless infection control measures can be adhered to at those locations. Guidelines on infection control practices in health care settings are available.^9,10

Quick response

Quick control of these outbreaks shows the value of the public health infrastructure. Disease surveillance and outbreak response is vital to the public health system, and its value is frequently under-appreciated by physicians and the public.

 

 

Measles is still a threat. Endemic transmission of measles no longer occurs in the United States (or any of the Americas), yet this highly infectious disease is still a threat from importation by visitors from other countries and from US residents who have traveled abroad. Two recent outbreaks (described at left) illustrate these risks.

 

 

3 infants too young to be vaccinated contracted measles in their doctor’s office in San Diego, in January 2008. (An infant with measles rash [above] is for illustration only, and does not depict any of the 3.)

What the CDC discovered

The 2 outbreaks of import-linked measles brought home—literally—the sobering facts about vulnerability among US residents. The CDC report ^1,2 of its investigation observed:

US travelers can be exposed almost anywhere, developed countries included. The California outbreak started with a visit to Switzerland.

Measles spreads rapidly in susceptible subgroups, unless effective control strategies are used. In California, on 2 consecutive days, 5 school children and 4 children in a doctor’s office were infected; all were unvaccinated.

People not considered at risk can contract measles. Although 2 doses of vaccine are 99% effective, vaccinated individuals, such as the college students, can contract measles. Likewise, people born before 1957 may not be immune, in contrast to the general definition of immunity (see Measles Basics. Case in point: the airline passenger, born in 1954.

Disease can be severe. The 40-year-old salesperson (no documented vaccination) was hospitalized with seizure, 105ºF fever, and pneumonia. One of the infants was hospitalized due to dehydration.

People in routine contact with travelers entering the United States can be exposed to measles—like the airline worker.

 

Take-home lessons for family physicians

Include measles in the differential diagnosis of patients who have fever and rash, especially if they have traveled to another country within the past 3 to 4 weeks. Any patient who meets the definition of measles (fever 101ºF or higher; rash; and at least 1 of the 3 Cs—cough, coryza, conjunctivitis) should be immediately reported to the local health department. The health department will provide instructions for collecting laboratory samples for confirmation; instructions on patient isolation; and assistance with notification and disease control measures for exposed individuals.

Immunize patients and staff. These recurring cases of imported measles underscore the importance of maintaining a high level of immunity. Outbreaks can happen even where immunity is 90% to 95%. When vaccination rates dip below 90%, sustained outbreaks can occur.⁶

Ensure that staff and patients are all immunized against vaccine-preventable diseases, and inform concerned parents about the safety and effectiveness of vaccines. Parents who refuse to have their children vaccinated place their children at risk and contribute to higher community risk. Communities that have higher rates of non-adherence to vaccine recommendations are more likely to have outbreaks.^7,8

 

Use strict infection control in the office. The recent outbreak in California where 4 children were infected in their physician’s office reinforces the need for strict infection-control practices. Do not allow patients with rash and fever to remain in a common waiting area. Move them to an examination room, preferably an airborne infection isolation room. Keep the door to the examination room closed, and be sure that all health care personnel who come in contact with such patients are immune. Do not use triage rooms for 2 hours after the patient suspected of having measles leaves. Do not send these patients to other health care facilities, such as laboratories, unless infection control measures can be adhered to at those locations. Guidelines on infection control practices in health care settings are available.^9,10

Quick response

Quick control of these outbreaks shows the value of the public health infrastructure. Disease surveillance and outbreak response is vital to the public health system, and its value is frequently under-appreciated by physicians and the public.

 

We give you facts of an actual malpractice case. Submit your verdict below and see how your colleagues voted.

Did the patient know the risks of risperidone?

THE PATIENT. A 53-year-old woman hospitalized for depression and suicidal thoughts was prescribed risperidone.

CASE FACTS. The patient developed excessive mouth and tongue movement—including pursed lips, protruding tongue, and biting the inside of her mouth—and uncontrollable urges to move her extremities. She was diagnosed with probable tardive dyskinesia (TD), and risperidone was tapered and discontinued.

THE PATIENT’S CLAIM. The psychiatrist failed to adequately monitor her and recognize early symptoms of TD and did not tell the patient to look for signs of TD.

THE DOCTOR’S DEFENSE. None

Submit your verdict and find out how the court ruled. Click on “Have more to say about this topic?” to comment.

We give you facts of an actual malpractice case. Submit your verdict below and see how your colleagues voted.

Did the patient know the risks of risperidone?

THE PATIENT. A 53-year-old woman hospitalized for depression and suicidal thoughts was prescribed risperidone.

CASE FACTS. The patient developed excessive mouth and tongue movement—including pursed lips, protruding tongue, and biting the inside of her mouth—and uncontrollable urges to move her extremities. She was diagnosed with probable tardive dyskinesia (TD), and risperidone was tapered and discontinued.

THE PATIENT’S CLAIM. The psychiatrist failed to adequately monitor her and recognize early symptoms of TD and did not tell the patient to look for signs of TD.

THE DOCTOR’S DEFENSE. None

Submit your verdict and find out how the court ruled. Click on “Have more to say about this topic?” to comment.

We give you facts of an actual malpractice case. Submit your verdict below and see how your colleagues voted.

Did the patient know the risks of risperidone?

THE PATIENT. A 53-year-old woman hospitalized for depression and suicidal thoughts was prescribed risperidone.

CASE FACTS. The patient developed excessive mouth and tongue movement—including pursed lips, protruding tongue, and biting the inside of her mouth—and uncontrollable urges to move her extremities. She was diagnosed with probable tardive dyskinesia (TD), and risperidone was tapered and discontinued.

THE PATIENT’S CLAIM. The psychiatrist failed to adequately monitor her and recognize early symptoms of TD and did not tell the patient to look for signs of TD.

THE DOCTOR’S DEFENSE. None

Submit your verdict and find out how the court ruled. Click on “Have more to say about this topic?” to comment.

Dear Dr. Mossman,

I prescribed topiramate for Mr. B, a patient with no history of kidney stones. Many months later he developed back pain. During the medical workup for a possible kidney stone, Mr. B and I revisited the risk of kidney stones with topiramate, which we had discussed at the beginning of therapy. Mr. B was adamantly opposed to stopping topiramate, even if he had a kidney stone. Testing revealed that Mr. B did not have a stone, but I wasn’t sure how to proceed. I worried that I might be found liable if Mr. B stayed on topiramate and did develop a kidney stone.—Submitted by Dr. A

When a patient develops a medical problem from a drug you prescribed, it is natural to feel responsible—after all, your treatment caused the adverse event. But did you commit malpractice? To answer this, let’s review the concept of “medical negligence.”

Malpractice law applies legal principles of negligence to professional conduct.¹ The elements of a negligence case (Table 1) can be summarized as “breach of duty causing damages.” Therefore, when you wonder whether possible harm to a patient might be considered malpractice, ask yourself, “Did I breach my professional duty?”

Physicians have a duty to practice within their specialty’s standard of care, and if they do this, they should not be held liable even if their treatments cause adverse effects. Each jurisdiction defines the standard of care differently, but the general expectation is “that physicians acting within the ambit of their professional work will exercise the skill, knowledge, and care normally possessed and exercised by other members of their profession…in the relevant medical community.”¹

It’s impossible to describe all the skills, knowledge, and care a psychiatrist normally employs when prescribing a drug, but elements of good practice include reasonable efforts to:

• make an appropriate diagnosis
  
• offer appropriate treatment
  
• monitor effects of treatment.
  

Further, treatment should occur only when a patient gives informed consent. Let’s examine each of these elements as they apply to Dr. A and Mr. B.

Table 1

Elements of a successful negligence case

Defendant owed the plaintiff a duty of care Defendant breached that duty Defendant’s conduct harmed the plaintiff Defendant’s conduct was a “proximate cause,” meaning it had a significant relationship to the harm Legally recognized damages, such as a physical injury, occurred
Source: Reference 1

Appropriate assessment

Despite the availability of guidelines for psychiatric evaluation,^2,3 it is tough to summarize everything psychiatrists do when assessing patients. But—focusing on Dr. A’s question—it is reasonable to ask: Did the psychiatric evaluation provide reasonably good evidence that Mr. B had a condition that topiramate might alleviate? Mr. B’s strong desire to keep taking the drug suggests that the answer is “yes.”

