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Thrombolytics in Pulmonary Embolism Associated with Lower Mortality, Increased Bleeding
Clinical question: What are the mortality benefits and bleeding risks associated with thrombolytic therapy, compared with other anticoagulants, in pulmonary embolism (PE)?
Background: Thrombolytics are not routinely administered for PE but can be considered in patients with hemodynamic instability with massive PE and those not responding to anticoagulation.
Study design: Meta-analysis.
Setting: Sixteen randomized clinical trials (RCTs) occurring in a variety of settings.
Synopsis: Trials involving 2,115 patients (thrombolytic therapy cohort 1,061; anticoagulation cohort 1,054) with PE were studied, with special attention given to those patients with intermediate risk PEs defined by subclinical cardiovascular compromise. Thrombolytics were compared with low molecular weight heparin, unfractionated heparin, vitamin K antagonists, and fondaparinux. The primary outcomes were all-cause mortality and major bleeding. Secondary outcomes included risk of recurrence of the PE and intracranial hemorrhage.
Thrombolytic therapy was associated with lower all-cause mortality and with higher risk of bleeding. There was a 9.24% rate of major bleeding in the thrombolytic therapy cohort and a 3.42% rate in the anticoagulation cohort. Intracranial hemorrhage was greater in the thrombolytic therapy cohort (1.46% vs. 0.19%). Patients with intermediate risk PE had greater major bleeding rate (7.74% vs. 2.25%) and lower mortality (1.39% vs. 2.92%) with thrombolytics compared to anticoagulation. A net clinical benefit calculation (mortality benefit accounting for intracranial hemorrhage risk) was performed and demonstrated a net clinical benefit of 0.81% (95% CI, 0.65%-1.01%) for those patients who received thrombolytics versus other anticoagulation.
Bottom line: This study suggested a mortality benefit of thrombolytics overall, including those patients with intermediate risk PE.
Citation: Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311(23):2414-2421.
Clinical question: What are the mortality benefits and bleeding risks associated with thrombolytic therapy, compared with other anticoagulants, in pulmonary embolism (PE)?
Background: Thrombolytics are not routinely administered for PE but can be considered in patients with hemodynamic instability with massive PE and those not responding to anticoagulation.
Study design: Meta-analysis.
Setting: Sixteen randomized clinical trials (RCTs) occurring in a variety of settings.
Synopsis: Trials involving 2,115 patients (thrombolytic therapy cohort 1,061; anticoagulation cohort 1,054) with PE were studied, with special attention given to those patients with intermediate risk PEs defined by subclinical cardiovascular compromise. Thrombolytics were compared with low molecular weight heparin, unfractionated heparin, vitamin K antagonists, and fondaparinux. The primary outcomes were all-cause mortality and major bleeding. Secondary outcomes included risk of recurrence of the PE and intracranial hemorrhage.
Thrombolytic therapy was associated with lower all-cause mortality and with higher risk of bleeding. There was a 9.24% rate of major bleeding in the thrombolytic therapy cohort and a 3.42% rate in the anticoagulation cohort. Intracranial hemorrhage was greater in the thrombolytic therapy cohort (1.46% vs. 0.19%). Patients with intermediate risk PE had greater major bleeding rate (7.74% vs. 2.25%) and lower mortality (1.39% vs. 2.92%) with thrombolytics compared to anticoagulation. A net clinical benefit calculation (mortality benefit accounting for intracranial hemorrhage risk) was performed and demonstrated a net clinical benefit of 0.81% (95% CI, 0.65%-1.01%) for those patients who received thrombolytics versus other anticoagulation.
Bottom line: This study suggested a mortality benefit of thrombolytics overall, including those patients with intermediate risk PE.
Citation: Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311(23):2414-2421.
Clinical question: What are the mortality benefits and bleeding risks associated with thrombolytic therapy, compared with other anticoagulants, in pulmonary embolism (PE)?
Background: Thrombolytics are not routinely administered for PE but can be considered in patients with hemodynamic instability with massive PE and those not responding to anticoagulation.
Study design: Meta-analysis.
Setting: Sixteen randomized clinical trials (RCTs) occurring in a variety of settings.
Synopsis: Trials involving 2,115 patients (thrombolytic therapy cohort 1,061; anticoagulation cohort 1,054) with PE were studied, with special attention given to those patients with intermediate risk PEs defined by subclinical cardiovascular compromise. Thrombolytics were compared with low molecular weight heparin, unfractionated heparin, vitamin K antagonists, and fondaparinux. The primary outcomes were all-cause mortality and major bleeding. Secondary outcomes included risk of recurrence of the PE and intracranial hemorrhage.
Thrombolytic therapy was associated with lower all-cause mortality and with higher risk of bleeding. There was a 9.24% rate of major bleeding in the thrombolytic therapy cohort and a 3.42% rate in the anticoagulation cohort. Intracranial hemorrhage was greater in the thrombolytic therapy cohort (1.46% vs. 0.19%). Patients with intermediate risk PE had greater major bleeding rate (7.74% vs. 2.25%) and lower mortality (1.39% vs. 2.92%) with thrombolytics compared to anticoagulation. A net clinical benefit calculation (mortality benefit accounting for intracranial hemorrhage risk) was performed and demonstrated a net clinical benefit of 0.81% (95% CI, 0.65%-1.01%) for those patients who received thrombolytics versus other anticoagulation.
Bottom line: This study suggested a mortality benefit of thrombolytics overall, including those patients with intermediate risk PE.
Citation: Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311(23):2414-2421.
Interventions Effective in Preventing Hospital Readmissions
Clinical question: Which interventions are most effective to prevent 30-day readmissions in medical or surgical patients?
Background: Preventing early readmissions has become a national priority. This study set out to determine which intervention had the largest impact on the prevention of early readmission.
Study design: Meta-analysis.
Setting: Forty-seven studies in multiple locations.
Synopsis: This study evaluated 47 randomized trials that assessed the effectiveness of peri-discharge interventions on the risk of all-cause or unplanned 30-day readmissions for medical and surgical patients. Outcomes included unplanned readmissions, all-cause readmissions, and a composite of unplanned and all-cause readmissions plus out-of-hospital deaths.
The included studies reported up to seven methods of preventing readmissions, including involvement of case management, home visits, education of patients, and self-care support. In 42 trials reporting readmission rates, the pooled relative risk of readmission was 0.82 (95 % CI, 0.73-0.91; P<0.001) within 30 days.
Multiple subgroup analyses noted that the most effective interventions on hospital readmission were those that were more complex and those that sought to augment patient capacity to access and enact dependable post-discharge care.
