CHICAGO - Gene therapy proved ineffective in critical limb ischemia patients with ischemic skin lesions unsuitable for revascularization in the largest-ever clinical trial of gene therapy for this application.

Results of the phase III, randomized, double-blind, 525-patient TAMARIS study showed a 37% rate of death or major amputation at 1 year in recipients of the gene controlling for the expression of angiogenic fibroblast growth factor 1, compared with a 33% rate in placebo-treated controls.

“This was a definitively negative trial,” Dr. William R. Hiatt declared in presenting the TAMARIS results at the annual scientific sessions of the American Heart Association.

The TAMARIS findings are particularly disappointing in light of the earlier, highly impressive results of the phase II TALISMAN study. In that 125-patient study, the same gene delivery system, known as NV1FGF, resulted in a 56% reduction in the combined end point of death or major amputation at 1 year, said Dr. Hiatt, professor of medicine and cardiology at the University of Colorado, Denver.
 
The delivered gene, FGF1, codes for heparin-binding growth factor 1, which is a known angiogenic factor.

“I would merely say that this confirms the importance of large, well-conducted, randomized controlled trials. You really shouldn't make therapeutic decisions based on phase II trials,” he said.

Gene therapy recipients received four 4-mg intramuscular injections of NV1FGF over a 6-week period.

Dr. Hiatt said the concept of therapeutic angiogenesis “remains alive,” but the focus should shift to stem cell-based therapies, which show great promise.
 
Indeed, elsewhere at the meeting Dr. Douglas W. Losordo presented the results of a phase II study of autologous CD34+ cells for critical limb ischemia unsuitable for surgical or percutaneous revascularization. In that 28-patient study, cell therapy recipients had a 74% greater amputation-free survival rate at 1 year than did placebo-treated controls.

Dr. Losordo, the designated discussant for the TAMARIS trial, said one possible explanation for the divergent results relative to the earlier phase II TALISMAN study is that TAMARIS was conducted in 30 countries on multiple continents, whereas TALISMAN was carried out in a more genetically homogeneous European population. It's possible, he theorized, that there are genetic differences in critical limb ischemia and in the response to gene therapy.

New treatments for critical limb ischemia with tissue loss are desperately needed. There are 100,000 amputations per year in the United States for this condition. The amputation rate hasn't changed in 3 decades, noted Dr. Losordo, professor of medicine and director of the Feinberg Cardiovascular Research Institute at Northwestern University, Chicago.
 
Dr. Hiatt disclosed that he has received a research grant from Sanofi-Aventis, which funded the TAMARIS trial. The CD34+ cell therapy study was sponsored by Baxter Healthcare. Dr. Losordo declared that he was previously a paid consultant to Baxter.

CHICAGO - Gene therapy proved ineffective in critical limb ischemia patients with ischemic skin lesions unsuitable for revascularization in the largest-ever clinical trial of gene therapy for this application.

Results of the phase III, randomized, double-blind, 525-patient TAMARIS study showed a 37% rate of death or major amputation at 1 year in recipients of the gene controlling for the expression of angiogenic fibroblast growth factor 1, compared with a 33% rate in placebo-treated controls.

“This was a definitively negative trial,” Dr. William R. Hiatt declared in presenting the TAMARIS results at the annual scientific sessions of the American Heart Association.

The TAMARIS findings are particularly disappointing in light of the earlier, highly impressive results of the phase II TALISMAN study. In that 125-patient study, the same gene delivery system, known as NV1FGF, resulted in a 56% reduction in the combined end point of death or major amputation at 1 year, said Dr. Hiatt, professor of medicine and cardiology at the University of Colorado, Denver.
 
The delivered gene, FGF1, codes for heparin-binding growth factor 1, which is a known angiogenic factor.

“I would merely say that this confirms the importance of large, well-conducted, randomized controlled trials. You really shouldn't make therapeutic decisions based on phase II trials,” he said.

Gene therapy recipients received four 4-mg intramuscular injections of NV1FGF over a 6-week period.

Dr. Hiatt said the concept of therapeutic angiogenesis “remains alive,” but the focus should shift to stem cell-based therapies, which show great promise.
 
Indeed, elsewhere at the meeting Dr. Douglas W. Losordo presented the results of a phase II study of autologous CD34+ cells for critical limb ischemia unsuitable for surgical or percutaneous revascularization. In that 28-patient study, cell therapy recipients had a 74% greater amputation-free survival rate at 1 year than did placebo-treated controls.

Dr. Losordo, the designated discussant for the TAMARIS trial, said one possible explanation for the divergent results relative to the earlier phase II TALISMAN study is that TAMARIS was conducted in 30 countries on multiple continents, whereas TALISMAN was carried out in a more genetically homogeneous European population. It's possible, he theorized, that there are genetic differences in critical limb ischemia and in the response to gene therapy.

New treatments for critical limb ischemia with tissue loss are desperately needed. There are 100,000 amputations per year in the United States for this condition. The amputation rate hasn't changed in 3 decades, noted Dr. Losordo, professor of medicine and director of the Feinberg Cardiovascular Research Institute at Northwestern University, Chicago.
 
Dr. Hiatt disclosed that he has received a research grant from Sanofi-Aventis, which funded the TAMARIS trial. The CD34+ cell therapy study was sponsored by Baxter Healthcare. Dr. Losordo declared that he was previously a paid consultant to Baxter.

CHICAGO - Gene therapy proved ineffective in critical limb ischemia patients with ischemic skin lesions unsuitable for revascularization in the largest-ever clinical trial of gene therapy for this application.

Results of the phase III, randomized, double-blind, 525-patient TAMARIS study showed a 37% rate of death or major amputation at 1 year in recipients of the gene controlling for the expression of angiogenic fibroblast growth factor 1, compared with a 33% rate in placebo-treated controls.

“This was a definitively negative trial,” Dr. William R. Hiatt declared in presenting the TAMARIS results at the annual scientific sessions of the American Heart Association.

The TAMARIS findings are particularly disappointing in light of the earlier, highly impressive results of the phase II TALISMAN study. In that 125-patient study, the same gene delivery system, known as NV1FGF, resulted in a 56% reduction in the combined end point of death or major amputation at 1 year, said Dr. Hiatt, professor of medicine and cardiology at the University of Colorado, Denver.
 
The delivered gene, FGF1, codes for heparin-binding growth factor 1, which is a known angiogenic factor.

“I would merely say that this confirms the importance of large, well-conducted, randomized controlled trials. You really shouldn't make therapeutic decisions based on phase II trials,” he said.

Gene therapy recipients received four 4-mg intramuscular injections of NV1FGF over a 6-week period.

Dr. Hiatt said the concept of therapeutic angiogenesis “remains alive,” but the focus should shift to stem cell-based therapies, which show great promise.
 
Indeed, elsewhere at the meeting Dr. Douglas W. Losordo presented the results of a phase II study of autologous CD34+ cells for critical limb ischemia unsuitable for surgical or percutaneous revascularization. In that 28-patient study, cell therapy recipients had a 74% greater amputation-free survival rate at 1 year than did placebo-treated controls.

Dr. Losordo, the designated discussant for the TAMARIS trial, said one possible explanation for the divergent results relative to the earlier phase II TALISMAN study is that TAMARIS was conducted in 30 countries on multiple continents, whereas TALISMAN was carried out in a more genetically homogeneous European population. It's possible, he theorized, that there are genetic differences in critical limb ischemia and in the response to gene therapy.

New treatments for critical limb ischemia with tissue loss are desperately needed. There are 100,000 amputations per year in the United States for this condition. The amputation rate hasn't changed in 3 decades, noted Dr. Losordo, professor of medicine and director of the Feinberg Cardiovascular Research Institute at Northwestern University, Chicago.
 
Dr. Hiatt disclosed that he has received a research grant from Sanofi-Aventis, which funded the TAMARIS trial. The CD34+ cell therapy study was sponsored by Baxter Healthcare. Dr. Losordo declared that he was previously a paid consultant to Baxter.

Researchers determined that MRI imaging may predict which persons with cognitive impairment will progress to Alzheimer’s disease in a report published in the April 6 online Radiology. Baseline MRI was obtained for 164 individuals with late-onset Alzheimer’s disease, 317 with mild cognitive impairment, and 203 healthy controls. The investigators then used MRI to measure the thickness and amount of atrophy in the cerebral cortex. “Individualized risk estimates from baseline MRI examinations indicated that the one-year risk of conversion to Alzheimer’s disease ranged from 3% to 40%,” the researchers reported. “Relative to the risk of conversion to Alzheimer’s disease conferred by the clinical diagnosis of mild cognitive impairment alone, MRI measures yield substantially more informative patient-specific risk estimates. Such predictive prognostic information will be critical if disease-modifying therapies become available.”

Cotinine, a compound derived from tobacco, reduced brain plaques associated with dementia and memory loss, according to a study published in the online February 14 Journal of Alzheimer’s Disease. A group of investigators studied the effects of cotinine on b-amyloid plaque aggregation in the brains of mice with Alzheimer’s disease. Mice treated with the compound performed better than untreated mice on tasks measuring working memory and thinking skills; long-term treatment also appeared to prevent spatial memory impairment. Overall, the treated mice showed a 26% reduction in amyloid plaque deposits. “Cotinine, the main metabolite of nicotine, has a long half-life and does not have cardiovascular or addictive side effects in humans,” the authors wrote. “The good safety profile in humans and its beneficial effects suggest that cotinine may be an excellent therapeutic candidate for the treatment of Alzheimer’s disease.”

A study published in the April 13 online Neurology provides evidence that treating certain vascular risk factors helps lower the risk for conversion from mild cognitive impairment to Alzheimer’s disease. Investigators assessed memory and thinking skills of 837 patients with mild cognitive impairment and then reassessed them five years later; 414 participants had at least one vascular risk factor at baseline. “At the end of follow-up 298 subjects converted to Alzheimer’s disease dementia, while 352 remained with mild cognitive impairment,” the investigators reported. “Treatment of individual vascular risk factors including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of Alzheimer’s disease conversion.” The findings of the study are observational, the authors concluded, but they suggest that active intervention and treatment of certain risk factors might reduce progression to Alzheimer’s disease.

Researchers have identified mutations of the synapsin 1 gene as a possible common genetic cause for both epilepsy and autism. Their study, published online in the April 12 Human Molecular Genetics, involved members of a large French-Canadian family who had autism spectrum disorders or epilepsy. The severe Q555X mutation appeared in all family members with epilepsy, and in all those who had an autism spectrum disorder. In addition, other mutations in synapsin 1 (A51G, A550T, and T567A) were found in 1% and 3.5% of a separate cohort of French-Canadian individuals with autism and epilepsy, respectively. “These results demonstrate that [synapsin 1] is a novel predisposing gene to [autism spectrum disorders], in addition to epilepsy,” the authors concluded. “[The results also] strengthen the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases.”

Men who reported chronic ecstasy (MDMA) use were more likely to develop structural brain damage than those who did not use ecstasy, according to a study that was published in the March 28 online Journal of Neurology, Neurosurgery and Psychiatry. Using MRI, researchers measured the hippocampal volume of 10 male ecstasy users (average age, 21.3), compared with seven age- and gender-matched subjects who did not use ecstasy. The hippocampal volume of ecstasy users was 10.5% smaller than those of nonusing peers; the overall proportion of gray matter was 4.6% smaller, suggesting that the drug’s effects are not limited to the hippocampus. “These data provide preliminary evidence that ecstasy users may be prone to incurring hippocampal damage,” the authors wrote, adding: “Hippocampal atrophy is a hallmark for disease of progressive cognitive impairment in older patients, such as Alzheimer’s disease.”

In a study published in the March 28 online Journal of Neurology, Neurosurgery and Psychiatry, researchers reported that epileptic seizures carry a subsequent risk for brain tumor. “Our study suggests that tumor as an underlying cause for epilepsy may not become apparent for several years after onset, and indicates a need for ongoing vigilance,” the authors stated. In the retrospective cohort study, the investigators examined data regarding individuals with first-time epilepsy admissions and determined that, compared with patients admitted for other common and minor disorders, patients with epilepsy were almost 20 times more likely to develop cerebral tumor. The risk for developing malignant tumors was more than twice the risk for developing benign tumors. “The risk was highest for those aged 15 to 44 years at initial admission for epilepsy,” the authors reported. “The risk of cerebral tumor was still raised several years after initial admission for epilepsy.”

A novel gene transfer vector, NP2, is safe and well tolerated for the treatment of intractable pain, researchers reported in the April 11 online Annals of Neurology. Investigators conducted a multicenter, dose-escalation, phase I clinical trial of intradermal NP2 injection in 10 subjects with persistent pain caused by cancer, despite treatment with morphine or other analgesic. Participants who received the low dose of NP2 reported no substantive change in pain; patients in the middle and high dose cohorts reported pain relief. “There were no placebo controls in this relatively small study,” the authors concluded. “But the dose-responsive analgesic effects suggest that NP2 may be effective in reducing pain and warrants further clinical investigation.”

The FDA has approved DaTscan (ioflupane I 123 injection) for detecting dopamine transporters in the brains of adults with suspected Parkinsonian syndromes. The radiopharmaceutical agent is intended for use with single photon emission CT imaging to evaluate neurodegenerative movement disorders. The injection may be used as an adjunct to other diagnostic evaluation tools to distinguish between essential tremor and tremor due to Parkinson’s disease, as ioflupane I 123 injection alone cannot differentiate between different types of parkinsonian syndromes. The FDA’s approval was based on two phase III clinical trials in which the drug was used to evaluate dopamine transporter distribution in the brains of adult patients. As a new diagnostic adjunct to clinical assessments, ioflupane  I 123 can potentially help physicians select the appropriate treatments for patients with movement disorders.