Another part of assessment is considering whether a patient has medical conditions that might contraindicate topiramate or affect prescribing. Typically, psychiatrists learn about these matters by careful history-taking and laboratory testing. In addition to kidney stones, topiramate is associated with increased risk for secondary angle closure glaucoma, hyperthermia, metabolic acidosis, cognitive dysfunction, mood changes, and sedation.⁴

Dr. A also should consider potential interactions between topiramate and any other medications that Mr. B is taking. A prudent clinician must judge whether the potential benefit of topiramate for Mr. B outweighs the risk of adverse effects. If Mr. B actually had developed a kidney stone, Dr. A might seek a nephrologist’s advice about how to minimize the risk of recurrence.

Appropriate treatment

Topiramate is FDA-approved only for treating seizures and for prophylaxis against migraine headaches. However, FDA approval limits only how pharmaceutical companies can promote a medication.⁴ Physicians may prescribe drugs for unapproved “off-label” uses, and doing so is accepted medical practice. Peer-reviewed publications support using topiramate to treat agitation,⁵ alcohol dependence,⁶ binge-eating disorder,⁷ and other conditions that psychiatrists often manage. A tendency to promote weight loss has made topiramate an attractive add-on medication for patients whose weight problems are causing other health difficulties.⁸

 

Assuming that Mr. B is taking topiramate for an off-label purpose, an appropriate question to ask is, “Does professional literature support use of topiramate in Mr. B’s circumstances?” Also, given everything known about Mr. B up to this point, is topiramate a good treatment choice?

Appropriate monitoring

As every clinician knows, medications can cause problems. Monitoring topiramate therapy involves periodic lab testing and assessment of effectiveness. Dr. A should feel reasonably sure that Mr. B—assisted by a family member or close friend, if necessary—can and will cooperate with monitoring requirements. Dr. A also should verify that Mr. B can grasp and follow instructions designed to avert complications—such as ample hydration to reduce risk of nephrolithiasis—and will promptly address problems if they occur.

Informed consent

Informed consent is especially important when a patient receives a treatment that has a known risk. Although the Physician’s Desk Reference does not list previous kidney stones as a contraindication to topiramate therapy, it urges caution under these circumstances.⁴ Therefore, if Dr. A wishes to prescribe topiramate for a patient with a history of kidney stone, the patient should meaningfully collaborate in the treatment decision.

Informed consent for treatment requires that patients not feel coerced by the doctor or setting and have the mental capacity or competence to give consent. Under the conceptualization developed by Appelbaum and Grisso,⁹ competent patients can:

• express a consistent choice
  
• understand medical information provided to them
  
• appreciate how this information applies to them and their condition
  
• reason logically about treatment.
  

Most psychiatric outpatients have capacity to consent to treatment, but if you have doubts, assess the patient’s capacity systematically. Appelbaum¹⁰ provides a superb summary of these concepts and suggested questions to ask your patient (Table 2).

What information should patients receive before giving consent? The legal standard varies, but in most U.S. jurisdictions, patients “are entitled to material information about the nature of any proposed medical procedure. For example, patients are entitled to information about the risks of the procedure, its necessity, and alternate procedures that might be preferable.”¹ Topiramate’s manufacturer instructs physicians to question and warn patients about the risk of kidney stones—which Dr. A did in Mr. B’s case. When you prescribe a drug off-label, you may want to tell patients this, but explain why the drug is appropriate nonetheless.

Table 2

Evaluating a patient’s capacity to consent to treatment

Is this patient able to?	Questions to ask
Express a clear treatment preference	What treatment have you chosen?
Understand basic information communicated by caregivers	Can you tell me in your own words about your condition and the treatment options I have told you about?
Appreciate his or her medical condition and how information about treatment applies	What do you think is wrong with your health now? Do you think you need some kind of treatment? What do you think treatment will do for you?
Reason logically when choosing treatment options	Why did you choose this treatment? Why is it better than your other treatment options?
Source: Adapted and reprinted with permission from Appelbaum PS. Assessment of patients’ competence to consent to treatment. N Engl J Med 2007;357:1834-40

Dear Dr. Mossman,

I prescribed topiramate for Mr. B, a patient with no history of kidney stones. Many months later he developed back pain. During the medical workup for a possible kidney stone, Mr. B and I revisited the risk of kidney stones with topiramate, which we had discussed at the beginning of therapy. Mr. B was adamantly opposed to stopping topiramate, even if he had a kidney stone. Testing revealed that Mr. B did not have a stone, but I wasn’t sure how to proceed. I worried that I might be found liable if Mr. B stayed on topiramate and did develop a kidney stone.—Submitted by Dr. A

When a patient develops a medical problem from a drug you prescribed, it is natural to feel responsible—after all, your treatment caused the adverse event. But did you commit malpractice? To answer this, let’s review the concept of “medical negligence.”

Malpractice law applies legal principles of negligence to professional conduct.¹ The elements of a negligence case (Table 1) can be summarized as “breach of duty causing damages.” Therefore, when you wonder whether possible harm to a patient might be considered malpractice, ask yourself, “Did I breach my professional duty?”

Physicians have a duty to practice within their specialty’s standard of care, and if they do this, they should not be held liable even if their treatments cause adverse effects. Each jurisdiction defines the standard of care differently, but the general expectation is “that physicians acting within the ambit of their professional work will exercise the skill, knowledge, and care normally possessed and exercised by other members of their profession…in the relevant medical community.”¹

It’s impossible to describe all the skills, knowledge, and care a psychiatrist normally employs when prescribing a drug, but elements of good practice include reasonable efforts to:

• make an appropriate diagnosis
  
• offer appropriate treatment
  
• monitor effects of treatment.
  

Further, treatment should occur only when a patient gives informed consent. Let’s examine each of these elements as they apply to Dr. A and Mr. B.

Table 1

Elements of a successful negligence case

Defendant owed the plaintiff a duty of care Defendant breached that duty Defendant’s conduct harmed the plaintiff Defendant’s conduct was a “proximate cause,” meaning it had a significant relationship to the harm Legally recognized damages, such as a physical injury, occurred
Source: Reference 1

Appropriate assessment

Despite the availability of guidelines for psychiatric evaluation,^2,3 it is tough to summarize everything psychiatrists do when assessing patients. But—focusing on Dr. A’s question—it is reasonable to ask: Did the psychiatric evaluation provide reasonably good evidence that Mr. B had a condition that topiramate might alleviate? Mr. B’s strong desire to keep taking the drug suggests that the answer is “yes.”

Another part of assessment is considering whether a patient has medical conditions that might contraindicate topiramate or affect prescribing. Typically, psychiatrists learn about these matters by careful history-taking and laboratory testing. In addition to kidney stones, topiramate is associated with increased risk for secondary angle closure glaucoma, hyperthermia, metabolic acidosis, cognitive dysfunction, mood changes, and sedation.⁴

Dr. A also should consider potential interactions between topiramate and any other medications that Mr. B is taking. A prudent clinician must judge whether the potential benefit of topiramate for Mr. B outweighs the risk of adverse effects. If Mr. B actually had developed a kidney stone, Dr. A might seek a nephrologist’s advice about how to minimize the risk of recurrence.

Appropriate treatment

Topiramate is FDA-approved only for treating seizures and for prophylaxis against migraine headaches. However, FDA approval limits only how pharmaceutical companies can promote a medication.⁴ Physicians may prescribe drugs for unapproved “off-label” uses, and doing so is accepted medical practice. Peer-reviewed publications support using topiramate to treat agitation,⁵ alcohol dependence,⁶ binge-eating disorder,⁷ and other conditions that psychiatrists often manage. A tendency to promote weight loss has made topiramate an attractive add-on medication for patients whose weight problems are causing other health difficulties.⁸

 

Assuming that Mr. B is taking topiramate for an off-label purpose, an appropriate question to ask is, “Does professional literature support use of topiramate in Mr. B’s circumstances?” Also, given everything known about Mr. B up to this point, is topiramate a good treatment choice?