Limitations included single-center academic studies, lack of standard for dealing with missing data, existence of publication bias, and differing methods used to evaluate intervention effects.
Bottom line: This study was the largest of its kind, to date, and suggests that the interventions analyzed in this study, although complex (e.g. enhancing capacity for self-care at home), were efficacious in reducing 30-day readmissions.
Citation: Leppin AL, Gionfriddo MR, Kessler M, et al. Preventing 30-day hospital readmissions: a systematic review and meta-analysis of randomized trials. JAMA Intern Med. 2014;174(7):1095-1107.
Clinical question: Which interventions are most effective to prevent 30-day readmissions in medical or surgical patients?
Background: Preventing early readmissions has become a national priority. This study set out to determine which intervention had the largest impact on the prevention of early readmission.
Study design: Meta-analysis.
Setting: Forty-seven studies in multiple locations.
Synopsis: This study evaluated 47 randomized trials that assessed the effectiveness of peri-discharge interventions on the risk of all-cause or unplanned 30-day readmissions for medical and surgical patients. Outcomes included unplanned readmissions, all-cause readmissions, and a composite of unplanned and all-cause readmissions plus out-of-hospital deaths.
The included studies reported up to seven methods of preventing readmissions, including involvement of case management, home visits, education of patients, and self-care support. In 42 trials reporting readmission rates, the pooled relative risk of readmission was 0.82 (95 % CI, 0.73-0.91; P<0.001) within 30 days.
Multiple subgroup analyses noted that the most effective interventions on hospital readmission were those that were more complex and those that sought to augment patient capacity to access and enact dependable post-discharge care.
Limitations included single-center academic studies, lack of standard for dealing with missing data, existence of publication bias, and differing methods used to evaluate intervention effects.
Bottom line: This study was the largest of its kind, to date, and suggests that the interventions analyzed in this study, although complex (e.g. enhancing capacity for self-care at home), were efficacious in reducing 30-day readmissions.
Citation: Leppin AL, Gionfriddo MR, Kessler M, et al. Preventing 30-day hospital readmissions: a systematic review and meta-analysis of randomized trials. JAMA Intern Med. 2014;174(7):1095-1107.
Clinical question: Which interventions are most effective to prevent 30-day readmissions in medical or surgical patients?
Background: Preventing early readmissions has become a national priority. This study set out to determine which intervention had the largest impact on the prevention of early readmission.
Study design: Meta-analysis.
Setting: Forty-seven studies in multiple locations.
Synopsis: This study evaluated 47 randomized trials that assessed the effectiveness of peri-discharge interventions on the risk of all-cause or unplanned 30-day readmissions for medical and surgical patients. Outcomes included unplanned readmissions, all-cause readmissions, and a composite of unplanned and all-cause readmissions plus out-of-hospital deaths.
The included studies reported up to seven methods of preventing readmissions, including involvement of case management, home visits, education of patients, and self-care support. In 42 trials reporting readmission rates, the pooled relative risk of readmission was 0.82 (95 % CI, 0.73-0.91; P<0.001) within 30 days.
Multiple subgroup analyses noted that the most effective interventions on hospital readmission were those that were more complex and those that sought to augment patient capacity to access and enact dependable post-discharge care.
Limitations included single-center academic studies, lack of standard for dealing with missing data, existence of publication bias, and differing methods used to evaluate intervention effects.
Bottom line: This study was the largest of its kind, to date, and suggests that the interventions analyzed in this study, although complex (e.g. enhancing capacity for self-care at home), were efficacious in reducing 30-day readmissions.
Citation: Leppin AL, Gionfriddo MR, Kessler M, et al. Preventing 30-day hospital readmissions: a systematic review and meta-analysis of randomized trials. JAMA Intern Med. 2014;174(7):1095-1107.
Long-Term Benzodiazepine Use May Increase Risk of Alzheimer’s Disease
Benzodiazepine use for three months or more is associated with a significantly increased likelihood of developing Alzheimer’s disease, and longer exposure is associated with greater likelihood, according to results from a case–control study published September 9 in BMJ.
Sophie Billioti de Gage, a doctoral candidate at the Université de Bordeaux in France, and colleagues conducted a nested case–control study of 1,796 members of a public drug plan in Québec, Canada, who were age 66 or older and had been diagnosed with Alzheimer’s disease at least six years before. The study also included more than 7,000 controls without Alzheimer’s disease, matched for age and sex.
The investigators found a cumulative dose–effect association between exposure to benzodiazepines at least five years before diagnosis and the odds of developing Alzheimer’s disease. The researchers observed a significantly greater likelihood of developing Alzheimer’s disease with benzodiazepine use of 90 or more consecutive days (adjusted odds ratio, 1.51) and with daily exposure to benzodiazepines for 180 or more days (adjusted OR, 1.84).
The researchers also found that the type of benzodiazepine prescribed affected the risk. Drugs with longer half-lives, such as diazepam and clonazepam, were associated with a greater likelihood of developing Alzheimer’s disease (OR, 1.70), compared with shorter-acting drugs, such as lorazepam and alprazolam (OR, 1.43). The association between benzodiazepine use and Alzheimer’s disease persisted after the investigators adjusted for symptoms that could indicate a future dementia diagnosis, including depression, anxiety, and insomnia.
Although the study authors noted that they could not rule out that anxiety and sleep disorders, two of the main indications for benzodiazepines, “could be associated with early beta-amyloid lesions in [the] brain, and persistent midlife anxiety could be associated with a greater risk of dementia in older people,” they also noted that their study was designed to reduce the possibility of reverse causation bias “and to provide additional arguments linking benzodiazepine use with Alzheimer’s disease, such as a dose–effect relation.” The findings underscore the necessity of “carefully evaluating the indications for use of this drug class ... especially considering the prevalence and chronicity of benzodiazepine use in older people and the high and increasing incidence of dementia in developed countries,” said Ms. Billioti de Gage.
—Jennie Smith
Suggested Reading
Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ. 2014 Sep 9;349:g5205.
Benzodiazepine use for three months or more is associated with a significantly increased likelihood of developing Alzheimer’s disease, and longer exposure is associated with greater likelihood, according to results from a case–control study published September 9 in BMJ.
Sophie Billioti de Gage, a doctoral candidate at the Université de Bordeaux in France, and colleagues conducted a nested case–control study of 1,796 members of a public drug plan in Québec, Canada, who were age 66 or older and had been diagnosed with Alzheimer’s disease at least six years before. The study also included more than 7,000 controls without Alzheimer’s disease, matched for age and sex.