Persons who are regularly exposed to welding fumes may be at an increased risk for brain damage, specifically in the same areas affected by Parkinson’s disease, researchers reported in the April 12 Neurology. “Welding exposes workers to manganese fumes, but it is unclear if this exposure damages dopaminergic neurons,” the authors stated. “The purpose of this study [was] to determine whether welding exposure is associated with damage to nigrostriatal neurons.” Using PET imaging on 20 welders with no parkinsonian symptoms, 20 individuals with symptoms, and 20 healthy controls, the investigators determined that asymptomatic welders had higher manganese levels in the blood and an average 11.7% reduction in dopamine in certain brain regions. The pattern of reduction seen in welders, however, was distinct from the dysfunction pattern found in symptomatic Parkinson’s disease.

The FDA has approved Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) for the treatment of pseudobulbar affect. The new therapy will help patients manage pseudobulbar affect that occurs secondary to multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, stroke, Parkinson’s disease, and other neurologic diseases. Nuedexta combines dextromethorphan hydrobromide and quinidine sulfate, a metabolic inhibitor that enables therapeutic dextromethorphan concentrations. These components act on NMDA receptors and sigma-1 in the brain, but the mechanism by which it exerts therapeutic effects in patients with pseudobulbar affect is unknown. The drug was tested in patients with ALS and MS and reduced involuntary laughing and crying episodes compared with placebo. 

Virtual reality may be an effective adjunctive therapy for patients experiencing upper arm motor deficits following stroke, according to a study published in the May Stroke. Researchers analyzed seven observational studies and five randomized trials that investigated the effects of virtual reality and video game technology on stroke patients’ upper arm strength and function. Among the observational studies, there was a 14.7% improvement in motor impairment and a 20.1% improvement in motor function; in the randomized trials, patients had an almost five times higher chance of improvement in motor function, compared with those who received traditional therapy. The researchers concluded, “Virtual reality and video game applications are novel and potentially useful technologies that can be combined with conventional rehabilitation for upper arm improvement after stroke.”

Investigators found that surgical revascularization can restore lost brain tissue in patients with cerebrovascular disease that impairs blood flow to the brain, as reported in the online April 14 Stroke. Twenty-nine patients who had undergone vascularization were included in the study. All patients had pre- and postsurgery studies of cerebrovascular reactivity using MRI, and cortical thickness in regions corresponding to steal physiology were measured. “At an average of 11 months after surgery, cortical thickness increased in every successfully revascularized hemisphere,” the authors stated. “Mean cortical thickness in the revascularized regions increased by 5.1%.” The investigators’ goal was to halt further loss of brain tissue due to strokes, “so it was remarkable to see the loss was actually reversed,” they commented.

Researchers determined that MRI imaging may predict which persons with cognitive impairment will progress to Alzheimer’s disease in a report published in the April 6 online Radiology. Baseline MRI was obtained for 164 individuals with late-onset Alzheimer’s disease, 317 with mild cognitive impairment, and 203 healthy controls. The investigators then used MRI to measure the thickness and amount of atrophy in the cerebral cortex. “Individualized risk estimates from baseline MRI examinations indicated that the one-year risk of conversion to Alzheimer’s disease ranged from 3% to 40%,” the researchers reported. “Relative to the risk of conversion to Alzheimer’s disease conferred by the clinical diagnosis of mild cognitive impairment alone, MRI measures yield substantially more informative patient-specific risk estimates. Such predictive prognostic information will be critical if disease-modifying therapies become available.”

Cotinine, a compound derived from tobacco, reduced brain plaques associated with dementia and memory loss, according to a study published in the online February 14 Journal of Alzheimer’s Disease. A group of investigators studied the effects of cotinine on b-amyloid plaque aggregation in the brains of mice with Alzheimer’s disease. Mice treated with the compound performed better than untreated mice on tasks measuring working memory and thinking skills; long-term treatment also appeared to prevent spatial memory impairment. Overall, the treated mice showed a 26% reduction in amyloid plaque deposits. “Cotinine, the main metabolite of nicotine, has a long half-life and does not have cardiovascular or addictive side effects in humans,” the authors wrote. “The good safety profile in humans and its beneficial effects suggest that cotinine may be an excellent therapeutic candidate for the treatment of Alzheimer’s disease.”

A study published in the April 13 online Neurology provides evidence that treating certain vascular risk factors helps lower the risk for conversion from mild cognitive impairment to Alzheimer’s disease. Investigators assessed memory and thinking skills of 837 patients with mild cognitive impairment and then reassessed them five years later; 414 participants had at least one vascular risk factor at baseline. “At the end of follow-up 298 subjects converted to Alzheimer’s disease dementia, while 352 remained with mild cognitive impairment,” the investigators reported. “Treatment of individual vascular risk factors including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of Alzheimer’s disease conversion.” The findings of the study are observational, the authors concluded, but they suggest that active intervention and treatment of certain risk factors might reduce progression to Alzheimer’s disease.

Researchers have identified mutations of the synapsin 1 gene as a possible common genetic cause for both epilepsy and autism. Their study, published online in the April 12 Human Molecular Genetics, involved members of a large French-Canadian family who had autism spectrum disorders or epilepsy. The severe Q555X mutation appeared in all family members with epilepsy, and in all those who had an autism spectrum disorder. In addition, other mutations in synapsin 1 (A51G, A550T, and T567A) were found in 1% and 3.5% of a separate cohort of French-Canadian individuals with autism and epilepsy, respectively. “These results demonstrate that [synapsin 1] is a novel predisposing gene to [autism spectrum disorders], in addition to epilepsy,” the authors concluded. “[The results also] strengthen the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases.”

Men who reported chronic ecstasy (MDMA) use were more likely to develop structural brain damage than those who did not use ecstasy, according to a study that was published in the March 28 online Journal of Neurology, Neurosurgery and Psychiatry. Using MRI, researchers measured the hippocampal volume of 10 male ecstasy users (average age, 21.3), compared with seven age- and gender-matched subjects who did not use ecstasy. The hippocampal volume of ecstasy users was 10.5% smaller than those of nonusing peers; the overall proportion of gray matter was 4.6% smaller, suggesting that the drug’s effects are not limited to the hippocampus. “These data provide preliminary evidence that ecstasy users may be prone to incurring hippocampal damage,” the authors wrote, adding: “Hippocampal atrophy is a hallmark for disease of progressive cognitive impairment in older patients, such as Alzheimer’s disease.”

In a study published in the March 28 online Journal of Neurology, Neurosurgery and Psychiatry, researchers reported that epileptic seizures carry a subsequent risk for brain tumor. “Our study suggests that tumor as an underlying cause for epilepsy may not become apparent for several years after onset, and indicates a need for ongoing vigilance,” the authors stated. In the retrospective cohort study, the investigators examined data regarding individuals with first-time epilepsy admissions and determined that, compared with patients admitted for other common and minor disorders, patients with epilepsy were almost 20 times more likely to develop cerebral tumor. The risk for developing malignant tumors was more than twice the risk for developing benign tumors. “The risk was highest for those aged 15 to 44 years at initial admission for epilepsy,” the authors reported. “The risk of cerebral tumor was still raised several years after initial admission for epilepsy.”

A novel gene transfer vector, NP2, is safe and well tolerated for the treatment of intractable pain, researchers reported in the April 11 online Annals of Neurology. Investigators conducted a multicenter, dose-escalation, phase I clinical trial of intradermal NP2 injection in 10 subjects with persistent pain caused by cancer, despite treatment with morphine or other analgesic. Participants who received the low dose of NP2 reported no substantive change in pain; patients in the middle and high dose cohorts reported pain relief. “There were no placebo controls in this relatively small study,” the authors concluded. “But the dose-responsive analgesic effects suggest that NP2 may be effective in reducing pain and warrants further clinical investigation.”

The FDA has approved DaTscan (ioflupane I 123 injection) for detecting dopamine transporters in the brains of adults with suspected Parkinsonian syndromes. The radiopharmaceutical agent is intended for use with single photon emission CT imaging to evaluate neurodegenerative movement disorders. The injection may be used as an adjunct to other diagnostic evaluation tools to distinguish between essential tremor and tremor due to Parkinson’s disease, as ioflupane I 123 injection alone cannot differentiate between different types of parkinsonian syndromes. The FDA’s approval was based on two phase III clinical trials in which the drug was used to evaluate dopamine transporter distribution in the brains of adult patients. As a new diagnostic adjunct to clinical assessments, ioflupane  I 123 can potentially help physicians select the appropriate treatments for patients with movement disorders.

Persons who are regularly exposed to welding fumes may be at an increased risk for brain damage, specifically in the same areas affected by Parkinson’s disease, researchers reported in the April 12 Neurology. “Welding exposes workers to manganese fumes, but it is unclear if this exposure damages dopaminergic neurons,” the authors stated. “The purpose of this study [was] to determine whether welding exposure is associated with damage to nigrostriatal neurons.” Using PET imaging on 20 welders with no parkinsonian symptoms, 20 individuals with symptoms, and 20 healthy controls, the investigators determined that asymptomatic welders had higher manganese levels in the blood and an average 11.7% reduction in dopamine in certain brain regions. The pattern of reduction seen in welders, however, was distinct from the dysfunction pattern found in symptomatic Parkinson’s disease.

The FDA has approved Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) for the treatment of pseudobulbar affect. The new therapy will help patients manage pseudobulbar affect that occurs secondary to multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, stroke, Parkinson’s disease, and other neurologic diseases. Nuedexta combines dextromethorphan hydrobromide and quinidine sulfate, a metabolic inhibitor that enables therapeutic dextromethorphan concentrations. These components act on NMDA receptors and sigma-1 in the brain, but the mechanism by which it exerts therapeutic effects in patients with pseudobulbar affect is unknown. The drug was tested in patients with ALS and MS and reduced involuntary laughing and crying episodes compared with placebo. 

Virtual reality may be an effective adjunctive therapy for patients experiencing upper arm motor deficits following stroke, according to a study published in the May Stroke. Researchers analyzed seven observational studies and five randomized trials that investigated the effects of virtual reality and video game technology on stroke patients’ upper arm strength and function. Among the observational studies, there was a 14.7% improvement in motor impairment and a 20.1% improvement in motor function; in the randomized trials, patients had an almost five times higher chance of improvement in motor function, compared with those who received traditional therapy. The researchers concluded, “Virtual reality and video game applications are novel and potentially useful technologies that can be combined with conventional rehabilitation for upper arm improvement after stroke.”

Investigators found that surgical revascularization can restore lost brain tissue in patients with cerebrovascular disease that impairs blood flow to the brain, as reported in the online April 14 Stroke. Twenty-nine patients who had undergone vascularization were included in the study. All patients had pre- and postsurgery studies of cerebrovascular reactivity using MRI, and cortical thickness in regions corresponding to steal physiology were measured. “At an average of 11 months after surgery, cortical thickness increased in every successfully revascularized hemisphere,” the authors stated. “Mean cortical thickness in the revascularized regions increased by 5.1%.” The investigators’ goal was to halt further loss of brain tissue due to strokes, “so it was remarkable to see the loss was actually reversed,” they commented.

Researchers determined that MRI imaging may predict which persons with cognitive impairment will progress to Alzheimer’s disease in a report published in the April 6 online Radiology. Baseline MRI was obtained for 164 individuals with late-onset Alzheimer’s disease, 317 with mild cognitive impairment, and 203 healthy controls. The investigators then used MRI to measure the thickness and amount of atrophy in the cerebral cortex. “Individualized risk estimates from baseline MRI examinations indicated that the one-year risk of conversion to Alzheimer’s disease ranged from 3% to 40%,” the researchers reported. “Relative to the risk of conversion to Alzheimer’s disease conferred by the clinical diagnosis of mild cognitive impairment alone, MRI measures yield substantially more informative patient-specific risk estimates. Such predictive prognostic information will be critical if disease-modifying therapies become available.”

Cotinine, a compound derived from tobacco, reduced brain plaques associated with dementia and memory loss, according to a study published in the online February 14 Journal of Alzheimer’s Disease. A group of investigators studied the effects of cotinine on b-amyloid plaque aggregation in the brains of mice with Alzheimer’s disease. Mice treated with the compound performed better than untreated mice on tasks measuring working memory and thinking skills; long-term treatment also appeared to prevent spatial memory impairment. Overall, the treated mice showed a 26% reduction in amyloid plaque deposits. “Cotinine, the main metabolite of nicotine, has a long half-life and does not have cardiovascular or addictive side effects in humans,” the authors wrote. “The good safety profile in humans and its beneficial effects suggest that cotinine may be an excellent therapeutic candidate for the treatment of Alzheimer’s disease.”

A study published in the April 13 online Neurology provides evidence that treating certain vascular risk factors helps lower the risk for conversion from mild cognitive impairment to Alzheimer’s disease. Investigators assessed memory and thinking skills of 837 patients with mild cognitive impairment and then reassessed them five years later; 414 participants had at least one vascular risk factor at baseline. “At the end of follow-up 298 subjects converted to Alzheimer’s disease dementia, while 352 remained with mild cognitive impairment,” the investigators reported. “Treatment of individual vascular risk factors including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of Alzheimer’s disease conversion.” The findings of the study are observational, the authors concluded, but they suggest that active intervention and treatment of certain risk factors might reduce progression to Alzheimer’s disease.

Researchers have identified mutations of the synapsin 1 gene as a possible common genetic cause for both epilepsy and autism. Their study, published online in the April 12 Human Molecular Genetics, involved members of a large French-Canadian family who had autism spectrum disorders or epilepsy. The severe Q555X mutation appeared in all family members with epilepsy, and in all those who had an autism spectrum disorder. In addition, other mutations in synapsin 1 (A51G, A550T, and T567A) were found in 1% and 3.5% of a separate cohort of French-Canadian individuals with autism and epilepsy, respectively. “These results demonstrate that [synapsin 1] is a novel predisposing gene to [autism spectrum disorders], in addition to epilepsy,” the authors concluded. “[The results also] strengthen the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases.”