Appropriate monitoring

As every clinician knows, medications can cause problems. Monitoring topiramate therapy involves periodic lab testing and assessment of effectiveness. Dr. A should feel reasonably sure that Mr. B—assisted by a family member or close friend, if necessary—can and will cooperate with monitoring requirements. Dr. A also should verify that Mr. B can grasp and follow instructions designed to avert complications—such as ample hydration to reduce risk of nephrolithiasis—and will promptly address problems if they occur.

Informed consent

Informed consent is especially important when a patient receives a treatment that has a known risk. Although the Physician’s Desk Reference does not list previous kidney stones as a contraindication to topiramate therapy, it urges caution under these circumstances.⁴ Therefore, if Dr. A wishes to prescribe topiramate for a patient with a history of kidney stone, the patient should meaningfully collaborate in the treatment decision.

Informed consent for treatment requires that patients not feel coerced by the doctor or setting and have the mental capacity or competence to give consent. Under the conceptualization developed by Appelbaum and Grisso,⁹ competent patients can:

• express a consistent choice
  
• understand medical information provided to them
  
• appreciate how this information applies to them and their condition
  
• reason logically about treatment.
  

Most psychiatric outpatients have capacity to consent to treatment, but if you have doubts, assess the patient’s capacity systematically. Appelbaum¹⁰ provides a superb summary of these concepts and suggested questions to ask your patient (Table 2).

What information should patients receive before giving consent? The legal standard varies, but in most U.S. jurisdictions, patients “are entitled to material information about the nature of any proposed medical procedure. For example, patients are entitled to information about the risks of the procedure, its necessity, and alternate procedures that might be preferable.”¹ Topiramate’s manufacturer instructs physicians to question and warn patients about the risk of kidney stones—which Dr. A did in Mr. B’s case. When you prescribe a drug off-label, you may want to tell patients this, but explain why the drug is appropriate nonetheless.

Table 2

Evaluating a patient’s capacity to consent to treatment

Is this patient able to?	Questions to ask
Express a clear treatment preference	What treatment have you chosen?
Understand basic information communicated by caregivers	Can you tell me in your own words about your condition and the treatment options I have told you about?
Appreciate his or her medical condition and how information about treatment applies	What do you think is wrong with your health now? Do you think you need some kind of treatment? What do you think treatment will do for you?
Reason logically when choosing treatment options	Why did you choose this treatment? Why is it better than your other treatment options?
Source: Adapted and reprinted with permission from Appelbaum PS. Assessment of patients’ competence to consent to treatment. N Engl J Med 2007;357:1834-40

Dear Dr. Mossman,

I prescribed topiramate for Mr. B, a patient with no history of kidney stones. Many months later he developed back pain. During the medical workup for a possible kidney stone, Mr. B and I revisited the risk of kidney stones with topiramate, which we had discussed at the beginning of therapy. Mr. B was adamantly opposed to stopping topiramate, even if he had a kidney stone. Testing revealed that Mr. B did not have a stone, but I wasn’t sure how to proceed. I worried that I might be found liable if Mr. B stayed on topiramate and did develop a kidney stone.—Submitted by Dr. A

When a patient develops a medical problem from a drug you prescribed, it is natural to feel responsible—after all, your treatment caused the adverse event. But did you commit malpractice? To answer this, let’s review the concept of “medical negligence.”

Malpractice law applies legal principles of negligence to professional conduct.¹ The elements of a negligence case (Table 1) can be summarized as “breach of duty causing damages.” Therefore, when you wonder whether possible harm to a patient might be considered malpractice, ask yourself, “Did I breach my professional duty?”

Physicians have a duty to practice within their specialty’s standard of care, and if they do this, they should not be held liable even if their treatments cause adverse effects. Each jurisdiction defines the standard of care differently, but the general expectation is “that physicians acting within the ambit of their professional work will exercise the skill, knowledge, and care normally possessed and exercised by other members of their profession…in the relevant medical community.”¹

It’s impossible to describe all the skills, knowledge, and care a psychiatrist normally employs when prescribing a drug, but elements of good practice include reasonable efforts to:

• make an appropriate diagnosis
  
• offer appropriate treatment
  
• monitor effects of treatment.
  

Further, treatment should occur only when a patient gives informed consent. Let’s examine each of these elements as they apply to Dr. A and Mr. B.

Table 1

Elements of a successful negligence case

Defendant owed the plaintiff a duty of care Defendant breached that duty Defendant’s conduct harmed the plaintiff Defendant’s conduct was a “proximate cause,” meaning it had a significant relationship to the harm Legally recognized damages, such as a physical injury, occurred
Source: Reference 1

Appropriate assessment

Despite the availability of guidelines for psychiatric evaluation,^2,3 it is tough to summarize everything psychiatrists do when assessing patients. But—focusing on Dr. A’s question—it is reasonable to ask: Did the psychiatric evaluation provide reasonably good evidence that Mr. B had a condition that topiramate might alleviate? Mr. B’s strong desire to keep taking the drug suggests that the answer is “yes.”

Another part of assessment is considering whether a patient has medical conditions that might contraindicate topiramate or affect prescribing. Typically, psychiatrists learn about these matters by careful history-taking and laboratory testing. In addition to kidney stones, topiramate is associated with increased risk for secondary angle closure glaucoma, hyperthermia, metabolic acidosis, cognitive dysfunction, mood changes, and sedation.⁴

Dr. A also should consider potential interactions between topiramate and any other medications that Mr. B is taking. A prudent clinician must judge whether the potential benefit of topiramate for Mr. B outweighs the risk of adverse effects. If Mr. B actually had developed a kidney stone, Dr. A might seek a nephrologist’s advice about how to minimize the risk of recurrence.

Appropriate treatment

Topiramate is FDA-approved only for treating seizures and for prophylaxis against migraine headaches. However, FDA approval limits only how pharmaceutical companies can promote a medication.⁴ Physicians may prescribe drugs for unapproved “off-label” uses, and doing so is accepted medical practice. Peer-reviewed publications support using topiramate to treat agitation,⁵ alcohol dependence,⁶ binge-eating disorder,⁷ and other conditions that psychiatrists often manage. A tendency to promote weight loss has made topiramate an attractive add-on medication for patients whose weight problems are causing other health difficulties.⁸

 

Assuming that Mr. B is taking topiramate for an off-label purpose, an appropriate question to ask is, “Does professional literature support use of topiramate in Mr. B’s circumstances?” Also, given everything known about Mr. B up to this point, is topiramate a good treatment choice?

Appropriate monitoring

As every clinician knows, medications can cause problems. Monitoring topiramate therapy involves periodic lab testing and assessment of effectiveness. Dr. A should feel reasonably sure that Mr. B—assisted by a family member or close friend, if necessary—can and will cooperate with monitoring requirements. Dr. A also should verify that Mr. B can grasp and follow instructions designed to avert complications—such as ample hydration to reduce risk of nephrolithiasis—and will promptly address problems if they occur.

Informed consent

Informed consent is especially important when a patient receives a treatment that has a known risk. Although the Physician’s Desk Reference does not list previous kidney stones as a contraindication to topiramate therapy, it urges caution under these circumstances.⁴ Therefore, if Dr. A wishes to prescribe topiramate for a patient with a history of kidney stone, the patient should meaningfully collaborate in the treatment decision.

Informed consent for treatment requires that patients not feel coerced by the doctor or setting and have the mental capacity or competence to give consent. Under the conceptualization developed by Appelbaum and Grisso,⁹ competent patients can:

• express a consistent choice
  
• understand medical information provided to them
  
• appreciate how this information applies to them and their condition
  
• reason logically about treatment.
  

Most psychiatric outpatients have capacity to consent to treatment, but if you have doubts, assess the patient’s capacity systematically. Appelbaum¹⁰ provides a superb summary of these concepts and suggested questions to ask your patient (Table 2).