The investigators found a cumulative dose–effect association between exposure to benzodiazepines at least five years before diagnosis and the odds of developing Alzheimer’s disease. The researchers observed a significantly greater likelihood of developing Alzheimer’s disease with benzodiazepine use of 90 or more consecutive days (adjusted odds ratio, 1.51) and with daily exposure to benzodiazepines for 180 or more days (adjusted OR, 1.84).
The researchers also found that the type of benzodiazepine prescribed affected the risk. Drugs with longer half-lives, such as diazepam and clonazepam, were associated with a greater likelihood of developing Alzheimer’s disease (OR, 1.70), compared with shorter-acting drugs, such as lorazepam and alprazolam (OR, 1.43). The association between benzodiazepine use and Alzheimer’s disease persisted after the investigators adjusted for symptoms that could indicate a future dementia diagnosis, including depression, anxiety, and insomnia.
Although the study authors noted that they could not rule out that anxiety and sleep disorders, two of the main indications for benzodiazepines, “could be associated with early beta-amyloid lesions in [the] brain, and persistent midlife anxiety could be associated with a greater risk of dementia in older people,” they also noted that their study was designed to reduce the possibility of reverse causation bias “and to provide additional arguments linking benzodiazepine use with Alzheimer’s disease, such as a dose–effect relation.” The findings underscore the necessity of “carefully evaluating the indications for use of this drug class ... especially considering the prevalence and chronicity of benzodiazepine use in older people and the high and increasing incidence of dementia in developed countries,” said Ms. Billioti de Gage.
—Jennie Smith
Benzodiazepine use for three months or more is associated with a significantly increased likelihood of developing Alzheimer’s disease, and longer exposure is associated with greater likelihood, according to results from a case–control study published September 9 in BMJ.
Sophie Billioti de Gage, a doctoral candidate at the Université de Bordeaux in France, and colleagues conducted a nested case–control study of 1,796 members of a public drug plan in Québec, Canada, who were age 66 or older and had been diagnosed with Alzheimer’s disease at least six years before. The study also included more than 7,000 controls without Alzheimer’s disease, matched for age and sex.
The investigators found a cumulative dose–effect association between exposure to benzodiazepines at least five years before diagnosis and the odds of developing Alzheimer’s disease. The researchers observed a significantly greater likelihood of developing Alzheimer’s disease with benzodiazepine use of 90 or more consecutive days (adjusted odds ratio, 1.51) and with daily exposure to benzodiazepines for 180 or more days (adjusted OR, 1.84).
The researchers also found that the type of benzodiazepine prescribed affected the risk. Drugs with longer half-lives, such as diazepam and clonazepam, were associated with a greater likelihood of developing Alzheimer’s disease (OR, 1.70), compared with shorter-acting drugs, such as lorazepam and alprazolam (OR, 1.43). The association between benzodiazepine use and Alzheimer’s disease persisted after the investigators adjusted for symptoms that could indicate a future dementia diagnosis, including depression, anxiety, and insomnia.
Although the study authors noted that they could not rule out that anxiety and sleep disorders, two of the main indications for benzodiazepines, “could be associated with early beta-amyloid lesions in [the] brain, and persistent midlife anxiety could be associated with a greater risk of dementia in older people,” they also noted that their study was designed to reduce the possibility of reverse causation bias “and to provide additional arguments linking benzodiazepine use with Alzheimer’s disease, such as a dose–effect relation.” The findings underscore the necessity of “carefully evaluating the indications for use of this drug class ... especially considering the prevalence and chronicity of benzodiazepine use in older people and the high and increasing incidence of dementia in developed countries,” said Ms. Billioti de Gage.
—Jennie Smith
Suggested Reading
Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ. 2014 Sep 9;349:g5205.
Suggested Reading
Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ. 2014 Sep 9;349:g5205.
Migraine in Midlife May Be Linked to Late-Life Parkinsonism
Patients with midlife migraine, especially migraine with aura (MA), have a higher risk of parkinsonian symptoms in later life, researchers reported online ahead of print September 17 in Neurology.
Ann I. Scher, PhD, and colleagues assessed 5,764 participants enrolled in the Age, Gene/Environment Susceptibility–Reykjavik Study cohort between 2002 and 2006 for symptoms of parkinsonism, diagnosis of Parkinson’s disease, family history of Parkinson’s disease, and restless legs syndrome (RLS)/Willis-Ekbom disease (WED). The investigators compared the risk of parkinsonism and RLS/WED in later life among participants with and without migraine in midlife. Patients had a mean age of 51 (range, 33 to 65) when they were asked about their headache symptoms in the Reykjavik Study. All remaining assessments were conducted during late-life interviews when patients had a mean age of 77 (range, 66 to 96).
Dr. Scher’s group found that patients with midlife migraine, particularly MA, were more likely than others in later life to report parkinsonian symptoms (odds ratio [ORMA], 3.6) and to be diagnosed with Parkinson’s disease (ORMA, 2.5). Women who had MA were more likely than others to have a parent (ORMA, 2.26) or sibling (ORMA, 1.78) with Parkinson’s disease. The risk of RLS/WED in later life was increased for headache in general. These associations were independent of cardiovascular disease and presumed ischemic lesions on MRI.
“We found that subjects with a midlife history of headache were, about 25 years later, more likely than others to report movement disorder symptoms (parkinsonism and RLS/WED), to have been diagnosed with Parkinson’s disease, and to have a family history of Parkinson’s disease (women),” stated Dr. Scher, Professor of Epidemiology, Department of Preventive Medicine and Biometrics, Uniformed Services University in Bethesda, Maryland, and colleagues. “Some findings differed by headache type. Risk of late-life RLS/WED was increased for all types of headache.
“Our finding linking migraine with different indicators of parkinsonism suggests shared cerebral vulnerability that could reflect common pathology, genetic or environmental risk factors, or changes in the brain from one condition that increases the likelihood of symptoms reflecting the other conditions,” Dr. Scher and colleagues concluded.”
—Colby Stong
Suggested Reading
Scher AI, Ross GW, Sigurdsson S, et al. Midlife migraine and late-life parkinsonism: AGES-Reykjavik Study. Neurology. 2014 September 17 [Epub ahead of print].
Patients with midlife migraine, especially migraine with aura (MA), have a higher risk of parkinsonian symptoms in later life, researchers reported online ahead of print September 17 in Neurology.