Men who reported chronic ecstasy (MDMA) use were more likely to develop structural brain damage than those who did not use ecstasy, according to a study that was published in the March 28 online Journal of Neurology, Neurosurgery and Psychiatry. Using MRI, researchers measured the hippocampal volume of 10 male ecstasy users (average age, 21.3), compared with seven age- and gender-matched subjects who did not use ecstasy. The hippocampal volume of ecstasy users was 10.5% smaller than those of nonusing peers; the overall proportion of gray matter was 4.6% smaller, suggesting that the drug’s effects are not limited to the hippocampus. “These data provide preliminary evidence that ecstasy users may be prone to incurring hippocampal damage,” the authors wrote, adding: “Hippocampal atrophy is a hallmark for disease of progressive cognitive impairment in older patients, such as Alzheimer’s disease.”

In a study published in the March 28 online Journal of Neurology, Neurosurgery and Psychiatry, researchers reported that epileptic seizures carry a subsequent risk for brain tumor. “Our study suggests that tumor as an underlying cause for epilepsy may not become apparent for several years after onset, and indicates a need for ongoing vigilance,” the authors stated. In the retrospective cohort study, the investigators examined data regarding individuals with first-time epilepsy admissions and determined that, compared with patients admitted for other common and minor disorders, patients with epilepsy were almost 20 times more likely to develop cerebral tumor. The risk for developing malignant tumors was more than twice the risk for developing benign tumors. “The risk was highest for those aged 15 to 44 years at initial admission for epilepsy,” the authors reported. “The risk of cerebral tumor was still raised several years after initial admission for epilepsy.”

A novel gene transfer vector, NP2, is safe and well tolerated for the treatment of intractable pain, researchers reported in the April 11 online Annals of Neurology. Investigators conducted a multicenter, dose-escalation, phase I clinical trial of intradermal NP2 injection in 10 subjects with persistent pain caused by cancer, despite treatment with morphine or other analgesic. Participants who received the low dose of NP2 reported no substantive change in pain; patients in the middle and high dose cohorts reported pain relief. “There were no placebo controls in this relatively small study,” the authors concluded. “But the dose-responsive analgesic effects suggest that NP2 may be effective in reducing pain and warrants further clinical investigation.”

The FDA has approved DaTscan (ioflupane I 123 injection) for detecting dopamine transporters in the brains of adults with suspected Parkinsonian syndromes. The radiopharmaceutical agent is intended for use with single photon emission CT imaging to evaluate neurodegenerative movement disorders. The injection may be used as an adjunct to other diagnostic evaluation tools to distinguish between essential tremor and tremor due to Parkinson’s disease, as ioflupane I 123 injection alone cannot differentiate between different types of parkinsonian syndromes. The FDA’s approval was based on two phase III clinical trials in which the drug was used to evaluate dopamine transporter distribution in the brains of adult patients. As a new diagnostic adjunct to clinical assessments, ioflupane  I 123 can potentially help physicians select the appropriate treatments for patients with movement disorders.

Persons who are regularly exposed to welding fumes may be at an increased risk for brain damage, specifically in the same areas affected by Parkinson’s disease, researchers reported in the April 12 Neurology. “Welding exposes workers to manganese fumes, but it is unclear if this exposure damages dopaminergic neurons,” the authors stated. “The purpose of this study [was] to determine whether welding exposure is associated with damage to nigrostriatal neurons.” Using PET imaging on 20 welders with no parkinsonian symptoms, 20 individuals with symptoms, and 20 healthy controls, the investigators determined that asymptomatic welders had higher manganese levels in the blood and an average 11.7% reduction in dopamine in certain brain regions. The pattern of reduction seen in welders, however, was distinct from the dysfunction pattern found in symptomatic Parkinson’s disease.

The FDA has approved Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) for the treatment of pseudobulbar affect. The new therapy will help patients manage pseudobulbar affect that occurs secondary to multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, stroke, Parkinson’s disease, and other neurologic diseases. Nuedexta combines dextromethorphan hydrobromide and quinidine sulfate, a metabolic inhibitor that enables therapeutic dextromethorphan concentrations. These components act on NMDA receptors and sigma-1 in the brain, but the mechanism by which it exerts therapeutic effects in patients with pseudobulbar affect is unknown. The drug was tested in patients with ALS and MS and reduced involuntary laughing and crying episodes compared with placebo. 

Virtual reality may be an effective adjunctive therapy for patients experiencing upper arm motor deficits following stroke, according to a study published in the May Stroke. Researchers analyzed seven observational studies and five randomized trials that investigated the effects of virtual reality and video game technology on stroke patients’ upper arm strength and function. Among the observational studies, there was a 14.7% improvement in motor impairment and a 20.1% improvement in motor function; in the randomized trials, patients had an almost five times higher chance of improvement in motor function, compared with those who received traditional therapy. The researchers concluded, “Virtual reality and video game applications are novel and potentially useful technologies that can be combined with conventional rehabilitation for upper arm improvement after stroke.”

Investigators found that surgical revascularization can restore lost brain tissue in patients with cerebrovascular disease that impairs blood flow to the brain, as reported in the online April 14 Stroke. Twenty-nine patients who had undergone vascularization were included in the study. All patients had pre- and postsurgery studies of cerebrovascular reactivity using MRI, and cortical thickness in regions corresponding to steal physiology were measured. “At an average of 11 months after surgery, cortical thickness increased in every successfully revascularized hemisphere,” the authors stated. “Mean cortical thickness in the revascularized regions increased by 5.1%.” The investigators’ goal was to halt further loss of brain tissue due to strokes, “so it was remarkable to see the loss was actually reversed,” they commented.

A 49-year-old woman presented to urgent care with complaints of worsening dyspnea for the previous two days. She reported that her symptoms had begun gradually; at the time of her presentation, however, she was also experiencing chest tightness, occasional wheezing, and a nonproductive cough. She had experienced similar symptoms in the past and obtained good results by using her albuterol inhaler. During the current episode, however, she had not had the usual response to inhaler treatment.

The patient’s medical history was positive for environmental allergies, asthma, and GERD. Two weeks earlier, she had undergone dilatation and curettage (D&C) for dysfunctional bleeding, with no associated complications.

In the social history, the patient reported drinking four to six caffeine beverages daily and consuming alcohol moderately (two to four glasses of wine per week). She was following no formal dietary regimen. The patient denied current or past history of tobacco use and had not traveled recently. She had no family history of coronary vascular disease.

Her medications included albuterol and desloratadine as needed, pantoprazole 40 mg/d, and drospirenone/ethinyl estradiol. The patient said she used her albuterol inhaler four to six times per month but more often in the summer and fall. Nighttime awakenings due to asthma symptoms occurred no more than twice per month. She denied prior history of acute asthma exacerbations requiring oral systemic corticosteroids. The patient stated that since her D&C, she had been using ibuprofen almost daily for mild abdominal cramping.

A review of systems was positive for mild fatigue since her D&C. The patient denied fever, chills, headache, sore throat, or cough. She did complain of daily nasal congestion but with no unusual drainage. The patient denied orthopnea, chest pain, palpitations, or peripheral edema, as well as nausea, vomiting, diarrhea, constipation, hematochezia, or melena. She admitted to daily heartburn for the previous two weeks that was relieved somewhat with pantoprazole. She had not experienced urinary frequency or urgency, dysuria, or hematuria. She also denied rash, pruritus, weakness, paresthesias, joint pain, or swelling.

Physical examination revealed an alert, oriented female who appeared slightly anxious but was in no acute distress. Specific findings were pulse, 110 beats/min; blood pressure, 138/88 mm Hg; respirations, 24 breaths/min; temperature, 97.7°F; O2 saturation, 92% on room air. Her height measured 5’2” and weight, 150 lb (BMI, 27.43).

Her conjunctiva were slightly injected, and the tympanic membranes were intact bilaterally with a light reflex; the septum was midline. The mucosa was pale, boggy, and moist with clear drainage and no inflammation. The nasopharynx had no erythema, and the tonsils appeared normal, although a cobblestone appearance was noted in the posterior pharynx. The neck was supple with no adenopathy.

The patient’s heart rate, 110 beats/min, was regular with no murmurs, rubs, or gallops. In the lungs, a prolonged expiratory phase was noted, with diffuse wheezing on chest auscultation bilaterally. Neither retractions nor use of accessory muscles with breathing was observed. The abdomen was soft, rounded, and nontender with no organomegaly. Bowel sounds were evident in all four quadrants. The patient’s skin was free of suspicious lesions or rashes. Her extremities were without edema, and no calf tenderness was noted; Homans’ sign was negative. Superficial varicosities were noted bilaterally.

The top differential diagnosis included:

• Acute asthma (risk factors: history of uncontrolled asthma, as evidenced by frequent use of albuterol)

• Acute anemia (risk factors: history of dysfunctional uterine bleeding, recent D&C)

• Pulmonary embolism (risk factors: recent surgery, recent start of oral contraceptive use).

Additional diagnoses to be considered less likely included:

• Acute coronary syndrome/MI (possible causes of chest tightness, dyspnea, dyspepsia; but no chest pain, diaphoresis, or nausea)

• Acute respiratory distress (history of tachycardia, possible dyspnea; but no diaphoresis, cyanosis, retractions, accessory muscle use, or lung crackles)

• Pneumonia (risk factors: recent surgery, possible cause of nonproductive cough; but no evidence of fever, chills, rales, or pleuritic chest pain).

Diagnostic testing included a 12-lead ECG to evaluate the patient for cardiac arrhythmia or injury; on it, tachycardia was noted, with a regular rate of 106 beats/min. The patient’s chest x-ray yielded normal results.

Laboratory testing included a complete blood count to screen for anemia and infection. Results included a white blood cell count of 8,200/mL (normal range, 4,500 to 11,000/mL); hematocrit, 38.2% (normal range for women, 36.1% to 44.3%); hemoglobin, 13.1 g/dL (normal for women, 12.1 to 15.1 g/dL). A comprehensive metabolic panel was performed to assess electrolyte levels and kidney and liver function; findings were normal. Results of a D-dimer assay, which was obtained to exclude pulmonary embolism,¹ were normal at 0.5 mg/L (range, 0.4 to 1.4 mg/L).

In the case of heightened suspicion for MI, the patient would have been transferred to the emergency department (ED) for evaluation, including serial cardiac troponin levels; elevated troponin levels are deemed the standard criterion to define and diagnose MI in a consensus document from the European Society of Cardiology and the American College of Cardiology.² (Troponin-T and troponin-I are more tissue-specific than the MB fraction of creatine kinase [CK-MB] in detecting MI; positive troponin levels are considered virtually diagnostic of MI.² Typically, cardiac troponin levels are measured two to three times over a 12- to 16-hour period.)

Peak expiratory flow (PEF), which was measured to evaluate the patient’s respiratory status, was 150 L/min (compared with personal best for a patient of her height and age, approximately 460 L/min). She was given 2.5 mg/3 mL of inhaled albuterol over 15 minutes. Her PEF increased to 350 L/min. O2 saturation improved to 96% on room air, pulse to 104 beats/min, and respirations 20 breaths/min; her blood pressure reading was now 140/90 mm Hg. A prolonged expiratory phase persisted in the lungs, but diffuse wheezing decreased by 40% on chest auscultation.

A second albuterol treatment was administered 20 minutes later, and the patient’s PEF increased to 380 L/min and O2 saturation to 99%. The lungs presently cleared with no further wheezing noted.

In addition, the patient was given a GI cocktail (ie, liquid antacid combined with an anticholinergic agent and viscous lidocaine). Within 10 minutes, her chest tightness was relieved 100%. Her blood pressure was then measured at 135/84 mm Hg; respirations, 18 breaths/min; and pulse rate, 96 beats/min.

According to the National Asthma Education and Prevention Program (NAEPP) 2007 Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 3 (EPR-3),³ the patient was classified as having intermittent, not-well-controlled asthma with an acute exacerbation. In addition, she was given a diagnosis of uncontrolled GERD.

DISCUSSION
Asthma Incidence and Risk Factors
Asthma affects approximately 300 million people worldwide and remains a global respiratory concern.⁴ In the United States, this chronic health condition has a prevalence of 8% to 10%. It is estimated that 5% to 10% of asthmatic patients have severe disease that does not respond typically to therapeutic interventions.⁵

Asthma involves bronchial hyperresponsiveness, airflow obstruction, and underlying inflammation. Acute episodes of asthma, arising from bronchospasm, usually manifest with progressively worsening cough, shortness of breath, chest tightness and wheezing (asthma’s hallmark symptoms), or a combination of symptoms.³

Symptoms of asthma or exacerbations of reactive airway disease vary from patient to patient. In addition to the hallmark symptoms noted, subacute or acute episodes of asthma exacerbation are characterized by decreases in expiratory airflow that can be documented by objective measurements of lung function, such as PEF or spirometry; these measures of airflow indicate the severity of an exacerbation more reliably than does perceived symptom severity.³ The EPR-3 panelists recommend determining asthma severity using a combination of objective criteria and clinical symptoms,³ although few clinicians use the objective criteria.⁶

Estimates of the prevalence of GERD among patients with asthma have varied from 34% to 89%.^7-9 Patients with GERD are 1.97 times more likely than patients without GERD to have asthma¹⁰; silent gastroesophageal reflux has been identified in 24% to 62% of patients with asthma, and early studies suggest that treatment for GERD may improve asthma control in patients with severe or difficult-to-control asthma.^8,11,12

The exact link between the two conditions is unclear. However, possible explanations why GERD and asthma coincide are that acid flow causes injury to the lining of the throat, airways, and lungs, making inhalation difficult and often causing a persistent cough; or that when acid enters the esophagus, a nerve reflex is triggered that causes the airways to narrow in order to prevent the acid from entering; this can explain dyspnea.^8,9

Economic Burden
Asthma is costly to treat, and because there is no cure, the expense is ongoing. According to a 2011 report,¹³ the average annual direct cost of care (eg, medications, hospital admissions, nonemergency office visits) for one asthma patient between 2002 and 2007 was $3,259. In 2007, the most current data available, the total cost of asthma in the US was $56 billion, with productivity losses due to mortality accounting for $2.1 billion and morbidity-related losses estimated at $3.8 billion.¹³ The economic consequences of asthma are substantial and can place a considerable burden on affected individuals, their families, the health care system, and society as a whole.³

Current Standard of Care
Based on the scientific literature and the opinions expressed by the NAEPP in the EPR-3,³ clinicians are advised to consider the following general principles and goals for managing asthma: early treatment, special attention to patients at high risk for asthma-related death, and special attention to infants.³ The guidelines emphasize the importance of a clinician/patient partnership to facilitate the asthma patient’s self-management.