What information should patients receive before giving consent? The legal standard varies, but in most U.S. jurisdictions, patients “are entitled to material information about the nature of any proposed medical procedure. For example, patients are entitled to information about the risks of the procedure, its necessity, and alternate procedures that might be preferable.”¹ Topiramate’s manufacturer instructs physicians to question and warn patients about the risk of kidney stones—which Dr. A did in Mr. B’s case. When you prescribe a drug off-label, you may want to tell patients this, but explain why the drug is appropriate nonetheless.

Table 2

Evaluating a patient’s capacity to consent to treatment

Is this patient able to?	Questions to ask
Express a clear treatment preference	What treatment have you chosen?
Understand basic information communicated by caregivers	Can you tell me in your own words about your condition and the treatment options I have told you about?
Appreciate his or her medical condition and how information about treatment applies	What do you think is wrong with your health now? Do you think you need some kind of treatment? What do you think treatment will do for you?
Reason logically when choosing treatment options	Why did you choose this treatment? Why is it better than your other treatment options?
Source: Adapted and reprinted with permission from Appelbaum PS. Assessment of patients’ competence to consent to treatment. N Engl J Med 2007;357:1834-40

The US Food and Drug Administration (FDA) has identified the structure and source of the contaminant found in lots of heparin.

The contaminant, which has been linked to severe allergic reactions and deaths, was found in crude lots of heparin at a Chinese processing plant. The substance has been identified as over-sulfated chondroitin sulfate.

Researchers initially had difficulty identifying the contaminant because it is so similar to heparin. Over-sulfated chondroitin sulfate has approximately the same molecular weight as heparin, and both materials belong to the class of molecules known as glucosaminoglycans (GAGs).

It is still unknown whether the over-sulfated chondroitin sulfate was a byproduct of the heparin production process or if it was intentionally added to the active pharmaceutical ingredient.

After learning about the source of the over-sulfated chondroitin sulfate, the FDA issued a border alert that requires all finished heparin, as well as heparin source material, to be tested before it is allowed into the US. Five heparin manufacturers, companies that supply most of the heparin used in this country, have agreed to conduct the tests.

Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said the agency would test heparin products made by companies that cannot conduct the testing themselves. Any product that is not tested or fails the tests will be destroyed.

Scientific Protein Laboratories is the company that supplied crude heparin from the Changzhou plant in China to the biopharmaceutical company Baxter. Scientific Protein Laboratories has said it is cooperating with the FDA, and the Changzhou plant is not currently producing heparin.

In addition to the new testing instituted at the US borders, the FDA said heparin testing is now being conducted worldwide. Germany and Japan are among the countries that have started testing.

Germany recalled heparin last week after a cluster of about 100 serious allergic reactions, including hypotension and anaphylaxis. Japan has also recalled heparin but has not reported any adverse events linked to heparin injections.

Both Scientific Protein Laboratories and Baxter have conducted massive voluntary recalls of heparin products. Since Baxter recalled all of its heparin vials, there have been no additional deaths.

Last week, the FDA received 785 reports of adverse events associated with heparin. Those reports included 46 deaths, but Dr Woodcock said only 19 were related to the allergic profile associated with the Baxter heparin.

Baxter has said it cannot confirm that heparin has caused any fatalities as a result of an allergic reaction. The company said there are 4 cases in which patients received Baxter heparin and suffered an allergic-type reaction to the drug.

Baxter also said there is not yet enough medical data available to draw a firm conclusion that the reaction caused death. In each of these cases, the patient had multiple underlying complex medical conditions. Three of the 4 patients had undergone, or were in the process of undergoing, invasive cardiac surgery.

The heparin saga began January 17 of this year, when Baxter recalled the first batch of heparin after receiving reports of the allergic reactions. Recalls of the drug have continued since that time.

The FDA released the news of the contaminant’s source March 14 and the discovery of its structure March 19.

The US Food and Drug Administration (FDA) has identified the structure and source of the contaminant found in lots of heparin.

The contaminant, which has been linked to severe allergic reactions and deaths, was found in crude lots of heparin at a Chinese processing plant. The substance has been identified as over-sulfated chondroitin sulfate.

Researchers initially had difficulty identifying the contaminant because it is so similar to heparin. Over-sulfated chondroitin sulfate has approximately the same molecular weight as heparin, and both materials belong to the class of molecules known as glucosaminoglycans (GAGs).

It is still unknown whether the over-sulfated chondroitin sulfate was a byproduct of the heparin production process or if it was intentionally added to the active pharmaceutical ingredient.

After learning about the source of the over-sulfated chondroitin sulfate, the FDA issued a border alert that requires all finished heparin, as well as heparin source material, to be tested before it is allowed into the US. Five heparin manufacturers, companies that supply most of the heparin used in this country, have agreed to conduct the tests.

Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said the agency would test heparin products made by companies that cannot conduct the testing themselves. Any product that is not tested or fails the tests will be destroyed.

Scientific Protein Laboratories is the company that supplied crude heparin from the Changzhou plant in China to the biopharmaceutical company Baxter. Scientific Protein Laboratories has said it is cooperating with the FDA, and the Changzhou plant is not currently producing heparin.

In addition to the new testing instituted at the US borders, the FDA said heparin testing is now being conducted worldwide. Germany and Japan are among the countries that have started testing.

Germany recalled heparin last week after a cluster of about 100 serious allergic reactions, including hypotension and anaphylaxis. Japan has also recalled heparin but has not reported any adverse events linked to heparin injections.

Both Scientific Protein Laboratories and Baxter have conducted massive voluntary recalls of heparin products. Since Baxter recalled all of its heparin vials, there have been no additional deaths.

Last week, the FDA received 785 reports of adverse events associated with heparin. Those reports included 46 deaths, but Dr Woodcock said only 19 were related to the allergic profile associated with the Baxter heparin.

Baxter has said it cannot confirm that heparin has caused any fatalities as a result of an allergic reaction. The company said there are 4 cases in which patients received Baxter heparin and suffered an allergic-type reaction to the drug.

Baxter also said there is not yet enough medical data available to draw a firm conclusion that the reaction caused death. In each of these cases, the patient had multiple underlying complex medical conditions. Three of the 4 patients had undergone, or were in the process of undergoing, invasive cardiac surgery.

The heparin saga began January 17 of this year, when Baxter recalled the first batch of heparin after receiving reports of the allergic reactions. Recalls of the drug have continued since that time.

The FDA released the news of the contaminant’s source March 14 and the discovery of its structure March 19.

The US Food and Drug Administration (FDA) has identified the structure and source of the contaminant found in lots of heparin.

The contaminant, which has been linked to severe allergic reactions and deaths, was found in crude lots of heparin at a Chinese processing plant. The substance has been identified as over-sulfated chondroitin sulfate.

Researchers initially had difficulty identifying the contaminant because it is so similar to heparin. Over-sulfated chondroitin sulfate has approximately the same molecular weight as heparin, and both materials belong to the class of molecules known as glucosaminoglycans (GAGs).

It is still unknown whether the over-sulfated chondroitin sulfate was a byproduct of the heparin production process or if it was intentionally added to the active pharmaceutical ingredient.

After learning about the source of the over-sulfated chondroitin sulfate, the FDA issued a border alert that requires all finished heparin, as well as heparin source material, to be tested before it is allowed into the US. Five heparin manufacturers, companies that supply most of the heparin used in this country, have agreed to conduct the tests.

Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said the agency would test heparin products made by companies that cannot conduct the testing themselves. Any product that is not tested or fails the tests will be destroyed.

Scientific Protein Laboratories is the company that supplied crude heparin from the Changzhou plant in China to the biopharmaceutical company Baxter. Scientific Protein Laboratories has said it is cooperating with the FDA, and the Changzhou plant is not currently producing heparin.

In addition to the new testing instituted at the US borders, the FDA said heparin testing is now being conducted worldwide. Germany and Japan are among the countries that have started testing.

Germany recalled heparin last week after a cluster of about 100 serious allergic reactions, including hypotension and anaphylaxis. Japan has also recalled heparin but has not reported any adverse events linked to heparin injections.

Both Scientific Protein Laboratories and Baxter have conducted massive voluntary recalls of heparin products. Since Baxter recalled all of its heparin vials, there have been no additional deaths.