Ann I. Scher, PhD, and colleagues assessed 5,764 participants enrolled in the Age, Gene/Environment Susceptibility–Reykjavik Study cohort between 2002 and 2006 for symptoms of parkinsonism, diagnosis of Parkinson’s disease, family history of Parkinson’s disease, and restless legs syndrome (RLS)/Willis-Ekbom disease (WED). The investigators compared the risk of parkinsonism and RLS/WED in later life among participants with and without migraine in midlife. Patients had a mean age of 51 (range, 33 to 65) when they were asked about their headache symptoms in the Reykjavik Study. All remaining assessments were conducted during late-life interviews when patients had a mean age of 77 (range, 66 to 96).
Dr. Scher’s group found that patients with midlife migraine, particularly MA, were more likely than others in later life to report parkinsonian symptoms (odds ratio [ORMA], 3.6) and to be diagnosed with Parkinson’s disease (ORMA, 2.5). Women who had MA were more likely than others to have a parent (ORMA, 2.26) or sibling (ORMA, 1.78) with Parkinson’s disease. The risk of RLS/WED in later life was increased for headache in general. These associations were independent of cardiovascular disease and presumed ischemic lesions on MRI.
“We found that subjects with a midlife history of headache were, about 25 years later, more likely than others to report movement disorder symptoms (parkinsonism and RLS/WED), to have been diagnosed with Parkinson’s disease, and to have a family history of Parkinson’s disease (women),” stated Dr. Scher, Professor of Epidemiology, Department of Preventive Medicine and Biometrics, Uniformed Services University in Bethesda, Maryland, and colleagues. “Some findings differed by headache type. Risk of late-life RLS/WED was increased for all types of headache.
“Our finding linking migraine with different indicators of parkinsonism suggests shared cerebral vulnerability that could reflect common pathology, genetic or environmental risk factors, or changes in the brain from one condition that increases the likelihood of symptoms reflecting the other conditions,” Dr. Scher and colleagues concluded.”
—Colby Stong
Patients with midlife migraine, especially migraine with aura (MA), have a higher risk of parkinsonian symptoms in later life, researchers reported online ahead of print September 17 in Neurology.
Ann I. Scher, PhD, and colleagues assessed 5,764 participants enrolled in the Age, Gene/Environment Susceptibility–Reykjavik Study cohort between 2002 and 2006 for symptoms of parkinsonism, diagnosis of Parkinson’s disease, family history of Parkinson’s disease, and restless legs syndrome (RLS)/Willis-Ekbom disease (WED). The investigators compared the risk of parkinsonism and RLS/WED in later life among participants with and without migraine in midlife. Patients had a mean age of 51 (range, 33 to 65) when they were asked about their headache symptoms in the Reykjavik Study. All remaining assessments were conducted during late-life interviews when patients had a mean age of 77 (range, 66 to 96).
Dr. Scher’s group found that patients with midlife migraine, particularly MA, were more likely than others in later life to report parkinsonian symptoms (odds ratio [ORMA], 3.6) and to be diagnosed with Parkinson’s disease (ORMA, 2.5). Women who had MA were more likely than others to have a parent (ORMA, 2.26) or sibling (ORMA, 1.78) with Parkinson’s disease. The risk of RLS/WED in later life was increased for headache in general. These associations were independent of cardiovascular disease and presumed ischemic lesions on MRI.
“We found that subjects with a midlife history of headache were, about 25 years later, more likely than others to report movement disorder symptoms (parkinsonism and RLS/WED), to have been diagnosed with Parkinson’s disease, and to have a family history of Parkinson’s disease (women),” stated Dr. Scher, Professor of Epidemiology, Department of Preventive Medicine and Biometrics, Uniformed Services University in Bethesda, Maryland, and colleagues. “Some findings differed by headache type. Risk of late-life RLS/WED was increased for all types of headache.
“Our finding linking migraine with different indicators of parkinsonism suggests shared cerebral vulnerability that could reflect common pathology, genetic or environmental risk factors, or changes in the brain from one condition that increases the likelihood of symptoms reflecting the other conditions,” Dr. Scher and colleagues concluded.”
—Colby Stong
Suggested Reading
Scher AI, Ross GW, Sigurdsson S, et al. Midlife migraine and late-life parkinsonism: AGES-Reykjavik Study. Neurology. 2014 September 17 [Epub ahead of print].
Suggested Reading
Scher AI, Ross GW, Sigurdsson S, et al. Midlife migraine and late-life parkinsonism: AGES-Reykjavik Study. Neurology. 2014 September 17 [Epub ahead of print].
Twin Study Confirms Genetic Basis of Several Epilepsy Syndromes
A study of twins with seizures confirms the genetic basis of idiopathic generalized epilepsy, genetic epilepsy with febrile seizures plus, and focal epilepsies, investigators reported online ahead of print August 8 in Neurology.
The analysis did not support a genetic basis for benign epilepsy with centrotemporal spikes (BECTS) because of a lack of concordance between monozygotic pairs of twins with the disorder, said Lata Vadlamudi, PhD, Senior Lecturer at the University of Queensland in Brisbane, Australia, and her associates.
The researchers calculated casewise concordance estimates for epilepsy syndromes in 558 pairs of twins with suspected epilepsy, 418 of whom had confirmed seizures. They grouped the participants based on the 2010 International League Against Epilepsy (ILAE) scheme and incorporated molecular data when applicable.
Genetics of BECTS May Be Complex
The estimated concordance for monozygotic twins exceeded that for dizygotic twins for idiopathic generalized epilepsies (0.77 vs 0.35), genetic epilepsy with febrile seizures plus (0.85 vs 0.25), and focal epilepsies (0.40 vs 0.03), the researchers reported.
Applying the 2010 ILAE scheme also confirmed genetic influences for syndromes classified as genetic, and 10.9% of individuals tested had large-effect mutations in known epilepsy genes or had validated susceptibility alleles. Mutations most often involved the SCN1A gene, which is seen as the most clinically relevant gene in epilepsy, they said.
The study also found “striking monozygotic and dizygotic discordance” for BECTS, which has been presumed to have a genetic basis, said the researchers. “Our analysis of the BECTS twins ... highlighted that the etiology and genetics of BECTS are more complicated than initially conceptualized.”
For patients with epilepsy, the results “highlight the potential to integrate well-established clinical data with molecular genetic findings and pave the way for targeted next-generation sequencing of large cohorts, which is likely to be the next phase in diagnosis, treatment guidance, and genetic counseling,” said Dr. Vadlamudi.