Early treatment is a particularly important component for management of asthma exacerbations. Important elements of early treatment include a written asthma action plan, combined with enhanced awareness of the early indicators of an exacerbation (ie, worsening PEF).^3,14 It is believed that if patients are able to monitor their respiratory condition and follow a plan of care based on their PEF and/or signs and symptoms of asthma, they are more likely to achieve optimal management of their disease.¹⁵

Written Asthma Action Plan. The EPR-3³ recommends that health care providers supply all asthmatic patients with a written asthma action plan that will define and support the patient’s efforts at self-management. Written asthma action plans are particularly beneficial for patients with moderate to severe persistent asthma, poorly controlled asthma, or a history of severe exacerbations.^3,14

The written asthma action plan should include instructions for daily management of asthma and ways to recognize and treat worsening asthma, including adjustments to medication dosing. Plans may be based on PEF and/or symptoms. Asthma action plans should be discussed and reevaluated at follow-up visits.³ A sample asthma action plan can be found at www.health.state.ny.us/diseases/asthma/pdf/4850.pdf.¹⁶

Peak Expiratory Flow (PEF). The EPR-3³ recommends PEF monitoring in all asthma patients, regardless of the severity of their exacerbations.¹⁷ PEF-based plans are especially useful for the patient who has difficulty perceiving early signs and symptoms of worsening asthma.^3,18 A PEF-based plan instructs the patient to use quick-relief medications if symptoms occur or if PEF drops below 80% of the patient’s personal or predicted best. (Measured personal best is the patient’s highest PEF in the previous two weeks of good asthma control,^3,19 whereas predicted best is calculated based on findings from a 1983 study by Knudson et al.^3,20)

A PEF between 50% and 79% requires the patient to carefully monitor his or her response to the quick-relief medication and, based on that response, consider whether to contact a health care provider. When PEF falls below 50%, a provider’s immediate intervention is usually recommended.³

In the urgent care or ED setting, according to EPR-3 recommendations,³ the PEF or forced expiratory volume in 1 second (FEV1) is used to indicate the following:

• ≥ 70% predicted PEF or FEV1: goal for discharge

• 40% to 69% predicted PEF or FEV1: incomplete response to treatment, frequent need for treatment in the ED

• 3

Treatment and Management
Asthma management interventions that target the treatment of active disease and predisposing triggers are designed to reduce the severity and/or duration of morbidity associated with asthma—principally, to prevent symptoms and exacerbations (see Table 1³).

When patients are discharged following an asthma exacerbation, their medications should include an oral corticosteroid burst and a short-acting b2-agonist (SABA); the clinician should also consider prescribing an inhaled corticosteroid (ICS).³

It is no longer recommended that ICS dosing be doubled in place of an oral steroid burst.^3,21 The addition of a leukotriene receptor antagonist (LTRA) may also be considered.^3,22

Patients should be given an action plan, and follow-up with a primary care provider should be scheduled within a few days—or even the following day, depending on the severity of the patient’s condition. The importance of follow-up with a primary care provider, a pulmonologist, or an asthma/allergy specialist should be emphasized.^3,23

For patients who have difficulty recognizing their symptoms, a peak flow meter may be useful. This device is also recommended for patients with moderate to severe asthma or a history of numerous severe exacerbations.³ Additionally, spacers should always be used with metered dose inhalers (MDIs), because they make it easier for medication to reach the lungs and reduce the amount deposited in the mouth and throat, where it can lead to irritation. At each office visit, use of the peak flow meter and inhaler technique should be observed, and the action plan reevaluated and changed if necessary.^3,14

Additional components of patient education include instruction in controlling environmental factors: avoiding environmental tobacco smoke, exposure to insect allergens, and molds. It is also important to stress controlling comorbid conditions that influence asthma, such as allergies or GERD. Patients with symptoms of GERD should be advised to take the steps shown in Table 2.^8,24

Clinical Implications
Assessment of the severity of an asthma exacerbation is an essential component of ambulatory asthma care. Underclassification of asthma severity has been associated with increased morbidity and mortality,⁶ and the NAEPP guidelines recommend that clinicians assess and document asthma severity at each clinic visit.^3,25 Patients who receive care based on evidence-based practice guidelines have been shown to experience 28% better outcomes.²⁶

PATIENT OUTCOME
The case patient was discharged on an oral corticosteroid burst and a low-dose ICS. She was instructed how and when to use her SABA and given a prescription for a spacer; use of a peak flow meter was initiated with an estimated personal best goal of 460 L/min. The patient was given a written asthma action plan to help her recognize early signs and symptoms of worsening asthma and was advised to use quick-relief medications if she experienced symptoms or if her PEF dropped below 80% of her predicted best.

The patient’s clinician emphasized the importance of controlling any asthma-triggering environmental factors and reviewed nonpharmacologic interventions to control GERD. The patient was advised to resume desloratadine 5 mg/d and pantoprazole 40 mg/d. She was also instructed to schedule an appointment with her primary care provider within 48 hours and to return to urgent care or the ED with any further exacerbation of respiratory symptoms not controlled by her SABA.

CONCLUSION
Asthma morbidity is a nationally recognized, major public health problem. Given the sharp rise in health care costs and limited resources, health care providers must factor in the comparative effectiveness, comparative cost, and cost-effectiveness of both new and existing health care interventions when making treatment decisions.

Many asthmatic patients face the challenges of health care access and quality. By promoting their self-care and awareness, clinicians can help asthmatic patients achieve better symptom management and use the health care system less often.

REFERENCES
1. Stein PD, Hull RD, Patel KC, et al. D-Dimer for the exclusion of acute venous thrombosis and pulmonary embolism. Ann Intern Med. 2004;140(8):589-602.

2. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined: a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36(3):959-969.

3. National Asthma Education and Prevention Program, National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007. US Department of Health and Human Services publication NIH 07-4051.

4. Lougheed DM. Variability in asthma: symptom perception, care, and outcomes. Can J Physiol Pharmacol. 2007;85(1):149-154.

5. Higgins JC. The ‘crashing asthmatic.’ Am Fam Physician. 2003;67(5):997-1004. 

6. Cowen MK, Wakefield DB, Cloutier MM. Classifying asthma severity: objective versus subjective measures. J Asthma. 2007;44(9):711-715.

7. Takenaka R, Matsuno O, Kitajima K, et al. The use of frequency scale for the symptoms of GERD in assessment of gastro-oesophageal reflux symptoms in asthma. Allergol Immunopathol (Madr). 2010;38(1):20-24.

8. Harding SM, Barnes PJ, Hollingsworth H. Gastroesophageal reflux and asthma (2010). www.uptodate.com/contents/gastroesophageal-reflux-and-asthma. Accessed April 5, 2011.

9. Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux disease and asthma: a systematic review. Gut. 2007;56(12):1654-1664.

10. Tsai MC, Lin HL, Lin CC, et al. Increased risk of concurrent asthma among patients with gastroesophageal reflux disease: a nationwide population-based study. Eur J Gastroenterol Hepatol. 2010;22(10):1169-1173.

11. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med. 1996;100(4):395-405.

12. Gibson PG, Henry RL, Coughlan JL. Gastro-oesophageal reflux treatment for asthma in adults and children. Cochrane Database Syst Rev. 2003;(2):CD001496.

13. Barnett SB, Nurmagambetov TA. Costs of asthma in the United States: 2002-2007. J Allergy Clin Immunol. 2011;127(1):145-152.

14. Walders N, Kercsmar C, Schluchter M, et al. An interdisciplinary intervention for undertreated pediatric asthma. Chest. 2006;129(2):292-299.

15. Morrow R, Fletcher J, Mulvihill M, Park H. The asthma dialogues: a model of interactive education for skills. J Contin Educ Health Prof. 2007;27(1): 49-58.

16. State of New York, Department of Health. Asthma action plan. www.health.state.ny.us/diseases/asthma/pdf/4850.pdf. Accessed April 11, 2011.

17. Picken HA, Greenfield S, Teres D, et al. Effects of local standards on the implementation of national guidelines for asthma: primary care agreement with national asthma guidelines. J Gen Intern Med. 1998;13(10):659-663.

18. Hardie GE, Gold WM, Janson S, et al. Understanding how asthmatics perceive symptom distress during a methacholine challenge. J Asthma. 2002;39(7):611-618.

19. Reddel HK, Marks GB, Jenkins CR. When can personal best peak flow be determined for asthma action plans? Thorax. 2004;59(11):922-924.

20. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 1983;127(6):725-734.

21. Ind PW, Dal Negro R, Colman NC, et al. Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma. Respir Med. 2003;97(5):555-562.

22. Price DB, Hernandez D, Magyar P, et al; Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) International Study Group. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax. 2003;58(3):211-216.

23. Schatz M, Zeiger RS, Mosen D, et al. Improved asthma outcomes from allergy specialist care: a population-based cross-sectional analysis. J Allergy Clin Immunol. 2005;116(6):1307-1313.

24. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med. 2005;143(3):199-211.

25. Cabana MD, Bruckman D, Meister K, et al. Documentation of asthma severity in pediatric outpatient clinics. Clin Pediatr (Phila). 2003;42(2):121-125.

26. Heater BS, Becker AM, Olson RK. Nursing interventions and patient outcomes: a meta-analysis of studies. Nurs Res. 1988;37(5):303-307.

A 49-year-old woman presented to urgent care with complaints of worsening dyspnea for the previous two days. She reported that her symptoms had begun gradually; at the time of her presentation, however, she was also experiencing chest tightness, occasional wheezing, and a nonproductive cough. She had experienced similar symptoms in the past and obtained good results by using her albuterol inhaler. During the current episode, however, she had not had the usual response to inhaler treatment.

The patient’s medical history was positive for environmental allergies, asthma, and GERD. Two weeks earlier, she had undergone dilatation and curettage (D&C) for dysfunctional bleeding, with no associated complications.

In the social history, the patient reported drinking four to six caffeine beverages daily and consuming alcohol moderately (two to four glasses of wine per week). She was following no formal dietary regimen. The patient denied current or past history of tobacco use and had not traveled recently. She had no family history of coronary vascular disease.

Her medications included albuterol and desloratadine as needed, pantoprazole 40 mg/d, and drospirenone/ethinyl estradiol. The patient said she used her albuterol inhaler four to six times per month but more often in the summer and fall. Nighttime awakenings due to asthma symptoms occurred no more than twice per month. She denied prior history of acute asthma exacerbations requiring oral systemic corticosteroids. The patient stated that since her D&C, she had been using ibuprofen almost daily for mild abdominal cramping.

A review of systems was positive for mild fatigue since her D&C. The patient denied fever, chills, headache, sore throat, or cough. She did complain of daily nasal congestion but with no unusual drainage. The patient denied orthopnea, chest pain, palpitations, or peripheral edema, as well as nausea, vomiting, diarrhea, constipation, hematochezia, or melena. She admitted to daily heartburn for the previous two weeks that was relieved somewhat with pantoprazole. She had not experienced urinary frequency or urgency, dysuria, or hematuria. She also denied rash, pruritus, weakness, paresthesias, joint pain, or swelling.

Physical examination revealed an alert, oriented female who appeared slightly anxious but was in no acute distress. Specific findings were pulse, 110 beats/min; blood pressure, 138/88 mm Hg; respirations, 24 breaths/min; temperature, 97.7°F; O2 saturation, 92% on room air. Her height measured 5’2” and weight, 150 lb (BMI, 27.43).

Her conjunctiva were slightly injected, and the tympanic membranes were intact bilaterally with a light reflex; the septum was midline. The mucosa was pale, boggy, and moist with clear drainage and no inflammation. The nasopharynx had no erythema, and the tonsils appeared normal, although a cobblestone appearance was noted in the posterior pharynx. The neck was supple with no adenopathy.

The patient’s heart rate, 110 beats/min, was regular with no murmurs, rubs, or gallops. In the lungs, a prolonged expiratory phase was noted, with diffuse wheezing on chest auscultation bilaterally. Neither retractions nor use of accessory muscles with breathing was observed. The abdomen was soft, rounded, and nontender with no organomegaly. Bowel sounds were evident in all four quadrants. The patient’s skin was free of suspicious lesions or rashes. Her extremities were without edema, and no calf tenderness was noted; Homans’ sign was negative. Superficial varicosities were noted bilaterally.

The top differential diagnosis included:

• Acute asthma (risk factors: history of uncontrolled asthma, as evidenced by frequent use of albuterol)

• Acute anemia (risk factors: history of dysfunctional uterine bleeding, recent D&C)

• Pulmonary embolism (risk factors: recent surgery, recent start of oral contraceptive use).