Last week, the FDA received 785 reports of adverse events associated with heparin. Those reports included 46 deaths, but Dr Woodcock said only 19 were related to the allergic profile associated with the Baxter heparin.

Baxter has said it cannot confirm that heparin has caused any fatalities as a result of an allergic reaction. The company said there are 4 cases in which patients received Baxter heparin and suffered an allergic-type reaction to the drug.

Baxter also said there is not yet enough medical data available to draw a firm conclusion that the reaction caused death. In each of these cases, the patient had multiple underlying complex medical conditions. Three of the 4 patients had undergone, or were in the process of undergoing, invasive cardiac surgery.

The heparin saga began January 17 of this year, when Baxter recalled the first batch of heparin after receiving reports of the allergic reactions. Recalls of the drug have continued since that time.

The FDA released the news of the contaminant’s source March 14 and the discovery of its structure March 19.

Supplement Editor:
Marc S. Penn, MD, PhD

Contents*^†

Introduction: Heart-brain medicine: Update 2007
Marc S. Penn, MD, PhD, and Earl E. Bakken, MD, HonC, (3) SciDHon

Depression in coronary artery disease: Does treatment help?
Peter A. Shapiro, MD

Case study in heart-brain interplay: A 53-year-old woman recovering from mitral valve repair
Thomas D. Callahan, IV, MD; Ubaid Khokhar, MD; Leo Pozuelo, MD; and James B. Young, MD

Emotional predictors and behavioral triggers of acute coronary syndrome
Karina W. Davidson, PhD

Impacts of depression and emotional distress on cardiac disease
Wei Jiang, MD

Inflammation as a link between brain injury and heart damage: The model of subarachnoid hemorrhage
Hazem Antar Mashaly, MD, and J. Javier Provencio, MD

Biofeedback: An overview in the context of heart-brain medicine
Michael G. McKee, PhD

Biofeedback therapy in cardiovascular disease: Rationale and research overview
Christine S. Moravec, PhD

Helping children and adults with hypnosis and biofeedback
Karen Olness, MD

Clinical hypnosis for reduction of atrial fibrillation after coronary artery bypass graft surgery
Roberto Novoa, MD, and Tracy Hammonds, BA

Depression and coronary heart disease: Association and implications for treatment
James A. Blumenthal, PhD

Cardiovascular autonomic dysfunction in patients with movement disorders
Benjamin L. Walter, MD

Deep brain stimulation: How does it work?
Jerrold L. Vitek, MD, PhD

Sudden unexpected death in epilepsy: Impact, mechanisms, and prevention
Lara Jehi, MD, and Imad M. Najm, MD

Evaluating brain function in patients with disorders of consciousness
Tristan Bekinschtein, PhD, and Facundo Manes, MD

Preconditioning paradigms and pathways in the brain
Karl B. Shpargel; Walid Jalabi, PhD; Yongming Jin; Alisher Dadabayev, MD; Marc S. Penn, MD, PhD,
and Bruce D. Trapp, PhD

Post-stroke exercise rehabilitation:What we know about retraining the motor system and how it may apply to retraining the heart
Andreas Luft, MD; Richard Macko, MD; Larry Forrester, PhD; Andrew Goldberg, MD; and Daniel F. Hanley, MD

Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial
D. Larry Sparks, PhD; Susan K. Lemieux, PhD; Marc W. Haut, PhD; Leslie C. Baxter, PhD; Sterling C. Johnson, PhD; Lisa M. Sparks, BS; Hemalatha Sampath, BSEE; Jean E. Lopez, RN; Marwan H. Sabbagh, MD; and Donald J. Connor, PhD

Heart-brain interactions in cardiac arrhythmias: Role of the autonomic nervous system
Douglas P. Zipes, MD

Insular Alzheimer disease pathology and the psychometric correlates of mortality
Donald R. Royall, MD

Poster abstracts


* These proceedings represent the large majority of presentations at the 2nd Heart-Brain Summit, but five Summit presentations were not able to be captured for publication here.

† Articles in these proceedings were either submitted as manuscripts by the Summit faculty or developed by the Cleveland Clinic Journal of Medicine staff from transcripts of audiotaped Summit presentations and then revised and approved by the Summit faculty.
 

Supplement Editor:
Marc S. Penn, MD, PhD

Contents*^†

Introduction: Heart-brain medicine: Update 2007
Marc S. Penn, MD, PhD, and Earl E. Bakken, MD, HonC, (3) SciDHon

Depression in coronary artery disease: Does treatment help?
Peter A. Shapiro, MD

Case study in heart-brain interplay: A 53-year-old woman recovering from mitral valve repair
Thomas D. Callahan, IV, MD; Ubaid Khokhar, MD; Leo Pozuelo, MD; and James B. Young, MD

Emotional predictors and behavioral triggers of acute coronary syndrome
Karina W. Davidson, PhD

Impacts of depression and emotional distress on cardiac disease
Wei Jiang, MD

Inflammation as a link between brain injury and heart damage: The model of subarachnoid hemorrhage
Hazem Antar Mashaly, MD, and J. Javier Provencio, MD

Biofeedback: An overview in the context of heart-brain medicine
Michael G. McKee, PhD

Biofeedback therapy in cardiovascular disease: Rationale and research overview
Christine S. Moravec, PhD

Helping children and adults with hypnosis and biofeedback
Karen Olness, MD

Clinical hypnosis for reduction of atrial fibrillation after coronary artery bypass graft surgery
Roberto Novoa, MD, and Tracy Hammonds, BA

Depression and coronary heart disease: Association and implications for treatment
James A. Blumenthal, PhD

Cardiovascular autonomic dysfunction in patients with movement disorders
Benjamin L. Walter, MD

Deep brain stimulation: How does it work?
Jerrold L. Vitek, MD, PhD

Sudden unexpected death in epilepsy: Impact, mechanisms, and prevention
Lara Jehi, MD, and Imad M. Najm, MD

Evaluating brain function in patients with disorders of consciousness
Tristan Bekinschtein, PhD, and Facundo Manes, MD

Preconditioning paradigms and pathways in the brain
Karl B. Shpargel; Walid Jalabi, PhD; Yongming Jin; Alisher Dadabayev, MD; Marc S. Penn, MD, PhD,
and Bruce D. Trapp, PhD

Post-stroke exercise rehabilitation:What we know about retraining the motor system and how it may apply to retraining the heart
Andreas Luft, MD; Richard Macko, MD; Larry Forrester, PhD; Andrew Goldberg, MD; and Daniel F. Hanley, MD

Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial
D. Larry Sparks, PhD; Susan K. Lemieux, PhD; Marc W. Haut, PhD; Leslie C. Baxter, PhD; Sterling C. Johnson, PhD; Lisa M. Sparks, BS; Hemalatha Sampath, BSEE; Jean E. Lopez, RN; Marwan H. Sabbagh, MD; and Donald J. Connor, PhD

Heart-brain interactions in cardiac arrhythmias: Role of the autonomic nervous system
Douglas P. Zipes, MD

Insular Alzheimer disease pathology and the psychometric correlates of mortality
Donald R. Royall, MD

Poster abstracts


* These proceedings represent the large majority of presentations at the 2nd Heart-Brain Summit, but five Summit presentations were not able to be captured for publication here.

† Articles in these proceedings were either submitted as manuscripts by the Summit faculty or developed by the Cleveland Clinic Journal of Medicine staff from transcripts of audiotaped Summit presentations and then revised and approved by the Summit faculty.
 