Study Illuminates Genetic Complexities of Epilepsy
The most common epilepsy syndromes do not follow a straightforward Mendelian inheritance pattern, but instead involve combinations of large-effect and small-effect alleles and environmental factors. This twin study illuminated the genetic complexities of epilepsy and the influence of genetic variance on complex phenotypes, said Renzo Guerrini, MD, a neurologist at the University of Florence in Italy, and Jeffrey Buchhalter, MD, PhD, a neurologist at the Alberta Children’s Hospital in Calgary, Canada, in an accompanying editorial.
The study confirmed the strong genetic component of genetic epilepsy with febrile seizures plus and revealed high monozygotic concordance for the syndrome, the neurologists noted. In addition, the analysis found “compelling evidence” for a strong genetic role in generalized epilepsy, corroborating the concept of genetic epilepsy and the role of genes in some nonlesional focal epilepsies.
But it remains unclear whether current classifications for epilepsy reflect the molecular profiles of these syndromes, said the coauthors. The category of genetic epilepsy might be arbitrary, for example, “as what is presumed to be symptomatic today may be revealed as genetic after molecular screening,” said Drs. Guerrini and Buchhalter.
The structural/metabolic epilepsy category also is heterogeneous, encompassing generalized and localized brain malformations that are determined by the time of origin of neurons with abnormal migration patterns. “This suggests the need for a category that includes the genetic defect and interposed structural abnormality,” Drs. Guerrini and Buchhalter added.
The lack of concordance for monozygotic twins with benign epilepsy with centrotemporal spikes also contradicts prior reports that BECTS is primarily genetic, they noted. But perhaps the current study did not include enough twins with BECTS to capture those with rare monozygotic inheritance, or perhaps postzygotic mutations led to genetic discordance in twin pairs, Drs. Guerrini and Buchhalter concluded.
—Amy Karon
Suggested Reading
Guerrini R, Buchhalter JR. Epilepsy phenotypes and genotype determinants: Identical twins teach lessons on complexity. Neurology. 2014 Aug 8 [Epub ahead of print].
Vadlamudi L, Milne RL, Lawrence K, et al. Genetics of epilepsy: The testimony of twins in the molecular era. Neurology. 2014 Aug 8 [Epub ahead of print].
Jeffrey Buchhalter
A study of twins with seizures confirms the genetic basis of idiopathic generalized epilepsy, genetic epilepsy with febrile seizures plus, and focal epilepsies, investigators reported online ahead of print August 8 in Neurology.
The analysis did not support a genetic basis for benign epilepsy with centrotemporal spikes (BECTS) because of a lack of concordance between monozygotic pairs of twins with the disorder, said Lata Vadlamudi, PhD, Senior Lecturer at the University of Queensland in Brisbane, Australia, and her associates.
The researchers calculated casewise concordance estimates for epilepsy syndromes in 558 pairs of twins with suspected epilepsy, 418 of whom had confirmed seizures. They grouped the participants based on the 2010 International League Against Epilepsy (ILAE) scheme and incorporated molecular data when applicable.
Genetics of BECTS May Be Complex
The estimated concordance for monozygotic twins exceeded that for dizygotic twins for idiopathic generalized epilepsies (0.77 vs 0.35), genetic epilepsy with febrile seizures plus (0.85 vs 0.25), and focal epilepsies (0.40 vs 0.03), the researchers reported.
Applying the 2010 ILAE scheme also confirmed genetic influences for syndromes classified as genetic, and 10.9% of individuals tested had large-effect mutations in known epilepsy genes or had validated susceptibility alleles. Mutations most often involved the SCN1A gene, which is seen as the most clinically relevant gene in epilepsy, they said.
The study also found “striking monozygotic and dizygotic discordance” for BECTS, which has been presumed to have a genetic basis, said the researchers. “Our analysis of the BECTS twins ... highlighted that the etiology and genetics of BECTS are more complicated than initially conceptualized.”
For patients with epilepsy, the results “highlight the potential to integrate well-established clinical data with molecular genetic findings and pave the way for targeted next-generation sequencing of large cohorts, which is likely to be the next phase in diagnosis, treatment guidance, and genetic counseling,” said Dr. Vadlamudi.
Study Illuminates Genetic Complexities of Epilepsy
The most common epilepsy syndromes do not follow a straightforward Mendelian inheritance pattern, but instead involve combinations of large-effect and small-effect alleles and environmental factors. This twin study illuminated the genetic complexities of epilepsy and the influence of genetic variance on complex phenotypes, said Renzo Guerrini, MD, a neurologist at the University of Florence in Italy, and Jeffrey Buchhalter, MD, PhD, a neurologist at the Alberta Children’s Hospital in Calgary, Canada, in an accompanying editorial.
The study confirmed the strong genetic component of genetic epilepsy with febrile seizures plus and revealed high monozygotic concordance for the syndrome, the neurologists noted. In addition, the analysis found “compelling evidence” for a strong genetic role in generalized epilepsy, corroborating the concept of genetic epilepsy and the role of genes in some nonlesional focal epilepsies.
But it remains unclear whether current classifications for epilepsy reflect the molecular profiles of these syndromes, said the coauthors. The category of genetic epilepsy might be arbitrary, for example, “as what is presumed to be symptomatic today may be revealed as genetic after molecular screening,” said Drs. Guerrini and Buchhalter.
The structural/metabolic epilepsy category also is heterogeneous, encompassing generalized and localized brain malformations that are determined by the time of origin of neurons with abnormal migration patterns. “This suggests the need for a category that includes the genetic defect and interposed structural abnormality,” Drs. Guerrini and Buchhalter added.
The lack of concordance for monozygotic twins with benign epilepsy with centrotemporal spikes also contradicts prior reports that BECTS is primarily genetic, they noted. But perhaps the current study did not include enough twins with BECTS to capture those with rare monozygotic inheritance, or perhaps postzygotic mutations led to genetic discordance in twin pairs, Drs. Guerrini and Buchhalter concluded.
—Amy Karon
A study of twins with seizures confirms the genetic basis of idiopathic generalized epilepsy, genetic epilepsy with febrile seizures plus, and focal epilepsies, investigators reported online ahead of print August 8 in Neurology.
The analysis did not support a genetic basis for benign epilepsy with centrotemporal spikes (BECTS) because of a lack of concordance between monozygotic pairs of twins with the disorder, said Lata Vadlamudi, PhD, Senior Lecturer at the University of Queensland in Brisbane, Australia, and her associates.