Additional diagnoses to be considered less likely included:

• Acute coronary syndrome/MI (possible causes of chest tightness, dyspnea, dyspepsia; but no chest pain, diaphoresis, or nausea)

• Acute respiratory distress (history of tachycardia, possible dyspnea; but no diaphoresis, cyanosis, retractions, accessory muscle use, or lung crackles)

• Pneumonia (risk factors: recent surgery, possible cause of nonproductive cough; but no evidence of fever, chills, rales, or pleuritic chest pain).

Diagnostic testing included a 12-lead ECG to evaluate the patient for cardiac arrhythmia or injury; on it, tachycardia was noted, with a regular rate of 106 beats/min. The patient’s chest x-ray yielded normal results.

Laboratory testing included a complete blood count to screen for anemia and infection. Results included a white blood cell count of 8,200/mL (normal range, 4,500 to 11,000/mL); hematocrit, 38.2% (normal range for women, 36.1% to 44.3%); hemoglobin, 13.1 g/dL (normal for women, 12.1 to 15.1 g/dL). A comprehensive metabolic panel was performed to assess electrolyte levels and kidney and liver function; findings were normal. Results of a D-dimer assay, which was obtained to exclude pulmonary embolism,¹ were normal at 0.5 mg/L (range, 0.4 to 1.4 mg/L).

In the case of heightened suspicion for MI, the patient would have been transferred to the emergency department (ED) for evaluation, including serial cardiac troponin levels; elevated troponin levels are deemed the standard criterion to define and diagnose MI in a consensus document from the European Society of Cardiology and the American College of Cardiology.² (Troponin-T and troponin-I are more tissue-specific than the MB fraction of creatine kinase [CK-MB] in detecting MI; positive troponin levels are considered virtually diagnostic of MI.² Typically, cardiac troponin levels are measured two to three times over a 12- to 16-hour period.)

Peak expiratory flow (PEF), which was measured to evaluate the patient’s respiratory status, was 150 L/min (compared with personal best for a patient of her height and age, approximately 460 L/min). She was given 2.5 mg/3 mL of inhaled albuterol over 15 minutes. Her PEF increased to 350 L/min. O2 saturation improved to 96% on room air, pulse to 104 beats/min, and respirations 20 breaths/min; her blood pressure reading was now 140/90 mm Hg. A prolonged expiratory phase persisted in the lungs, but diffuse wheezing decreased by 40% on chest auscultation.

A second albuterol treatment was administered 20 minutes later, and the patient’s PEF increased to 380 L/min and O2 saturation to 99%. The lungs presently cleared with no further wheezing noted.

In addition, the patient was given a GI cocktail (ie, liquid antacid combined with an anticholinergic agent and viscous lidocaine). Within 10 minutes, her chest tightness was relieved 100%. Her blood pressure was then measured at 135/84 mm Hg; respirations, 18 breaths/min; and pulse rate, 96 beats/min.

According to the National Asthma Education and Prevention Program (NAEPP) 2007 Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 3 (EPR-3),³ the patient was classified as having intermittent, not-well-controlled asthma with an acute exacerbation. In addition, she was given a diagnosis of uncontrolled GERD.

DISCUSSION
Asthma Incidence and Risk Factors
Asthma affects approximately 300 million people worldwide and remains a global respiratory concern.⁴ In the United States, this chronic health condition has a prevalence of 8% to 10%. It is estimated that 5% to 10% of asthmatic patients have severe disease that does not respond typically to therapeutic interventions.⁵

Asthma involves bronchial hyperresponsiveness, airflow obstruction, and underlying inflammation. Acute episodes of asthma, arising from bronchospasm, usually manifest with progressively worsening cough, shortness of breath, chest tightness and wheezing (asthma’s hallmark symptoms), or a combination of symptoms.³

Symptoms of asthma or exacerbations of reactive airway disease vary from patient to patient. In addition to the hallmark symptoms noted, subacute or acute episodes of asthma exacerbation are characterized by decreases in expiratory airflow that can be documented by objective measurements of lung function, such as PEF or spirometry; these measures of airflow indicate the severity of an exacerbation more reliably than does perceived symptom severity.³ The EPR-3 panelists recommend determining asthma severity using a combination of objective criteria and clinical symptoms,³ although few clinicians use the objective criteria.⁶

Estimates of the prevalence of GERD among patients with asthma have varied from 34% to 89%.^7-9 Patients with GERD are 1.97 times more likely than patients without GERD to have asthma¹⁰; silent gastroesophageal reflux has been identified in 24% to 62% of patients with asthma, and early studies suggest that treatment for GERD may improve asthma control in patients with severe or difficult-to-control asthma.^8,11,12

The exact link between the two conditions is unclear. However, possible explanations why GERD and asthma coincide are that acid flow causes injury to the lining of the throat, airways, and lungs, making inhalation difficult and often causing a persistent cough; or that when acid enters the esophagus, a nerve reflex is triggered that causes the airways to narrow in order to prevent the acid from entering; this can explain dyspnea.^8,9

Economic Burden
Asthma is costly to treat, and because there is no cure, the expense is ongoing. According to a 2011 report,¹³ the average annual direct cost of care (eg, medications, hospital admissions, nonemergency office visits) for one asthma patient between 2002 and 2007 was $3,259. In 2007, the most current data available, the total cost of asthma in the US was $56 billion, with productivity losses due to mortality accounting for $2.1 billion and morbidity-related losses estimated at $3.8 billion.¹³ The economic consequences of asthma are substantial and can place a considerable burden on affected individuals, their families, the health care system, and society as a whole.³

Current Standard of Care
Based on the scientific literature and the opinions expressed by the NAEPP in the EPR-3,³ clinicians are advised to consider the following general principles and goals for managing asthma: early treatment, special attention to patients at high risk for asthma-related death, and special attention to infants.³ The guidelines emphasize the importance of a clinician/patient partnership to facilitate the asthma patient’s self-management.

Early treatment is a particularly important component for management of asthma exacerbations. Important elements of early treatment include a written asthma action plan, combined with enhanced awareness of the early indicators of an exacerbation (ie, worsening PEF).^3,14 It is believed that if patients are able to monitor their respiratory condition and follow a plan of care based on their PEF and/or signs and symptoms of asthma, they are more likely to achieve optimal management of their disease.¹⁵

Written Asthma Action Plan. The EPR-3³ recommends that health care providers supply all asthmatic patients with a written asthma action plan that will define and support the patient’s efforts at self-management. Written asthma action plans are particularly beneficial for patients with moderate to severe persistent asthma, poorly controlled asthma, or a history of severe exacerbations.^3,14

The written asthma action plan should include instructions for daily management of asthma and ways to recognize and treat worsening asthma, including adjustments to medication dosing. Plans may be based on PEF and/or symptoms. Asthma action plans should be discussed and reevaluated at follow-up visits.³ A sample asthma action plan can be found at www.health.state.ny.us/diseases/asthma/pdf/4850.pdf.¹⁶

Peak Expiratory Flow (PEF). The EPR-3³ recommends PEF monitoring in all asthma patients, regardless of the severity of their exacerbations.¹⁷ PEF-based plans are especially useful for the patient who has difficulty perceiving early signs and symptoms of worsening asthma.^3,18 A PEF-based plan instructs the patient to use quick-relief medications if symptoms occur or if PEF drops below 80% of the patient’s personal or predicted best. (Measured personal best is the patient’s highest PEF in the previous two weeks of good asthma control,^3,19 whereas predicted best is calculated based on findings from a 1983 study by Knudson et al.^3,20)

A PEF between 50% and 79% requires the patient to carefully monitor his or her response to the quick-relief medication and, based on that response, consider whether to contact a health care provider. When PEF falls below 50%, a provider’s immediate intervention is usually recommended.³

In the urgent care or ED setting, according to EPR-3 recommendations,³ the PEF or forced expiratory volume in 1 second (FEV1) is used to indicate the following:

• ≥ 70% predicted PEF or FEV1: goal for discharge

• 40% to 69% predicted PEF or FEV1: incomplete response to treatment, frequent need for treatment in the ED

• 3

Treatment and Management
Asthma management interventions that target the treatment of active disease and predisposing triggers are designed to reduce the severity and/or duration of morbidity associated with asthma—principally, to prevent symptoms and exacerbations (see Table 1³).

When patients are discharged following an asthma exacerbation, their medications should include an oral corticosteroid burst and a short-acting b2-agonist (SABA); the clinician should also consider prescribing an inhaled corticosteroid (ICS).³

It is no longer recommended that ICS dosing be doubled in place of an oral steroid burst.^3,21 The addition of a leukotriene receptor antagonist (LTRA) may also be considered.^3,22

Patients should be given an action plan, and follow-up with a primary care provider should be scheduled within a few days—or even the following day, depending on the severity of the patient’s condition. The importance of follow-up with a primary care provider, a pulmonologist, or an asthma/allergy specialist should be emphasized.^3,23

For patients who have difficulty recognizing their symptoms, a peak flow meter may be useful. This device is also recommended for patients with moderate to severe asthma or a history of numerous severe exacerbations.³ Additionally, spacers should always be used with metered dose inhalers (MDIs), because they make it easier for medication to reach the lungs and reduce the amount deposited in the mouth and throat, where it can lead to irritation. At each office visit, use of the peak flow meter and inhaler technique should be observed, and the action plan reevaluated and changed if necessary.^3,14

Additional components of patient education include instruction in controlling environmental factors: avoiding environmental tobacco smoke, exposure to insect allergens, and molds. It is also important to stress controlling comorbid conditions that influence asthma, such as allergies or GERD. Patients with symptoms of GERD should be advised to take the steps shown in Table 2.^8,24

Clinical Implications
Assessment of the severity of an asthma exacerbation is an essential component of ambulatory asthma care. Underclassification of asthma severity has been associated with increased morbidity and mortality,⁶ and the NAEPP guidelines recommend that clinicians assess and document asthma severity at each clinic visit.^3,25 Patients who receive care based on evidence-based practice guidelines have been shown to experience 28% better outcomes.²⁶

PATIENT OUTCOME
The case patient was discharged on an oral corticosteroid burst and a low-dose ICS. She was instructed how and when to use her SABA and given a prescription for a spacer; use of a peak flow meter was initiated with an estimated personal best goal of 460 L/min. The patient was given a written asthma action plan to help her recognize early signs and symptoms of worsening asthma and was advised to use quick-relief medications if she experienced symptoms or if her PEF dropped below 80% of her predicted best.

The patient’s clinician emphasized the importance of controlling any asthma-triggering environmental factors and reviewed nonpharmacologic interventions to control GERD. The patient was advised to resume desloratadine 5 mg/d and pantoprazole 40 mg/d. She was also instructed to schedule an appointment with her primary care provider within 48 hours and to return to urgent care or the ED with any further exacerbation of respiratory symptoms not controlled by her SABA.

CONCLUSION
Asthma morbidity is a nationally recognized, major public health problem. Given the sharp rise in health care costs and limited resources, health care providers must factor in the comparative effectiveness, comparative cost, and cost-effectiveness of both new and existing health care interventions when making treatment decisions.

Many asthmatic patients face the challenges of health care access and quality. By promoting their self-care and awareness, clinicians can help asthmatic patients achieve better symptom management and use the health care system less often.

REFERENCES
1. Stein PD, Hull RD, Patel KC, et al. D-Dimer for the exclusion of acute venous thrombosis and pulmonary embolism. Ann Intern Med. 2004;140(8):589-602.

2. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined: a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36(3):959-969.

3. National Asthma Education and Prevention Program, National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007. US Department of Health and Human Services publication NIH 07-4051.

4. Lougheed DM. Variability in asthma: symptom perception, care, and outcomes. Can J Physiol Pharmacol. 2007;85(1):149-154.

5. Higgins JC. The ‘crashing asthmatic.’ Am Fam Physician. 2003;67(5):997-1004. 

6. Cowen MK, Wakefield DB, Cloutier MM. Classifying asthma severity: objective versus subjective measures. J Asthma. 2007;44(9):711-715.

7. Takenaka R, Matsuno O, Kitajima K, et al. The use of frequency scale for the symptoms of GERD in assessment of gastro-oesophageal reflux symptoms in asthma. Allergol Immunopathol (Madr). 2010;38(1):20-24.

8. Harding SM, Barnes PJ, Hollingsworth H. Gastroesophageal reflux and asthma (2010). www.uptodate.com/contents/gastroesophageal-reflux-and-asthma. Accessed April 5, 2011.

9. Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux disease and asthma: a systematic review. Gut. 2007;56(12):1654-1664.

10. Tsai MC, Lin HL, Lin CC, et al. Increased risk of concurrent asthma among patients with gastroesophageal reflux disease: a nationwide population-based study. Eur J Gastroenterol Hepatol. 2010;22(10):1169-1173.

11. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med. 1996;100(4):395-405.

12. Gibson PG, Henry RL, Coughlan JL. Gastro-oesophageal reflux treatment for asthma in adults and children. Cochrane Database Syst Rev. 2003;(2):CD001496.

13. Barnett SB, Nurmagambetov TA. Costs of asthma in the United States: 2002-2007. J Allergy Clin Immunol. 2011;127(1):145-152.

14. Walders N, Kercsmar C, Schluchter M, et al. An interdisciplinary intervention for undertreated pediatric asthma. Chest. 2006;129(2):292-299.

15. Morrow R, Fletcher J, Mulvihill M, Park H. The asthma dialogues: a model of interactive education for skills. J Contin Educ Health Prof. 2007;27(1): 49-58.

16. State of New York, Department of Health. Asthma action plan. www.health.state.ny.us/diseases/asthma/pdf/4850.pdf. Accessed April 11, 2011.

17. Picken HA, Greenfield S, Teres D, et al. Effects of local standards on the implementation of national guidelines for asthma: primary care agreement with national asthma guidelines. J Gen Intern Med. 1998;13(10):659-663.