Supplement Editor:
Marc S. Penn, MD, PhD

Contents*^†

Introduction: Heart-brain medicine: Update 2007
Marc S. Penn, MD, PhD, and Earl E. Bakken, MD, HonC, (3) SciDHon

Depression in coronary artery disease: Does treatment help?
Peter A. Shapiro, MD

Case study in heart-brain interplay: A 53-year-old woman recovering from mitral valve repair
Thomas D. Callahan, IV, MD; Ubaid Khokhar, MD; Leo Pozuelo, MD; and James B. Young, MD

Emotional predictors and behavioral triggers of acute coronary syndrome
Karina W. Davidson, PhD

Impacts of depression and emotional distress on cardiac disease
Wei Jiang, MD

Inflammation as a link between brain injury and heart damage: The model of subarachnoid hemorrhage
Hazem Antar Mashaly, MD, and J. Javier Provencio, MD

Biofeedback: An overview in the context of heart-brain medicine
Michael G. McKee, PhD

Biofeedback therapy in cardiovascular disease: Rationale and research overview
Christine S. Moravec, PhD

Helping children and adults with hypnosis and biofeedback
Karen Olness, MD

Clinical hypnosis for reduction of atrial fibrillation after coronary artery bypass graft surgery
Roberto Novoa, MD, and Tracy Hammonds, BA

Depression and coronary heart disease: Association and implications for treatment
James A. Blumenthal, PhD

Cardiovascular autonomic dysfunction in patients with movement disorders
Benjamin L. Walter, MD

Deep brain stimulation: How does it work?
Jerrold L. Vitek, MD, PhD

Sudden unexpected death in epilepsy: Impact, mechanisms, and prevention
Lara Jehi, MD, and Imad M. Najm, MD

Evaluating brain function in patients with disorders of consciousness
Tristan Bekinschtein, PhD, and Facundo Manes, MD

Preconditioning paradigms and pathways in the brain
Karl B. Shpargel; Walid Jalabi, PhD; Yongming Jin; Alisher Dadabayev, MD; Marc S. Penn, MD, PhD,
and Bruce D. Trapp, PhD

Post-stroke exercise rehabilitation:What we know about retraining the motor system and how it may apply to retraining the heart
Andreas Luft, MD; Richard Macko, MD; Larry Forrester, PhD; Andrew Goldberg, MD; and Daniel F. Hanley, MD

Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial
D. Larry Sparks, PhD; Susan K. Lemieux, PhD; Marc W. Haut, PhD; Leslie C. Baxter, PhD; Sterling C. Johnson, PhD; Lisa M. Sparks, BS; Hemalatha Sampath, BSEE; Jean E. Lopez, RN; Marwan H. Sabbagh, MD; and Donald J. Connor, PhD

Heart-brain interactions in cardiac arrhythmias: Role of the autonomic nervous system
Douglas P. Zipes, MD

Insular Alzheimer disease pathology and the psychometric correlates of mortality
Donald R. Royall, MD

Poster abstracts


* These proceedings represent the large majority of presentations at the 2nd Heart-Brain Summit, but five Summit presentations were not able to be captured for publication here.

† Articles in these proceedings were either submitted as manuscripts by the Summit faculty or developed by the Cleveland Clinic Journal of Medicine staff from transcripts of audiotaped Summit presentations and then revised and approved by the Summit faculty.
 

Ideally, rehabilitation following a stroke that leads to functional deficit will result in a rapid return to normal function. In the real world, however, a rapid improvement in function is rarely achieved. Between 80% and 90% of stroke survivors have a motor deficit, with impairments in walking being the most common motor deficits.¹ Most stroke survivors have a diminished fitness reserve that is stable and resistant to routine rehabilitative interventions. Recent research has begun to assess the value of exercise and other modalities of training during this period of stability to improve function long after cessation of other therapeutic interventions. This article will review this research and provide insight into those issues in post-stroke rehabilitation that remain to be addressed and may affect heart and brain physiology.

STROKE REDUCES AEROBIC CAPACITY

At all ages, the fitness level of stroke survivors, as measured by maximum oxygen consumption, is reduced by approximately 50% below that of an age-matched normal population. In a study comparing peak oxygen consumption during treadmill walking between stroke survivors and age-matched sedentary controls, we found that the stroke participants had an approximately 50% lower level of peak fitness relative to the control subjects.² During treadmill walking at self-selected speeds, the stroke volunteers used 75% of their functional capacity, compared with 27% for the age-matched healthy controls. Furthermore, compared with the controls, the stroke subjects demonstrated a poorer economy of gait that required greater oxygen consumption to sustain their self-selected walking speeds.

CLINICAL TRIALS OF POST-STROKE EXERCISE REHABILITATION

In light of the efficacy of treadmill exercise in cardiac rehabilitation, we are evaluating whether treadmill exercise can similarly improve fitness, endurance, and walking velocity in stroke survivors. We have completed 6 months of treadmill training in two separate cohorts that show highly consistent results in terms of improved walking abilities in hemiparetic stroke subjects.^3,4 A third cohort is in progress to confirm these findings and examine the effects of intensity on the functional benefits⁵ and mechanisms⁶ underlying the effects of treadmill training.

Treadmill exercise results in functional benefits and improved glucose metabolism

The first cohort was a before-and-after comparison of stable stroke survivors who underwent a three-times-weekly treadmill exercise program for 6 months.³ Peak exercise capacity testing (VO₂peak) revealed functional benefits with minimal cardiac and injury risk compared with baseline, demonstrating the feasibility and safety of treadmill exercise therapy in stroke-impaired adults.

Reprinted, with permission, from Macko RF, et al. Treadmill exercise rehabilitation improves ambulatory function and cardiovascular fitness in patients with chronic stroke. A randomized, controlled trial. Stroke 2005; 36:2206–2211.

The second cohort involved patients with chronic hemiparetic gait following ischemic stroke who were randomized to either treadmill aerobic training (three times weekly for 6 months) (n = 25) or a control rehabilitation program of stretching (n = 20).⁴ The aerobic training group selected its own walking speed and increased its speed as tolerated; some participants in this group started with as little as 2 minutes on the treadmill. As shown in Figure 1, performance on the 6-minute walk test improved significantly in the aerobic training group, relative to the control group, over the 6-month study. Six-minute walk results parallelled the improved functional performance.

Potential mechanisms for the benefits

These findings raise the question of whether these beneficial effects of treadmill exercise are attributable to muscle training effects, cardiopulmonary circulatory training effects, or perhaps neural mechanisms involving economy of gait movements and neuroplasticity of the motor system.

This question is being examined in our third cohort, now under investigation. This cohort will evaluate the effects of treadmill exercise on 32 chronically disabled stroke survivors in a single-center study design that is randomizing 64 subjects to 6 months of three-times-weekly treadmill training or conventional physiotherapy.⁶ Similar to our prior studies, subjects are randomized at least 6 months after their index stroke; this lengthy interval is deliberate because subjects are considered to be in a “plateau” phase of recovery, as they have previously completed rehabilitative therapy.

This group of 32 subjects will undergo both treadmill training and functional magnetic resonance imaging (fMRI) during unilateral knee movements to assess alterations in brain function during such movements over the 6-month study (Figure 2). Previous fMRI studies of healthy controls and stroke patients identified activation of regions in the right side of the cerebral hemisphere with left knee movement.^7,8 In the new fMRI study, functional activation patterns of paretic and nonparetic knee movement will be compared between the exercise group and the control group, and the relationship between the activation pattern and the location of the brain-activation region will be characterized for the paretic and nonparetic knee movements.

Activation will be measured in five prespecified “regions of interest”: the precentral gyrus, the postcentral gyrus, the supplementary motor area, the midbrain, and the cerebellum (anterior/posterior lobes). Difference activation maps of post-training minus pretraining fMRIs of paretic knee movement across all patients undergoing treadmill therapy will then be analyzed. The control group, which will receive dose-matched stretching activity from physical therapy, can be contrasted by comparing the patterns of pre/post differences in each region. This will allow for assessment of increased regional activation in the brain that should be specific to the treadmill training intervention. Furthermore, if a specifically localized regional activation difference is found, then individual fMRI and VO₂ training responses (VO₂peak, increase in walking speeds) can be correlated to further assess the relationship between regional activation and magnitude of functional response to the treadmill intervention.