The researchers calculated casewise concordance estimates for epilepsy syndromes in 558 pairs of twins with suspected epilepsy, 418 of whom had confirmed seizures. They grouped the participants based on the 2010 International League Against Epilepsy (ILAE) scheme and incorporated molecular data when applicable.
Genetics of BECTS May Be Complex
The estimated concordance for monozygotic twins exceeded that for dizygotic twins for idiopathic generalized epilepsies (0.77 vs 0.35), genetic epilepsy with febrile seizures plus (0.85 vs 0.25), and focal epilepsies (0.40 vs 0.03), the researchers reported.
Applying the 2010 ILAE scheme also confirmed genetic influences for syndromes classified as genetic, and 10.9% of individuals tested had large-effect mutations in known epilepsy genes or had validated susceptibility alleles. Mutations most often involved the SCN1A gene, which is seen as the most clinically relevant gene in epilepsy, they said.
The study also found “striking monozygotic and dizygotic discordance” for BECTS, which has been presumed to have a genetic basis, said the researchers. “Our analysis of the BECTS twins ... highlighted that the etiology and genetics of BECTS are more complicated than initially conceptualized.”
For patients with epilepsy, the results “highlight the potential to integrate well-established clinical data with molecular genetic findings and pave the way for targeted next-generation sequencing of large cohorts, which is likely to be the next phase in diagnosis, treatment guidance, and genetic counseling,” said Dr. Vadlamudi.
Study Illuminates Genetic Complexities of Epilepsy
The most common epilepsy syndromes do not follow a straightforward Mendelian inheritance pattern, but instead involve combinations of large-effect and small-effect alleles and environmental factors. This twin study illuminated the genetic complexities of epilepsy and the influence of genetic variance on complex phenotypes, said Renzo Guerrini, MD, a neurologist at the University of Florence in Italy, and Jeffrey Buchhalter, MD, PhD, a neurologist at the Alberta Children’s Hospital in Calgary, Canada, in an accompanying editorial.
The study confirmed the strong genetic component of genetic epilepsy with febrile seizures plus and revealed high monozygotic concordance for the syndrome, the neurologists noted. In addition, the analysis found “compelling evidence” for a strong genetic role in generalized epilepsy, corroborating the concept of genetic epilepsy and the role of genes in some nonlesional focal epilepsies.
But it remains unclear whether current classifications for epilepsy reflect the molecular profiles of these syndromes, said the coauthors. The category of genetic epilepsy might be arbitrary, for example, “as what is presumed to be symptomatic today may be revealed as genetic after molecular screening,” said Drs. Guerrini and Buchhalter.
The structural/metabolic epilepsy category also is heterogeneous, encompassing generalized and localized brain malformations that are determined by the time of origin of neurons with abnormal migration patterns. “This suggests the need for a category that includes the genetic defect and interposed structural abnormality,” Drs. Guerrini and Buchhalter added.
The lack of concordance for monozygotic twins with benign epilepsy with centrotemporal spikes also contradicts prior reports that BECTS is primarily genetic, they noted. But perhaps the current study did not include enough twins with BECTS to capture those with rare monozygotic inheritance, or perhaps postzygotic mutations led to genetic discordance in twin pairs, Drs. Guerrini and Buchhalter concluded.
—Amy Karon
Suggested Reading
Guerrini R, Buchhalter JR. Epilepsy phenotypes and genotype determinants: Identical twins teach lessons on complexity. Neurology. 2014 Aug 8 [Epub ahead of print].
Vadlamudi L, Milne RL, Lawrence K, et al. Genetics of epilepsy: The testimony of twins in the molecular era. Neurology. 2014 Aug 8 [Epub ahead of print].
Suggested Reading
Guerrini R, Buchhalter JR. Epilepsy phenotypes and genotype determinants: Identical twins teach lessons on complexity. Neurology. 2014 Aug 8 [Epub ahead of print].
Vadlamudi L, Milne RL, Lawrence K, et al. Genetics of epilepsy: The testimony of twins in the molecular era. Neurology. 2014 Aug 8 [Epub ahead of print].
Jeffrey Buchhalter
Jeffrey Buchhalter
Sodium Intake Is Linked to Increased Disease Activity in MS
A higher sodium intake is associated with increased clinical and radiologic disease activity among patients with multiple sclerosis (MS), according to research published online ahead of print August 28 in the Journal of Neurology, Neurosurgery, and Psychiatry.
Mauricio F. Farez, MD, from the Department of Neurology at Raúl Carrea Institute for Neurological Research in Buenos Aires, and colleagues conducted an observational study of 70 patients with relapsing-remitting MS who were followed for two years. The researchers estimated sodium intake from sodium excretion in urine samples and used regression analysis to estimate the effect of sodium intake on MS disease activity. The findings were subsequently replicated in a separate group of 52 patients with MS.
Dr. Farez’s group found a positive correlation between exacerbation rates and sodium intake in a multivariate model after adjusting for age, gender, disease duration, smoking status, vitamin D level, BMI, and treatment. The exacerbation rate was 2.75-fold higher in patients with medium or high sodium intake, compared with the rate in subjects who had a low sodium intake.
In addition, participants with a high sodium intake had a 3.4-fold greater risk of having a new lesion revealed by MRI. This group also had, on average, eight more T2 lesions on MRI than other participants. The investigators observed a similar relationship in the independent replication group.
The authors noted several study limitations, including a small cohort size and the inability to exclude potential confounders such as diet, role of commensal microbiota, stress, and other behavior that may affect food preference and treatment compliance or healthy overall behavior.
“Thus, even though an association between increased sodium intake and increased disease activity was shown, we cannot claim causality and we cannot exclude the possibility of reverse causation: individuals with more relapses received more steroids, and thus their salt intake and excretion is increased because they have higher disease activity, and not the other way around,” stated the researchers. “Another possible caveat relates to changes in salt consumption over time. We tried to overcome this [variation] by retesting the same patients at different time points, finding no significant changes.”
The investigators also noted that although studies have found that dietary salt has a role in regulating blood pressure, the effects of sodium on the risk of MS may involve additional factors. For example, sodium chloride has been shown to have pleiotropic effects on kidney homeostasis and T-cell function, and other evidence suggests a reciprocal relationship between sodium chloride and the immune system.
“Whether high blood pressure interacts with the typical autoimmune mechanisms associated with MS is an interesting question that remains to be answered,” commented Dr. Farez and colleagues. “Nevertheless, our findings suggest that clinical trials with a salt intake reduction as an intervention are needed to establish whether sodium intake control benefits patients with MS.”