18. Hardie GE, Gold WM, Janson S, et al. Understanding how asthmatics perceive symptom distress during a methacholine challenge. J Asthma. 2002;39(7):611-618.

19. Reddel HK, Marks GB, Jenkins CR. When can personal best peak flow be determined for asthma action plans? Thorax. 2004;59(11):922-924.

20. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 1983;127(6):725-734.

21. Ind PW, Dal Negro R, Colman NC, et al. Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma. Respir Med. 2003;97(5):555-562.

22. Price DB, Hernandez D, Magyar P, et al; Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) International Study Group. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax. 2003;58(3):211-216.

23. Schatz M, Zeiger RS, Mosen D, et al. Improved asthma outcomes from allergy specialist care: a population-based cross-sectional analysis. J Allergy Clin Immunol. 2005;116(6):1307-1313.

24. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med. 2005;143(3):199-211.

25. Cabana MD, Bruckman D, Meister K, et al. Documentation of asthma severity in pediatric outpatient clinics. Clin Pediatr (Phila). 2003;42(2):121-125.

26. Heater BS, Becker AM, Olson RK. Nursing interventions and patient outcomes: a meta-analysis of studies. Nurs Res. 1988;37(5):303-307.

A 49-year-old woman presented to urgent care with complaints of worsening dyspnea for the previous two days. She reported that her symptoms had begun gradually; at the time of her presentation, however, she was also experiencing chest tightness, occasional wheezing, and a nonproductive cough. She had experienced similar symptoms in the past and obtained good results by using her albuterol inhaler. During the current episode, however, she had not had the usual response to inhaler treatment.

The patient’s medical history was positive for environmental allergies, asthma, and GERD. Two weeks earlier, she had undergone dilatation and curettage (D&C) for dysfunctional bleeding, with no associated complications.

In the social history, the patient reported drinking four to six caffeine beverages daily and consuming alcohol moderately (two to four glasses of wine per week). She was following no formal dietary regimen. The patient denied current or past history of tobacco use and had not traveled recently. She had no family history of coronary vascular disease.

Her medications included albuterol and desloratadine as needed, pantoprazole 40 mg/d, and drospirenone/ethinyl estradiol. The patient said she used her albuterol inhaler four to six times per month but more often in the summer and fall. Nighttime awakenings due to asthma symptoms occurred no more than twice per month. She denied prior history of acute asthma exacerbations requiring oral systemic corticosteroids. The patient stated that since her D&C, she had been using ibuprofen almost daily for mild abdominal cramping.

A review of systems was positive for mild fatigue since her D&C. The patient denied fever, chills, headache, sore throat, or cough. She did complain of daily nasal congestion but with no unusual drainage. The patient denied orthopnea, chest pain, palpitations, or peripheral edema, as well as nausea, vomiting, diarrhea, constipation, hematochezia, or melena. She admitted to daily heartburn for the previous two weeks that was relieved somewhat with pantoprazole. She had not experienced urinary frequency or urgency, dysuria, or hematuria. She also denied rash, pruritus, weakness, paresthesias, joint pain, or swelling.

Physical examination revealed an alert, oriented female who appeared slightly anxious but was in no acute distress. Specific findings were pulse, 110 beats/min; blood pressure, 138/88 mm Hg; respirations, 24 breaths/min; temperature, 97.7°F; O2 saturation, 92% on room air. Her height measured 5’2” and weight, 150 lb (BMI, 27.43).

Her conjunctiva were slightly injected, and the tympanic membranes were intact bilaterally with a light reflex; the septum was midline. The mucosa was pale, boggy, and moist with clear drainage and no inflammation. The nasopharynx had no erythema, and the tonsils appeared normal, although a cobblestone appearance was noted in the posterior pharynx. The neck was supple with no adenopathy.

The patient’s heart rate, 110 beats/min, was regular with no murmurs, rubs, or gallops. In the lungs, a prolonged expiratory phase was noted, with diffuse wheezing on chest auscultation bilaterally. Neither retractions nor use of accessory muscles with breathing was observed. The abdomen was soft, rounded, and nontender with no organomegaly. Bowel sounds were evident in all four quadrants. The patient’s skin was free of suspicious lesions or rashes. Her extremities were without edema, and no calf tenderness was noted; Homans’ sign was negative. Superficial varicosities were noted bilaterally.

The top differential diagnosis included:

• Acute asthma (risk factors: history of uncontrolled asthma, as evidenced by frequent use of albuterol)

• Acute anemia (risk factors: history of dysfunctional uterine bleeding, recent D&C)

• Pulmonary embolism (risk factors: recent surgery, recent start of oral contraceptive use).

Additional diagnoses to be considered less likely included:

• Acute coronary syndrome/MI (possible causes of chest tightness, dyspnea, dyspepsia; but no chest pain, diaphoresis, or nausea)

• Acute respiratory distress (history of tachycardia, possible dyspnea; but no diaphoresis, cyanosis, retractions, accessory muscle use, or lung crackles)

• Pneumonia (risk factors: recent surgery, possible cause of nonproductive cough; but no evidence of fever, chills, rales, or pleuritic chest pain).

Diagnostic testing included a 12-lead ECG to evaluate the patient for cardiac arrhythmia or injury; on it, tachycardia was noted, with a regular rate of 106 beats/min. The patient’s chest x-ray yielded normal results.

Laboratory testing included a complete blood count to screen for anemia and infection. Results included a white blood cell count of 8,200/mL (normal range, 4,500 to 11,000/mL); hematocrit, 38.2% (normal range for women, 36.1% to 44.3%); hemoglobin, 13.1 g/dL (normal for women, 12.1 to 15.1 g/dL). A comprehensive metabolic panel was performed to assess electrolyte levels and kidney and liver function; findings were normal. Results of a D-dimer assay, which was obtained to exclude pulmonary embolism,¹ were normal at 0.5 mg/L (range, 0.4 to 1.4 mg/L).

In the case of heightened suspicion for MI, the patient would have been transferred to the emergency department (ED) for evaluation, including serial cardiac troponin levels; elevated troponin levels are deemed the standard criterion to define and diagnose MI in a consensus document from the European Society of Cardiology and the American College of Cardiology.² (Troponin-T and troponin-I are more tissue-specific than the MB fraction of creatine kinase [CK-MB] in detecting MI; positive troponin levels are considered virtually diagnostic of MI.² Typically, cardiac troponin levels are measured two to three times over a 12- to 16-hour period.)

Peak expiratory flow (PEF), which was measured to evaluate the patient’s respiratory status, was 150 L/min (compared with personal best for a patient of her height and age, approximately 460 L/min). She was given 2.5 mg/3 mL of inhaled albuterol over 15 minutes. Her PEF increased to 350 L/min. O2 saturation improved to 96% on room air, pulse to 104 beats/min, and respirations 20 breaths/min; her blood pressure reading was now 140/90 mm Hg. A prolonged expiratory phase persisted in the lungs, but diffuse wheezing decreased by 40% on chest auscultation.

A second albuterol treatment was administered 20 minutes later, and the patient’s PEF increased to 380 L/min and O2 saturation to 99%. The lungs presently cleared with no further wheezing noted.

In addition, the patient was given a GI cocktail (ie, liquid antacid combined with an anticholinergic agent and viscous lidocaine). Within 10 minutes, her chest tightness was relieved 100%. Her blood pressure was then measured at 135/84 mm Hg; respirations, 18 breaths/min; and pulse rate, 96 beats/min.

According to the National Asthma Education and Prevention Program (NAEPP) 2007 Guidelines for the Diagnosis and Management of Asthma, Expert Panel Report 3 (EPR-3),³ the patient was classified as having intermittent, not-well-controlled asthma with an acute exacerbation. In addition, she was given a diagnosis of uncontrolled GERD.

DISCUSSION
Asthma Incidence and Risk Factors
Asthma affects approximately 300 million people worldwide and remains a global respiratory concern.⁴ In the United States, this chronic health condition has a prevalence of 8% to 10%. It is estimated that 5% to 10% of asthmatic patients have severe disease that does not respond typically to therapeutic interventions.⁵

Asthma involves bronchial hyperresponsiveness, airflow obstruction, and underlying inflammation. Acute episodes of asthma, arising from bronchospasm, usually manifest with progressively worsening cough, shortness of breath, chest tightness and wheezing (asthma’s hallmark symptoms), or a combination of symptoms.³

Symptoms of asthma or exacerbations of reactive airway disease vary from patient to patient. In addition to the hallmark symptoms noted, subacute or acute episodes of asthma exacerbation are characterized by decreases in expiratory airflow that can be documented by objective measurements of lung function, such as PEF or spirometry; these measures of airflow indicate the severity of an exacerbation more reliably than does perceived symptom severity.³ The EPR-3 panelists recommend determining asthma severity using a combination of objective criteria and clinical symptoms,³ although few clinicians use the objective criteria.⁶

Estimates of the prevalence of GERD among patients with asthma have varied from 34% to 89%.^7-9 Patients with GERD are 1.97 times more likely than patients without GERD to have asthma¹⁰; silent gastroesophageal reflux has been identified in 24% to 62% of patients with asthma, and early studies suggest that treatment for GERD may improve asthma control in patients with severe or difficult-to-control asthma.^8,11,12

The exact link between the two conditions is unclear. However, possible explanations why GERD and asthma coincide are that acid flow causes injury to the lining of the throat, airways, and lungs, making inhalation difficult and often causing a persistent cough; or that when acid enters the esophagus, a nerve reflex is triggered that causes the airways to narrow in order to prevent the acid from entering; this can explain dyspnea.^8,9

Economic Burden
Asthma is costly to treat, and because there is no cure, the expense is ongoing. According to a 2011 report,¹³ the average annual direct cost of care (eg, medications, hospital admissions, nonemergency office visits) for one asthma patient between 2002 and 2007 was $3,259. In 2007, the most current data available, the total cost of asthma in the US was $56 billion, with productivity losses due to mortality accounting for $2.1 billion and morbidity-related losses estimated at $3.8 billion.¹³ The economic consequences of asthma are substantial and can place a considerable burden on affected individuals, their families, the health care system, and society as a whole.³

Current Standard of Care
Based on the scientific literature and the opinions expressed by the NAEPP in the EPR-3,³ clinicians are advised to consider the following general principles and goals for managing asthma: early treatment, special attention to patients at high risk for asthma-related death, and special attention to infants.³ The guidelines emphasize the importance of a clinician/patient partnership to facilitate the asthma patient’s self-management.

Early treatment is a particularly important component for management of asthma exacerbations. Important elements of early treatment include a written asthma action plan, combined with enhanced awareness of the early indicators of an exacerbation (ie, worsening PEF).^3,14 It is believed that if patients are able to monitor their respiratory condition and follow a plan of care based on their PEF and/or signs and symptoms of asthma, they are more likely to achieve optimal management of their disease.¹⁵

Written Asthma Action Plan. The EPR-3³ recommends that health care providers supply all asthmatic patients with a written asthma action plan that will define and support the patient’s efforts at self-management. Written asthma action plans are particularly beneficial for patients with moderate to severe persistent asthma, poorly controlled asthma, or a history of severe exacerbations.^3,14

The written asthma action plan should include instructions for daily management of asthma and ways to recognize and treat worsening asthma, including adjustments to medication dosing. Plans may be based on PEF and/or symptoms. Asthma action plans should be discussed and reevaluated at follow-up visits.³ A sample asthma action plan can be found at www.health.state.ny.us/diseases/asthma/pdf/4850.pdf.¹⁶

Peak Expiratory Flow (PEF). The EPR-3³ recommends PEF monitoring in all asthma patients, regardless of the severity of their exacerbations.¹⁷ PEF-based plans are especially useful for the patient who has difficulty perceiving early signs and symptoms of worsening asthma.^3,18 A PEF-based plan instructs the patient to use quick-relief medications if symptoms occur or if PEF drops below 80% of the patient’s personal or predicted best. (Measured personal best is the patient’s highest PEF in the previous two weeks of good asthma control,^3,19 whereas predicted best is calculated based on findings from a 1983 study by Knudson et al.^3,20)

A PEF between 50% and 79% requires the patient to carefully monitor his or her response to the quick-relief medication and, based on that response, consider whether to contact a health care provider. When PEF falls below 50%, a provider’s immediate intervention is usually recommended.³

In the urgent care or ED setting, according to EPR-3 recommendations,³ the PEF or forced expiratory volume in 1 second (FEV1) is used to indicate the following:

• ≥ 70% predicted PEF or FEV1: goal for discharge

• 40% to 69% predicted PEF or FEV1: incomplete response to treatment, frequent need for treatment in the ED

• 3

Treatment and Management
Asthma management interventions that target the treatment of active disease and predisposing triggers are designed to reduce the severity and/or duration of morbidity associated with asthma—principally, to prevent symptoms and exacerbations (see Table 1³).