 

 

DISCUSSION AND CONCLUSIONS

Central control of walking

Control of gait in animals is mediated by the cortex, brainstem/cerebellum,^9,10 and spinal cord—the so-called cervical gait and lumbar gait pattern-generating areas of the spinal cord. In humans, cortical and spinal gait pattern areas are thought to be major regulatory centers of ambulation. Whether the cortical areas influence ambulatory recovery mediated by exercise training or whether the recruitment of spinal gait areas is needed to improve motor control after stroke is not known in humans. We will test the hypothesis that the recruitment of cortical and/or subcortical areas is relevant to some or all of the exercise-induced neuroplasticity response to treadmill rehabilitation. If a consistent pattern of brain regional activation is associated with an improvement in walking ability, this finding will suggest potential brain targets for neurally directed rehabilitation interventions. If brain targets for rehabilitation produce viable therapeutic improvement in walking and cardiocirculatory performance (such as VO₂), this will be further evidence of heart-brain interactions.

Future research directions

Studies to date demonstrate that long-term treadmill exercise affects both the brain and cardiac physiology. This has holistic implications for the function of the whole person as well. Yet several pressing issues continue to confront researchers in post-stroke rehabilitation. One is the optimal therapeutic target and the intensity of the rehabilitative effort. Is this improvement solely a response of muscle and cardiac tissue to exercise, or is it possible that improved neuromotor control is a critical component to a major recovery of walking function? Furthermore, the most efficacious elements of rehabilitative therapy are not known. Should treadmill training be high- or low-intensity, and should it be accompanied by strength training, agility and flexibility activities, or other elements directed at reacquisition of finer degrees of gait-related motor training and neuropsychological input, as achieved by tai-chi or yoga? Another issue is the proper dose of rehabilitative therapy, which has barely been explored, although recent preliminary work suggests that the response is dose-dependent. Finally, predictors of response have not been established because the mechanisms of therapy and surrogate markers for early response are not well understood.

Our future research plans are to assess whether a better understanding of neural targets for rehabilitative treatment will be a fruitful avenue to improve recovery. Additionally, this plan will assess whether fMRI can serve as a surrogate marker of recovery by offering a noninvasive means to measure response to rehabilitation.

Ideally, rehabilitation following a stroke that leads to functional deficit will result in a rapid return to normal function. In the real world, however, a rapid improvement in function is rarely achieved. Between 80% and 90% of stroke survivors have a motor deficit, with impairments in walking being the most common motor deficits.¹ Most stroke survivors have a diminished fitness reserve that is stable and resistant to routine rehabilitative interventions. Recent research has begun to assess the value of exercise and other modalities of training during this period of stability to improve function long after cessation of other therapeutic interventions. This article will review this research and provide insight into those issues in post-stroke rehabilitation that remain to be addressed and may affect heart and brain physiology.

STROKE REDUCES AEROBIC CAPACITY

At all ages, the fitness level of stroke survivors, as measured by maximum oxygen consumption, is reduced by approximately 50% below that of an age-matched normal population. In a study comparing peak oxygen consumption during treadmill walking between stroke survivors and age-matched sedentary controls, we found that the stroke participants had an approximately 50% lower level of peak fitness relative to the control subjects.² During treadmill walking at self-selected speeds, the stroke volunteers used 75% of their functional capacity, compared with 27% for the age-matched healthy controls. Furthermore, compared with the controls, the stroke subjects demonstrated a poorer economy of gait that required greater oxygen consumption to sustain their self-selected walking speeds.

CLINICAL TRIALS OF POST-STROKE EXERCISE REHABILITATION

In light of the efficacy of treadmill exercise in cardiac rehabilitation, we are evaluating whether treadmill exercise can similarly improve fitness, endurance, and walking velocity in stroke survivors. We have completed 6 months of treadmill training in two separate cohorts that show highly consistent results in terms of improved walking abilities in hemiparetic stroke subjects.^3,4 A third cohort is in progress to confirm these findings and examine the effects of intensity on the functional benefits⁵ and mechanisms⁶ underlying the effects of treadmill training.

Treadmill exercise results in functional benefits and improved glucose metabolism

The first cohort was a before-and-after comparison of stable stroke survivors who underwent a three-times-weekly treadmill exercise program for 6 months.³ Peak exercise capacity testing (VO₂peak) revealed functional benefits with minimal cardiac and injury risk compared with baseline, demonstrating the feasibility and safety of treadmill exercise therapy in stroke-impaired adults.

Reprinted, with permission, from Macko RF, et al. Treadmill exercise rehabilitation improves ambulatory function and cardiovascular fitness in patients with chronic stroke. A randomized, controlled trial. Stroke 2005; 36:2206–2211.

The second cohort involved patients with chronic hemiparetic gait following ischemic stroke who were randomized to either treadmill aerobic training (three times weekly for 6 months) (n = 25) or a control rehabilitation program of stretching (n = 20).⁴ The aerobic training group selected its own walking speed and increased its speed as tolerated; some participants in this group started with as little as 2 minutes on the treadmill. As shown in Figure 1, performance on the 6-minute walk test improved significantly in the aerobic training group, relative to the control group, over the 6-month study. Six-minute walk results parallelled the improved functional performance.

Potential mechanisms for the benefits

These findings raise the question of whether these beneficial effects of treadmill exercise are attributable to muscle training effects, cardiopulmonary circulatory training effects, or perhaps neural mechanisms involving economy of gait movements and neuroplasticity of the motor system.

This question is being examined in our third cohort, now under investigation. This cohort will evaluate the effects of treadmill exercise on 32 chronically disabled stroke survivors in a single-center study design that is randomizing 64 subjects to 6 months of three-times-weekly treadmill training or conventional physiotherapy.⁶ Similar to our prior studies, subjects are randomized at least 6 months after their index stroke; this lengthy interval is deliberate because subjects are considered to be in a “plateau” phase of recovery, as they have previously completed rehabilitative therapy.

This group of 32 subjects will undergo both treadmill training and functional magnetic resonance imaging (fMRI) during unilateral knee movements to assess alterations in brain function during such movements over the 6-month study (Figure 2). Previous fMRI studies of healthy controls and stroke patients identified activation of regions in the right side of the cerebral hemisphere with left knee movement.^7,8 In the new fMRI study, functional activation patterns of paretic and nonparetic knee movement will be compared between the exercise group and the control group, and the relationship between the activation pattern and the location of the brain-activation region will be characterized for the paretic and nonparetic knee movements.

Activation will be measured in five prespecified “regions of interest”: the precentral gyrus, the postcentral gyrus, the supplementary motor area, the midbrain, and the cerebellum (anterior/posterior lobes). Difference activation maps of post-training minus pretraining fMRIs of paretic knee movement across all patients undergoing treadmill therapy will then be analyzed. The control group, which will receive dose-matched stretching activity from physical therapy, can be contrasted by comparing the patterns of pre/post differences in each region. This will allow for assessment of increased regional activation in the brain that should be specific to the treadmill training intervention. Furthermore, if a specifically localized regional activation difference is found, then individual fMRI and VO₂ training responses (VO₂peak, increase in walking speeds) can be correlated to further assess the relationship between regional activation and magnitude of functional response to the treadmill intervention.

 

 

DISCUSSION AND CONCLUSIONS

Central control of walking

Control of gait in animals is mediated by the cortex, brainstem/cerebellum,^9,10 and spinal cord—the so-called cervical gait and lumbar gait pattern-generating areas of the spinal cord. In humans, cortical and spinal gait pattern areas are thought to be major regulatory centers of ambulation. Whether the cortical areas influence ambulatory recovery mediated by exercise training or whether the recruitment of spinal gait areas is needed to improve motor control after stroke is not known in humans. We will test the hypothesis that the recruitment of cortical and/or subcortical areas is relevant to some or all of the exercise-induced neuroplasticity response to treadmill rehabilitation. If a consistent pattern of brain regional activation is associated with an improvement in walking ability, this finding will suggest potential brain targets for neurally directed rehabilitation interventions. If brain targets for rehabilitation produce viable therapeutic improvement in walking and cardiocirculatory performance (such as VO₂), this will be further evidence of heart-brain interactions.