—Colby Stong
Suggested Reading
Farez MF, Fiol MP, Gaitán MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014; August 28 [Epub ahead of print].
A higher sodium intake is associated with increased clinical and radiologic disease activity among patients with multiple sclerosis (MS), according to research published online ahead of print August 28 in the Journal of Neurology, Neurosurgery, and Psychiatry.
Mauricio F. Farez, MD, from the Department of Neurology at Raúl Carrea Institute for Neurological Research in Buenos Aires, and colleagues conducted an observational study of 70 patients with relapsing-remitting MS who were followed for two years. The researchers estimated sodium intake from sodium excretion in urine samples and used regression analysis to estimate the effect of sodium intake on MS disease activity. The findings were subsequently replicated in a separate group of 52 patients with MS.
Dr. Farez’s group found a positive correlation between exacerbation rates and sodium intake in a multivariate model after adjusting for age, gender, disease duration, smoking status, vitamin D level, BMI, and treatment. The exacerbation rate was 2.75-fold higher in patients with medium or high sodium intake, compared with the rate in subjects who had a low sodium intake.
In addition, participants with a high sodium intake had a 3.4-fold greater risk of having a new lesion revealed by MRI. This group also had, on average, eight more T2 lesions on MRI than other participants. The investigators observed a similar relationship in the independent replication group.
The authors noted several study limitations, including a small cohort size and the inability to exclude potential confounders such as diet, role of commensal microbiota, stress, and other behavior that may affect food preference and treatment compliance or healthy overall behavior.
“Thus, even though an association between increased sodium intake and increased disease activity was shown, we cannot claim causality and we cannot exclude the possibility of reverse causation: individuals with more relapses received more steroids, and thus their salt intake and excretion is increased because they have higher disease activity, and not the other way around,” stated the researchers. “Another possible caveat relates to changes in salt consumption over time. We tried to overcome this [variation] by retesting the same patients at different time points, finding no significant changes.”
The investigators also noted that although studies have found that dietary salt has a role in regulating blood pressure, the effects of sodium on the risk of MS may involve additional factors. For example, sodium chloride has been shown to have pleiotropic effects on kidney homeostasis and T-cell function, and other evidence suggests a reciprocal relationship between sodium chloride and the immune system.
“Whether high blood pressure interacts with the typical autoimmune mechanisms associated with MS is an interesting question that remains to be answered,” commented Dr. Farez and colleagues. “Nevertheless, our findings suggest that clinical trials with a salt intake reduction as an intervention are needed to establish whether sodium intake control benefits patients with MS.”
—Colby Stong
A higher sodium intake is associated with increased clinical and radiologic disease activity among patients with multiple sclerosis (MS), according to research published online ahead of print August 28 in the Journal of Neurology, Neurosurgery, and Psychiatry.
Mauricio F. Farez, MD, from the Department of Neurology at Raúl Carrea Institute for Neurological Research in Buenos Aires, and colleagues conducted an observational study of 70 patients with relapsing-remitting MS who were followed for two years. The researchers estimated sodium intake from sodium excretion in urine samples and used regression analysis to estimate the effect of sodium intake on MS disease activity. The findings were subsequently replicated in a separate group of 52 patients with MS.
Dr. Farez’s group found a positive correlation between exacerbation rates and sodium intake in a multivariate model after adjusting for age, gender, disease duration, smoking status, vitamin D level, BMI, and treatment. The exacerbation rate was 2.75-fold higher in patients with medium or high sodium intake, compared with the rate in subjects who had a low sodium intake.
In addition, participants with a high sodium intake had a 3.4-fold greater risk of having a new lesion revealed by MRI. This group also had, on average, eight more T2 lesions on MRI than other participants. The investigators observed a similar relationship in the independent replication group.
The authors noted several study limitations, including a small cohort size and the inability to exclude potential confounders such as diet, role of commensal microbiota, stress, and other behavior that may affect food preference and treatment compliance or healthy overall behavior.
“Thus, even though an association between increased sodium intake and increased disease activity was shown, we cannot claim causality and we cannot exclude the possibility of reverse causation: individuals with more relapses received more steroids, and thus their salt intake and excretion is increased because they have higher disease activity, and not the other way around,” stated the researchers. “Another possible caveat relates to changes in salt consumption over time. We tried to overcome this [variation] by retesting the same patients at different time points, finding no significant changes.”
The investigators also noted that although studies have found that dietary salt has a role in regulating blood pressure, the effects of sodium on the risk of MS may involve additional factors. For example, sodium chloride has been shown to have pleiotropic effects on kidney homeostasis and T-cell function, and other evidence suggests a reciprocal relationship between sodium chloride and the immune system.
“Whether high blood pressure interacts with the typical autoimmune mechanisms associated with MS is an interesting question that remains to be answered,” commented Dr. Farez and colleagues. “Nevertheless, our findings suggest that clinical trials with a salt intake reduction as an intervention are needed to establish whether sodium intake control benefits patients with MS.”
—Colby Stong
Suggested Reading
Farez MF, Fiol MP, Gaitán MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014; August 28 [Epub ahead of print].
Suggested Reading
Farez MF, Fiol MP, Gaitán MI, et al. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014; August 28 [Epub ahead of print].
Dexamethasone Equivalent to Prednisone/Prednisolone in Symptomatic Improvement, Risk of Revisit for Acute Asthma Exacerbations
Clinical question: Are clinical outcomes for dexamethasone equivalent to currently recommended corticosteroids for the treatment of children with mild to moderate asthma exacerbations?
Background: National and international guidelines uniformly agree that administration of a systemic corticosteroid is appropriate for children hospitalized with mild to moderate asthma exacerbations. Based on available literature, a 2007 update to an expert panel report developed by the National Asthma Education and Prevention Program recommended prednisone, methylprednisolone, or prednisolone at 1-2 mg/kg daily in two divided doses (maximum 60 mg/day).
Recent small studies have begun to examine the use of dexamethasone in acute asthma exacerbations. The longer half-life of dexamethasone enables shorter treatment regimens, which can improve compliance. Additionally, its taste is considered superior compared to currently recommended corticosteroids.
Study designs: Two meta-analyses of randomized controlled trials (RCT).
Setting: Six RCTs published between 1997 and 2008.
Synopsis: Both groups searched Medline for RCTs using the search terms “dexamethasone” and “asthma”; additional search terms included “decadron” and “status asthmaticus.” Limiting the search to a pediatric population was achieved by either using appropriate medical subject heading terms or by using an age limiter of ≤18 years of age.