When patients are discharged following an asthma exacerbation, their medications should include an oral corticosteroid burst and a short-acting b2-agonist (SABA); the clinician should also consider prescribing an inhaled corticosteroid (ICS).³

It is no longer recommended that ICS dosing be doubled in place of an oral steroid burst.^3,21 The addition of a leukotriene receptor antagonist (LTRA) may also be considered.^3,22

Patients should be given an action plan, and follow-up with a primary care provider should be scheduled within a few days—or even the following day, depending on the severity of the patient’s condition. The importance of follow-up with a primary care provider, a pulmonologist, or an asthma/allergy specialist should be emphasized.^3,23

For patients who have difficulty recognizing their symptoms, a peak flow meter may be useful. This device is also recommended for patients with moderate to severe asthma or a history of numerous severe exacerbations.³ Additionally, spacers should always be used with metered dose inhalers (MDIs), because they make it easier for medication to reach the lungs and reduce the amount deposited in the mouth and throat, where it can lead to irritation. At each office visit, use of the peak flow meter and inhaler technique should be observed, and the action plan reevaluated and changed if necessary.^3,14

Additional components of patient education include instruction in controlling environmental factors: avoiding environmental tobacco smoke, exposure to insect allergens, and molds. It is also important to stress controlling comorbid conditions that influence asthma, such as allergies or GERD. Patients with symptoms of GERD should be advised to take the steps shown in Table 2.^8,24

Clinical Implications
Assessment of the severity of an asthma exacerbation is an essential component of ambulatory asthma care. Underclassification of asthma severity has been associated with increased morbidity and mortality,⁶ and the NAEPP guidelines recommend that clinicians assess and document asthma severity at each clinic visit.^3,25 Patients who receive care based on evidence-based practice guidelines have been shown to experience 28% better outcomes.²⁶

PATIENT OUTCOME
The case patient was discharged on an oral corticosteroid burst and a low-dose ICS. She was instructed how and when to use her SABA and given a prescription for a spacer; use of a peak flow meter was initiated with an estimated personal best goal of 460 L/min. The patient was given a written asthma action plan to help her recognize early signs and symptoms of worsening asthma and was advised to use quick-relief medications if she experienced symptoms or if her PEF dropped below 80% of her predicted best.

The patient’s clinician emphasized the importance of controlling any asthma-triggering environmental factors and reviewed nonpharmacologic interventions to control GERD. The patient was advised to resume desloratadine 5 mg/d and pantoprazole 40 mg/d. She was also instructed to schedule an appointment with her primary care provider within 48 hours and to return to urgent care or the ED with any further exacerbation of respiratory symptoms not controlled by her SABA.

CONCLUSION
Asthma morbidity is a nationally recognized, major public health problem. Given the sharp rise in health care costs and limited resources, health care providers must factor in the comparative effectiveness, comparative cost, and cost-effectiveness of both new and existing health care interventions when making treatment decisions.

Many asthmatic patients face the challenges of health care access and quality. By promoting their self-care and awareness, clinicians can help asthmatic patients achieve better symptom management and use the health care system less often.

REFERENCES
1. Stein PD, Hull RD, Patel KC, et al. D-Dimer for the exclusion of acute venous thrombosis and pulmonary embolism. Ann Intern Med. 2004;140(8):589-602.

2. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined: a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36(3):959-969.

3. National Asthma Education and Prevention Program, National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007. US Department of Health and Human Services publication NIH 07-4051.

4. Lougheed DM. Variability in asthma: symptom perception, care, and outcomes. Can J Physiol Pharmacol. 2007;85(1):149-154.

5. Higgins JC. The ‘crashing asthmatic.’ Am Fam Physician. 2003;67(5):997-1004. 

6. Cowen MK, Wakefield DB, Cloutier MM. Classifying asthma severity: objective versus subjective measures. J Asthma. 2007;44(9):711-715.

7. Takenaka R, Matsuno O, Kitajima K, et al. The use of frequency scale for the symptoms of GERD in assessment of gastro-oesophageal reflux symptoms in asthma. Allergol Immunopathol (Madr). 2010;38(1):20-24.

8. Harding SM, Barnes PJ, Hollingsworth H. Gastroesophageal reflux and asthma (2010). www.uptodate.com/contents/gastroesophageal-reflux-and-asthma. Accessed April 5, 2011.

9. Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux disease and asthma: a systematic review. Gut. 2007;56(12):1654-1664.

10. Tsai MC, Lin HL, Lin CC, et al. Increased risk of concurrent asthma among patients with gastroesophageal reflux disease: a nationwide population-based study. Eur J Gastroenterol Hepatol. 2010;22(10):1169-1173.

11. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med. 1996;100(4):395-405.

12. Gibson PG, Henry RL, Coughlan JL. Gastro-oesophageal reflux treatment for asthma in adults and children. Cochrane Database Syst Rev. 2003;(2):CD001496.

13. Barnett SB, Nurmagambetov TA. Costs of asthma in the United States: 2002-2007. J Allergy Clin Immunol. 2011;127(1):145-152.

14. Walders N, Kercsmar C, Schluchter M, et al. An interdisciplinary intervention for undertreated pediatric asthma. Chest. 2006;129(2):292-299.

15. Morrow R, Fletcher J, Mulvihill M, Park H. The asthma dialogues: a model of interactive education for skills. J Contin Educ Health Prof. 2007;27(1): 49-58.

16. State of New York, Department of Health. Asthma action plan. www.health.state.ny.us/diseases/asthma/pdf/4850.pdf. Accessed April 11, 2011.

17. Picken HA, Greenfield S, Teres D, et al. Effects of local standards on the implementation of national guidelines for asthma: primary care agreement with national asthma guidelines. J Gen Intern Med. 1998;13(10):659-663.

18. Hardie GE, Gold WM, Janson S, et al. Understanding how asthmatics perceive symptom distress during a methacholine challenge. J Asthma. 2002;39(7):611-618.

19. Reddel HK, Marks GB, Jenkins CR. When can personal best peak flow be determined for asthma action plans? Thorax. 2004;59(11):922-924.

20. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 1983;127(6):725-734.

21. Ind PW, Dal Negro R, Colman NC, et al. Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma. Respir Med. 2003;97(5):555-562.

22. Price DB, Hernandez D, Magyar P, et al; Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) International Study Group. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax. 2003;58(3):211-216.

23. Schatz M, Zeiger RS, Mosen D, et al. Improved asthma outcomes from allergy specialist care: a population-based cross-sectional analysis. J Allergy Clin Immunol. 2005;116(6):1307-1313.

24. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med. 2005;143(3):199-211.

25. Cabana MD, Bruckman D, Meister K, et al. Documentation of asthma severity in pediatric outpatient clinics. Clin Pediatr (Phila). 2003;42(2):121-125.

26. Heater BS, Becker AM, Olson RK. Nursing interventions and patient outcomes: a meta-analysis of studies. Nurs Res. 1988;37(5):303-307.

In response to “Traumatic brain injury: Pharmacotherapy options for cognitive deficits” (Med/Psych Update, Current Psychiatry, February 2011, p. 21-37), traumatic brain injury (TBI) has been recognized as a risk factor for cognitive impairment, but TBI also has been shown to be a risk factor for hypopituitarism, presenting most frequently with growth hormone deficiency (GHD). GHD is associated not only with changes in body composition but also with impaired quality of life, cognitive dysfunctions, and psychiatric sequelae, usually classified as “depression.”

In a case study we evaluated the impact of GH therapy on the mental status of TBI patients.¹ Psychiatric and cognitive functions were tested in 6 GHD patients at baseline (minimum 3 years after TBI) and reassessed after 6 months of GH therapy and 12 months after discontinuing GH therapy. Psychiatric and cognitive examinations included semi-structured interviews and 3 instruments: Symptom Checklist-90-Revised, Zung Depression Inventory, and a standard composite neuropsychological battery.

Our results showed that 6 months of GH therapy in GHD TBI patients improved cognitive abilities (particularly verbal and nonverbal memory) and significantly improved psychiatric functioning. Depression severity decreased, as did intensity of interpersonal sensitivity, hostility, paranoid ideation, anxiety, and psychoticism. Somatization, obsessive-compulsive symptoms, and phobic anxiety decreased in all but 1 patient. In 3 GHD patients who stopped GH therapy for 12 months, we observed worsening verbal and nonverbal memory, interpersonal sensitivity, anxiety, and paranoid ideation. Thus, GHD might be associated with affective and cognitive symptoms in TBI patients and GH replacement therapy could be beneficial. Screening for pituitary dysfunction in TBI patients is strongly recommended, particularly in presence of cognitive and affective symptoms.

Nadja Maric, MD, PhD
Associate Professor
Head of Department for Research and Early
Interventions in Psychiatry
Clinic for Psychiatry, Clinical Centre of Serbia
University of Belgrade School of Medicine
Belgrade, Serbia

In response to “Traumatic brain injury: Pharmacotherapy options for cognitive deficits” (Med/Psych Update, Current Psychiatry, February 2011, p. 21-37), traumatic brain injury (TBI) has been recognized as a risk factor for cognitive impairment, but TBI also has been shown to be a risk factor for hypopituitarism, presenting most frequently with growth hormone deficiency (GHD). GHD is associated not only with changes in body composition but also with impaired quality of life, cognitive dysfunctions, and psychiatric sequelae, usually classified as “depression.”

In a case study we evaluated the impact of GH therapy on the mental status of TBI patients.¹ Psychiatric and cognitive functions were tested in 6 GHD patients at baseline (minimum 3 years after TBI) and reassessed after 6 months of GH therapy and 12 months after discontinuing GH therapy. Psychiatric and cognitive examinations included semi-structured interviews and 3 instruments: Symptom Checklist-90-Revised, Zung Depression Inventory, and a standard composite neuropsychological battery.

Our results showed that 6 months of GH therapy in GHD TBI patients improved cognitive abilities (particularly verbal and nonverbal memory) and significantly improved psychiatric functioning. Depression severity decreased, as did intensity of interpersonal sensitivity, hostility, paranoid ideation, anxiety, and psychoticism. Somatization, obsessive-compulsive symptoms, and phobic anxiety decreased in all but 1 patient. In 3 GHD patients who stopped GH therapy for 12 months, we observed worsening verbal and nonverbal memory, interpersonal sensitivity, anxiety, and paranoid ideation. Thus, GHD might be associated with affective and cognitive symptoms in TBI patients and GH replacement therapy could be beneficial. Screening for pituitary dysfunction in TBI patients is strongly recommended, particularly in presence of cognitive and affective symptoms.

Nadja Maric, MD, PhD
Associate Professor
Head of Department for Research and Early
Interventions in Psychiatry
Clinic for Psychiatry, Clinical Centre of Serbia
University of Belgrade School of Medicine
Belgrade, Serbia

In response to “Traumatic brain injury: Pharmacotherapy options for cognitive deficits” (Med/Psych Update, Current Psychiatry, February 2011, p. 21-37), traumatic brain injury (TBI) has been recognized as a risk factor for cognitive impairment, but TBI also has been shown to be a risk factor for hypopituitarism, presenting most frequently with growth hormone deficiency (GHD). GHD is associated not only with changes in body composition but also with impaired quality of life, cognitive dysfunctions, and psychiatric sequelae, usually classified as “depression.”

In a case study we evaluated the impact of GH therapy on the mental status of TBI patients.¹ Psychiatric and cognitive functions were tested in 6 GHD patients at baseline (minimum 3 years after TBI) and reassessed after 6 months of GH therapy and 12 months after discontinuing GH therapy. Psychiatric and cognitive examinations included semi-structured interviews and 3 instruments: Symptom Checklist-90-Revised, Zung Depression Inventory, and a standard composite neuropsychological battery.

Our results showed that 6 months of GH therapy in GHD TBI patients improved cognitive abilities (particularly verbal and nonverbal memory) and significantly improved psychiatric functioning. Depression severity decreased, as did intensity of interpersonal sensitivity, hostility, paranoid ideation, anxiety, and psychoticism. Somatization, obsessive-compulsive symptoms, and phobic anxiety decreased in all but 1 patient. In 3 GHD patients who stopped GH therapy for 12 months, we observed worsening verbal and nonverbal memory, interpersonal sensitivity, anxiety, and paranoid ideation. Thus, GHD might be associated with affective and cognitive symptoms in TBI patients and GH replacement therapy could be beneficial. Screening for pituitary dysfunction in TBI patients is strongly recommended, particularly in presence of cognitive and affective symptoms.

Nadja Maric, MD, PhD
Associate Professor
Head of Department for Research and Early
Interventions in Psychiatry
Clinic for Psychiatry, Clinical Centre of Serbia
University of Belgrade School of Medicine
Belgrade, Serbia

Some of patients’ most common complaints involve sleep: too little, too late, never enough. Although sleep disruptions often are related to the psychiatric disorder for which the person seeks treatment, cognitive and behavioral factors play significant roles.¹ Unfortunately, quite often patients expect to be given “something” to foster sleep.

Before writing a prescription, be prepared to evaluate sleep disturbances and educate patients about sleep and how it can be facilitated without medication. The mnemonic SLEEP can help you readily access a basic set of nonpharmacologic aids to assess and treat uncomplicated sleep disturbances.

Schedule. Ask patients about their sleep-wake schedule. Is their pattern routine and regular, or unpredictable? Are they “in synch” with the sleep/activity patterns of those with whom they live, or is their schedule “off track” and disrupted by household noise and activities? Consistency is key to normalizing sleep.

Limit. Sensible limits on caffeinated beverages need to be addressed. Strongly encourage patients to limit nicotine and alcohol in-take. Assess the amount as well as timing of their use of these substances. Remind your patient that alcohol and smoking have a direct impact on sleep initiation and can disrupt sleep because of nocturnal withdrawal.

Eliminate. Removing noxious environmental stimuli is critical. Ask patients about the level of nighttime noise, excessive light, and ventilation and temperature of their sleeping area (cooler is better). Eliminate factors that create a “hostile” sleep environment.

Exercise. Regular exercise performed during the day (but not immediately before going to bed) may be an effective antidote to the psychic stress and physical tension that often contribute to insomnia.² A several-times-per-week routine of brisk walking, riding a bicycle, swimming, or yoga can reduce sleep-onset latency and improve sleep maintenance. An exercise routine can enhance a patient’s overall health and knock out a daytime sleep habit.