Future research directions

Studies to date demonstrate that long-term treadmill exercise affects both the brain and cardiac physiology. This has holistic implications for the function of the whole person as well. Yet several pressing issues continue to confront researchers in post-stroke rehabilitation. One is the optimal therapeutic target and the intensity of the rehabilitative effort. Is this improvement solely a response of muscle and cardiac tissue to exercise, or is it possible that improved neuromotor control is a critical component to a major recovery of walking function? Furthermore, the most efficacious elements of rehabilitative therapy are not known. Should treadmill training be high- or low-intensity, and should it be accompanied by strength training, agility and flexibility activities, or other elements directed at reacquisition of finer degrees of gait-related motor training and neuropsychological input, as achieved by tai-chi or yoga? Another issue is the proper dose of rehabilitative therapy, which has barely been explored, although recent preliminary work suggests that the response is dose-dependent. Finally, predictors of response have not been established because the mechanisms of therapy and surrogate markers for early response are not well understood.

Our future research plans are to assess whether a better understanding of neural targets for rehabilitative treatment will be a fruitful avenue to improve recovery. Additionally, this plan will assess whether fMRI can serve as a surrogate marker of recovery by offering a noninvasive means to measure response to rehabilitation.

Ideally, rehabilitation following a stroke that leads to functional deficit will result in a rapid return to normal function. In the real world, however, a rapid improvement in function is rarely achieved. Between 80% and 90% of stroke survivors have a motor deficit, with impairments in walking being the most common motor deficits.¹ Most stroke survivors have a diminished fitness reserve that is stable and resistant to routine rehabilitative interventions. Recent research has begun to assess the value of exercise and other modalities of training during this period of stability to improve function long after cessation of other therapeutic interventions. This article will review this research and provide insight into those issues in post-stroke rehabilitation that remain to be addressed and may affect heart and brain physiology.

STROKE REDUCES AEROBIC CAPACITY

At all ages, the fitness level of stroke survivors, as measured by maximum oxygen consumption, is reduced by approximately 50% below that of an age-matched normal population. In a study comparing peak oxygen consumption during treadmill walking between stroke survivors and age-matched sedentary controls, we found that the stroke participants had an approximately 50% lower level of peak fitness relative to the control subjects.² During treadmill walking at self-selected speeds, the stroke volunteers used 75% of their functional capacity, compared with 27% for the age-matched healthy controls. Furthermore, compared with the controls, the stroke subjects demonstrated a poorer economy of gait that required greater oxygen consumption to sustain their self-selected walking speeds.

CLINICAL TRIALS OF POST-STROKE EXERCISE REHABILITATION

In light of the efficacy of treadmill exercise in cardiac rehabilitation, we are evaluating whether treadmill exercise can similarly improve fitness, endurance, and walking velocity in stroke survivors. We have completed 6 months of treadmill training in two separate cohorts that show highly consistent results in terms of improved walking abilities in hemiparetic stroke subjects.^3,4 A third cohort is in progress to confirm these findings and examine the effects of intensity on the functional benefits⁵ and mechanisms⁶ underlying the effects of treadmill training.

Treadmill exercise results in functional benefits and improved glucose metabolism

The first cohort was a before-and-after comparison of stable stroke survivors who underwent a three-times-weekly treadmill exercise program for 6 months.³ Peak exercise capacity testing (VO₂peak) revealed functional benefits with minimal cardiac and injury risk compared with baseline, demonstrating the feasibility and safety of treadmill exercise therapy in stroke-impaired adults.

Reprinted, with permission, from Macko RF, et al. Treadmill exercise rehabilitation improves ambulatory function and cardiovascular fitness in patients with chronic stroke. A randomized, controlled trial. Stroke 2005; 36:2206–2211.

The second cohort involved patients with chronic hemiparetic gait following ischemic stroke who were randomized to either treadmill aerobic training (three times weekly for 6 months) (n = 25) or a control rehabilitation program of stretching (n = 20).⁴ The aerobic training group selected its own walking speed and increased its speed as tolerated; some participants in this group started with as little as 2 minutes on the treadmill. As shown in Figure 1, performance on the 6-minute walk test improved significantly in the aerobic training group, relative to the control group, over the 6-month study. Six-minute walk results parallelled the improved functional performance.

Potential mechanisms for the benefits

These findings raise the question of whether these beneficial effects of treadmill exercise are attributable to muscle training effects, cardiopulmonary circulatory training effects, or perhaps neural mechanisms involving economy of gait movements and neuroplasticity of the motor system.

This question is being examined in our third cohort, now under investigation. This cohort will evaluate the effects of treadmill exercise on 32 chronically disabled stroke survivors in a single-center study design that is randomizing 64 subjects to 6 months of three-times-weekly treadmill training or conventional physiotherapy.⁶ Similar to our prior studies, subjects are randomized at least 6 months after their index stroke; this lengthy interval is deliberate because subjects are considered to be in a “plateau” phase of recovery, as they have previously completed rehabilitative therapy.

This group of 32 subjects will undergo both treadmill training and functional magnetic resonance imaging (fMRI) during unilateral knee movements to assess alterations in brain function during such movements over the 6-month study (Figure 2). Previous fMRI studies of healthy controls and stroke patients identified activation of regions in the right side of the cerebral hemisphere with left knee movement.^7,8 In the new fMRI study, functional activation patterns of paretic and nonparetic knee movement will be compared between the exercise group and the control group, and the relationship between the activation pattern and the location of the brain-activation region will be characterized for the paretic and nonparetic knee movements.

Activation will be measured in five prespecified “regions of interest”: the precentral gyrus, the postcentral gyrus, the supplementary motor area, the midbrain, and the cerebellum (anterior/posterior lobes). Difference activation maps of post-training minus pretraining fMRIs of paretic knee movement across all patients undergoing treadmill therapy will then be analyzed. The control group, which will receive dose-matched stretching activity from physical therapy, can be contrasted by comparing the patterns of pre/post differences in each region. This will allow for assessment of increased regional activation in the brain that should be specific to the treadmill training intervention. Furthermore, if a specifically localized regional activation difference is found, then individual fMRI and VO₂ training responses (VO₂peak, increase in walking speeds) can be correlated to further assess the relationship between regional activation and magnitude of functional response to the treadmill intervention.

 

 

DISCUSSION AND CONCLUSIONS

Central control of walking

Control of gait in animals is mediated by the cortex, brainstem/cerebellum,^9,10 and spinal cord—the so-called cervical gait and lumbar gait pattern-generating areas of the spinal cord. In humans, cortical and spinal gait pattern areas are thought to be major regulatory centers of ambulation. Whether the cortical areas influence ambulatory recovery mediated by exercise training or whether the recruitment of spinal gait areas is needed to improve motor control after stroke is not known in humans. We will test the hypothesis that the recruitment of cortical and/or subcortical areas is relevant to some or all of the exercise-induced neuroplasticity response to treadmill rehabilitation. If a consistent pattern of brain regional activation is associated with an improvement in walking ability, this finding will suggest potential brain targets for neurally directed rehabilitation interventions. If brain targets for rehabilitation produce viable therapeutic improvement in walking and cardiocirculatory performance (such as VO₂), this will be further evidence of heart-brain interactions.

Future research directions

Studies to date demonstrate that long-term treadmill exercise affects both the brain and cardiac physiology. This has holistic implications for the function of the whole person as well. Yet several pressing issues continue to confront researchers in post-stroke rehabilitation. One is the optimal therapeutic target and the intensity of the rehabilitative effort. Is this improvement solely a response of muscle and cardiac tissue to exercise, or is it possible that improved neuromotor control is a critical component to a major recovery of walking function? Furthermore, the most efficacious elements of rehabilitative therapy are not known. Should treadmill training be high- or low-intensity, and should it be accompanied by strength training, agility and flexibility activities, or other elements directed at reacquisition of finer degrees of gait-related motor training and neuropsychological input, as achieved by tai-chi or yoga? Another issue is the proper dose of rehabilitative therapy, which has barely been explored, although recent preliminary work suggests that the response is dose-dependent. Finally, predictors of response have not been established because the mechanisms of therapy and surrogate markers for early response are not well understood.

Our future research plans are to assess whether a better understanding of neural targets for rehabilitative treatment will be a fruitful avenue to improve recovery. Additionally, this plan will assess whether fMRI can serve as a surrogate marker of recovery by offering a noninvasive means to measure response to rehabilitation.