Psychotherapy. Cognitive-behavioral therapy for insomnia has demonstrated efficacy in treating sleep disorders.³ Learning how to “catch, check, and change” distorted and negative cognitions regarding sleep onset can be a valuable tool for persons who are motivated to alter their thoughts and behaviors that contribute to sleep complaints, and may simultaneously improve associated anxiety and/or depression.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Some of patients’ most common complaints involve sleep: too little, too late, never enough. Although sleep disruptions often are related to the psychiatric disorder for which the person seeks treatment, cognitive and behavioral factors play significant roles.¹ Unfortunately, quite often patients expect to be given “something” to foster sleep.

Before writing a prescription, be prepared to evaluate sleep disturbances and educate patients about sleep and how it can be facilitated without medication. The mnemonic SLEEP can help you readily access a basic set of nonpharmacologic aids to assess and treat uncomplicated sleep disturbances.

Schedule. Ask patients about their sleep-wake schedule. Is their pattern routine and regular, or unpredictable? Are they “in synch” with the sleep/activity patterns of those with whom they live, or is their schedule “off track” and disrupted by household noise and activities? Consistency is key to normalizing sleep.

Limit. Sensible limits on caffeinated beverages need to be addressed. Strongly encourage patients to limit nicotine and alcohol in-take. Assess the amount as well as timing of their use of these substances. Remind your patient that alcohol and smoking have a direct impact on sleep initiation and can disrupt sleep because of nocturnal withdrawal.

Eliminate. Removing noxious environmental stimuli is critical. Ask patients about the level of nighttime noise, excessive light, and ventilation and temperature of their sleeping area (cooler is better). Eliminate factors that create a “hostile” sleep environment.

Exercise. Regular exercise performed during the day (but not immediately before going to bed) may be an effective antidote to the psychic stress and physical tension that often contribute to insomnia.² A several-times-per-week routine of brisk walking, riding a bicycle, swimming, or yoga can reduce sleep-onset latency and improve sleep maintenance. An exercise routine can enhance a patient’s overall health and knock out a daytime sleep habit.

Psychotherapy. Cognitive-behavioral therapy for insomnia has demonstrated efficacy in treating sleep disorders.³ Learning how to “catch, check, and change” distorted and negative cognitions regarding sleep onset can be a valuable tool for persons who are motivated to alter their thoughts and behaviors that contribute to sleep complaints, and may simultaneously improve associated anxiety and/or depression.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Some of patients’ most common complaints involve sleep: too little, too late, never enough. Although sleep disruptions often are related to the psychiatric disorder for which the person seeks treatment, cognitive and behavioral factors play significant roles.¹ Unfortunately, quite often patients expect to be given “something” to foster sleep.

Before writing a prescription, be prepared to evaluate sleep disturbances and educate patients about sleep and how it can be facilitated without medication. The mnemonic SLEEP can help you readily access a basic set of nonpharmacologic aids to assess and treat uncomplicated sleep disturbances.

Schedule. Ask patients about their sleep-wake schedule. Is their pattern routine and regular, or unpredictable? Are they “in synch” with the sleep/activity patterns of those with whom they live, or is their schedule “off track” and disrupted by household noise and activities? Consistency is key to normalizing sleep.

Limit. Sensible limits on caffeinated beverages need to be addressed. Strongly encourage patients to limit nicotine and alcohol in-take. Assess the amount as well as timing of their use of these substances. Remind your patient that alcohol and smoking have a direct impact on sleep initiation and can disrupt sleep because of nocturnal withdrawal.

Eliminate. Removing noxious environmental stimuli is critical. Ask patients about the level of nighttime noise, excessive light, and ventilation and temperature of their sleeping area (cooler is better). Eliminate factors that create a “hostile” sleep environment.

Exercise. Regular exercise performed during the day (but not immediately before going to bed) may be an effective antidote to the psychic stress and physical tension that often contribute to insomnia.² A several-times-per-week routine of brisk walking, riding a bicycle, swimming, or yoga can reduce sleep-onset latency and improve sleep maintenance. An exercise routine can enhance a patient’s overall health and knock out a daytime sleep habit.

Psychotherapy. Cognitive-behavioral therapy for insomnia has demonstrated efficacy in treating sleep disorders.³ Learning how to “catch, check, and change” distorted and negative cognitions regarding sleep onset can be a valuable tool for persons who are motivated to alter their thoughts and behaviors that contribute to sleep complaints, and may simultaneously improve associated anxiety and/or depression.

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

“An alternative to oral NSAIDs for acute musculoskeletal injuries,” (PURLs, J Fam Pract. 2011;60:147-148) promotes an unreasonable conclusion. The Cochrane review on which it is based found a 50% response rate to topical diclofenac for ankle sprains, compared with a 25% response to placebo. (A response was defined as ≥50% reduction in pain.) The authors of the Cochrane review seem to think this is adequate, and the authors of this PURL apparently agree.

First, they overstate the benefit. If we consider that 1 in 4 patients respond to placebo, we find that only 1 in 4 patients actually have what the authors describe as an adequate response to topical diclofenac. That still means that half the patients I see for ankle sprain could be calling at 11:00 PM to complain about inadequate pain relief.

Second, the Cochrane reviewers did not use an active control group with oral NSAIDs, leaving us to guess whether oral NSAIDs are equally effective, worse, or better than topical agents. The great majority of people I treat for ankle sprains obtain adequate pain relief with oral therapy. Studies have compared topical and oral NSAIDs, but the authors make no mention of these comparisons.

I trust and rely on the Cochrane reviews, but they are not the word of God. This review did not provide useful information. The space would have been better devoted to a topic I can put into practice.

Dean M. Center, MD
Bozeman, MT

I find it difficult to believe that these ivory tower researchers used topical diclofenac as their base. I’ve used topical agents for acute musculoskeletal pain for 40 years, costing one-tenth (or less) of the price of diclofenac. Only a few patients have complained of skin reactions. For more severe cases, capsaicin is a good choice; otherwise, a methyl salicylate product is very effective, at a concentration of 30% or more. Both are available as generics and do not require a prescription.

Robert Migliorino, DO
Lake Preston, SD

The authors respond:

We appreciate the issues raised by the letter writers. Dr. Center notes that there are few head-to-head trials with other therapy options, such as oral NSAIDs or acetaminophen. We agree. This Cochrane review demonstrates another possible option for pain relief for patients who cannot tolerate oral NSAIDs or prefer not to take them. The body of literature comparing topical to oral NSAIDs is small, but we could not find any high-quality evidence to suggest that oral NSAIDs are more effective.

Dr. Center also questions the clinical utility of a medication that must be given to 4 patients in order for 1 to have a 50% reduction in pain (number needed to treat [NNT]=4). The NNT for topical NSAIDs is about the same.¹ For acute musculoskeletal injuries, 1 patient in 4 will respond to placebo, 1 in 4 will respond to active topical or oral therapy, and 2 in 4 will fail treatment. Whether these response rates are acceptable is an individual clinical decision to be made with the patient. We believe they are acceptable to most patients.

We thank Dr. Migliorino for bringing to light other topical pain medications. Diclofenac is the only topical NSAID available in the United States, which is why we chose to highlight it. The Cochrane review did not include salicylates because they are no longer classified as topical NSAIDS, and capsaicin was not included as it is not an NSAID. Both may very well offer pain relief.

The purpose of PURLs (Priority Updates from the Research Literature) is to identify and disseminate evidence that should change the practice of family medicine. We believe that this Cochrane review demonstrates that topical NSAIDs are effective options for acute musculoskeletal injuries and that many primary care physicians would be unfamiliar with this option.

Nina V. Rogers, MD
Kate Rowland, MD
Chicago

“An alternative to oral NSAIDs for acute musculoskeletal injuries,” (PURLs, J Fam Pract. 2011;60:147-148) promotes an unreasonable conclusion. The Cochrane review on which it is based found a 50% response rate to topical diclofenac for ankle sprains, compared with a 25% response to placebo. (A response was defined as ≥50% reduction in pain.) The authors of the Cochrane review seem to think this is adequate, and the authors of this PURL apparently agree.

First, they overstate the benefit. If we consider that 1 in 4 patients respond to placebo, we find that only 1 in 4 patients actually have what the authors describe as an adequate response to topical diclofenac. That still means that half the patients I see for ankle sprain could be calling at 11:00 PM to complain about inadequate pain relief.

Second, the Cochrane reviewers did not use an active control group with oral NSAIDs, leaving us to guess whether oral NSAIDs are equally effective, worse, or better than topical agents. The great majority of people I treat for ankle sprains obtain adequate pain relief with oral therapy. Studies have compared topical and oral NSAIDs, but the authors make no mention of these comparisons.

I trust and rely on the Cochrane reviews, but they are not the word of God. This review did not provide useful information. The space would have been better devoted to a topic I can put into practice.

Dean M. Center, MD
Bozeman, MT

I find it difficult to believe that these ivory tower researchers used topical diclofenac as their base. I’ve used topical agents for acute musculoskeletal pain for 40 years, costing one-tenth (or less) of the price of diclofenac. Only a few patients have complained of skin reactions. For more severe cases, capsaicin is a good choice; otherwise, a methyl salicylate product is very effective, at a concentration of 30% or more. Both are available as generics and do not require a prescription.

Robert Migliorino, DO
Lake Preston, SD

The authors respond:

We appreciate the issues raised by the letter writers. Dr. Center notes that there are few head-to-head trials with other therapy options, such as oral NSAIDs or acetaminophen. We agree. This Cochrane review demonstrates another possible option for pain relief for patients who cannot tolerate oral NSAIDs or prefer not to take them. The body of literature comparing topical to oral NSAIDs is small, but we could not find any high-quality evidence to suggest that oral NSAIDs are more effective.

Dr. Center also questions the clinical utility of a medication that must be given to 4 patients in order for 1 to have a 50% reduction in pain (number needed to treat [NNT]=4). The NNT for topical NSAIDs is about the same.¹ For acute musculoskeletal injuries, 1 patient in 4 will respond to placebo, 1 in 4 will respond to active topical or oral therapy, and 2 in 4 will fail treatment. Whether these response rates are acceptable is an individual clinical decision to be made with the patient. We believe they are acceptable to most patients.

We thank Dr. Migliorino for bringing to light other topical pain medications. Diclofenac is the only topical NSAID available in the United States, which is why we chose to highlight it. The Cochrane review did not include salicylates because they are no longer classified as topical NSAIDS, and capsaicin was not included as it is not an NSAID. Both may very well offer pain relief.

The purpose of PURLs (Priority Updates from the Research Literature) is to identify and disseminate evidence that should change the practice of family medicine. We believe that this Cochrane review demonstrates that topical NSAIDs are effective options for acute musculoskeletal injuries and that many primary care physicians would be unfamiliar with this option.

Nina V. Rogers, MD
Kate Rowland, MD
Chicago

“An alternative to oral NSAIDs for acute musculoskeletal injuries,” (PURLs, J Fam Pract. 2011;60:147-148) promotes an unreasonable conclusion. The Cochrane review on which it is based found a 50% response rate to topical diclofenac for ankle sprains, compared with a 25% response to placebo. (A response was defined as ≥50% reduction in pain.) The authors of the Cochrane review seem to think this is adequate, and the authors of this PURL apparently agree.

First, they overstate the benefit. If we consider that 1 in 4 patients respond to placebo, we find that only 1 in 4 patients actually have what the authors describe as an adequate response to topical diclofenac. That still means that half the patients I see for ankle sprain could be calling at 11:00 PM to complain about inadequate pain relief.

Second, the Cochrane reviewers did not use an active control group with oral NSAIDs, leaving us to guess whether oral NSAIDs are equally effective, worse, or better than topical agents. The great majority of people I treat for ankle sprains obtain adequate pain relief with oral therapy. Studies have compared topical and oral NSAIDs, but the authors make no mention of these comparisons.

I trust and rely on the Cochrane reviews, but they are not the word of God. This review did not provide useful information. The space would have been better devoted to a topic I can put into practice.

Dean M. Center, MD
Bozeman, MT

I find it difficult to believe that these ivory tower researchers used topical diclofenac as their base. I’ve used topical agents for acute musculoskeletal pain for 40 years, costing one-tenth (or less) of the price of diclofenac. Only a few patients have complained of skin reactions. For more severe cases, capsaicin is a good choice; otherwise, a methyl salicylate product is very effective, at a concentration of 30% or more. Both are available as generics and do not require a prescription.

Robert Migliorino, DO
Lake Preston, SD

The authors respond:

We appreciate the issues raised by the letter writers. Dr. Center notes that there are few head-to-head trials with other therapy options, such as oral NSAIDs or acetaminophen. We agree. This Cochrane review demonstrates another possible option for pain relief for patients who cannot tolerate oral NSAIDs or prefer not to take them. The body of literature comparing topical to oral NSAIDs is small, but we could not find any high-quality evidence to suggest that oral NSAIDs are more effective.

Dr. Center also questions the clinical utility of a medication that must be given to 4 patients in order for 1 to have a 50% reduction in pain (number needed to treat [NNT]=4). The NNT for topical NSAIDs is about the same.¹ For acute musculoskeletal injuries, 1 patient in 4 will respond to placebo, 1 in 4 will respond to active topical or oral therapy, and 2 in 4 will fail treatment. Whether these response rates are acceptable is an individual clinical decision to be made with the patient. We believe they are acceptable to most patients.

We thank Dr. Migliorino for bringing to light other topical pain medications. Diclofenac is the only topical NSAID available in the United States, which is why we chose to highlight it. The Cochrane review did not include salicylates because they are no longer classified as topical NSAIDS, and capsaicin was not included as it is not an NSAID. Both may very well offer pain relief.

The purpose of PURLs (Priority Updates from the Research Literature) is to identify and disseminate evidence that should change the practice of family medicine. We believe that this Cochrane review demonstrates that topical NSAIDs are effective options for acute musculoskeletal injuries and that many primary care physicians would be unfamiliar with this option.

Nina V. Rogers, MD
Kate Rowland, MD
Chicago