Both groups performed meta-analyses of clinical outcomes, including rates of revisit to a healthcare provider and symptomatic improvement. Adverse effects, specifically vomiting, also underwent meta-analysis by both groups.
Interestingly, both groups analyzed the same six studies, and all six studies were in the ED setting. The dexamethasone regimens in the analyzed studies included single-dose intramuscular (0.3-1.7 mg/kg), single-dose oral (0.6 mg/kg), or two-dose (0.6 mg/kg/day given once daily) oral regimens. These were compared to three- or five-day regimens of prednisone or prednisolone. Not surprisingly, both groups reached similar conclusions.
Regarding symptomatic improvement and revisit rates, there was no significant difference between dexamethasone and prednisone/prednisolone groups. Vomiting was less likely in the dexamethasone groups overall.
Bottom line: Meta-analyses of small RCTs examining dexamethasone in the treatment of acute asthma exacerbations show that it is equivalent to prednisone/prednisolone in symptomatic improvement and risk of revisit, and possibly superior with regard to the risk of vomiting.
Citations: Meyer JS, Riese J, Biondi E. Is dexamethasone an effective alternative to oral prednisone in the treatment of pediatric asthma exacerbations? Hosp Pediatr. 2014;4(3):172-180. Keeney GE, Gray MP, Morrison AK. Dexamethasone for acute asthma exacerbations in children: a meta-analysis. Pediatrics. 2014;133(3):493-499.
Reviewed by Pediatric Editor Weijen Chang, MD, SFHM, FAAP, associate clinical professor of medicine and pediatrics at the University of California at San Diego School of Medicine, and a hospitalist at both UCSD Medical Center and Rady Children’s Hospital.
Clinical question: Are clinical outcomes for dexamethasone equivalent to currently recommended corticosteroids for the treatment of children with mild to moderate asthma exacerbations?
Background: National and international guidelines uniformly agree that administration of a systemic corticosteroid is appropriate for children hospitalized with mild to moderate asthma exacerbations. Based on available literature, a 2007 update to an expert panel report developed by the National Asthma Education and Prevention Program recommended prednisone, methylprednisolone, or prednisolone at 1-2 mg/kg daily in two divided doses (maximum 60 mg/day).
Recent small studies have begun to examine the use of dexamethasone in acute asthma exacerbations. The longer half-life of dexamethasone enables shorter treatment regimens, which can improve compliance. Additionally, its taste is considered superior compared to currently recommended corticosteroids.
Study designs: Two meta-analyses of randomized controlled trials (RCT).
Setting: Six RCTs published between 1997 and 2008.
Synopsis: Both groups searched Medline for RCTs using the search terms “dexamethasone” and “asthma”; additional search terms included “decadron” and “status asthmaticus.” Limiting the search to a pediatric population was achieved by either using appropriate medical subject heading terms or by using an age limiter of ≤18 years of age.
Both groups performed meta-analyses of clinical outcomes, including rates of revisit to a healthcare provider and symptomatic improvement. Adverse effects, specifically vomiting, also underwent meta-analysis by both groups.
Interestingly, both groups analyzed the same six studies, and all six studies were in the ED setting. The dexamethasone regimens in the analyzed studies included single-dose intramuscular (0.3-1.7 mg/kg), single-dose oral (0.6 mg/kg), or two-dose (0.6 mg/kg/day given once daily) oral regimens. These were compared to three- or five-day regimens of prednisone or prednisolone. Not surprisingly, both groups reached similar conclusions.
Regarding symptomatic improvement and revisit rates, there was no significant difference between dexamethasone and prednisone/prednisolone groups. Vomiting was less likely in the dexamethasone groups overall.
Bottom line: Meta-analyses of small RCTs examining dexamethasone in the treatment of acute asthma exacerbations show that it is equivalent to prednisone/prednisolone in symptomatic improvement and risk of revisit, and possibly superior with regard to the risk of vomiting.
Citations: Meyer JS, Riese J, Biondi E. Is dexamethasone an effective alternative to oral prednisone in the treatment of pediatric asthma exacerbations? Hosp Pediatr. 2014;4(3):172-180. Keeney GE, Gray MP, Morrison AK. Dexamethasone for acute asthma exacerbations in children: a meta-analysis. Pediatrics. 2014;133(3):493-499.
Reviewed by Pediatric Editor Weijen Chang, MD, SFHM, FAAP, associate clinical professor of medicine and pediatrics at the University of California at San Diego School of Medicine, and a hospitalist at both UCSD Medical Center and Rady Children’s Hospital.
Clinical question: Are clinical outcomes for dexamethasone equivalent to currently recommended corticosteroids for the treatment of children with mild to moderate asthma exacerbations?
Background: National and international guidelines uniformly agree that administration of a systemic corticosteroid is appropriate for children hospitalized with mild to moderate asthma exacerbations. Based on available literature, a 2007 update to an expert panel report developed by the National Asthma Education and Prevention Program recommended prednisone, methylprednisolone, or prednisolone at 1-2 mg/kg daily in two divided doses (maximum 60 mg/day).
Recent small studies have begun to examine the use of dexamethasone in acute asthma exacerbations. The longer half-life of dexamethasone enables shorter treatment regimens, which can improve compliance. Additionally, its taste is considered superior compared to currently recommended corticosteroids.
Study designs: Two meta-analyses of randomized controlled trials (RCT).
Setting: Six RCTs published between 1997 and 2008.
Synopsis: Both groups searched Medline for RCTs using the search terms “dexamethasone” and “asthma”; additional search terms included “decadron” and “status asthmaticus.” Limiting the search to a pediatric population was achieved by either using appropriate medical subject heading terms or by using an age limiter of ≤18 years of age.
Both groups performed meta-analyses of clinical outcomes, including rates of revisit to a healthcare provider and symptomatic improvement. Adverse effects, specifically vomiting, also underwent meta-analysis by both groups.
Interestingly, both groups analyzed the same six studies, and all six studies were in the ED setting. The dexamethasone regimens in the analyzed studies included single-dose intramuscular (0.3-1.7 mg/kg), single-dose oral (0.6 mg/kg), or two-dose (0.6 mg/kg/day given once daily) oral regimens. These were compared to three- or five-day regimens of prednisone or prednisolone. Not surprisingly, both groups reached similar conclusions.
Regarding symptomatic improvement and revisit rates, there was no significant difference between dexamethasone and prednisone/prednisolone groups. Vomiting was less likely in the dexamethasone groups overall.
Bottom line: Meta-analyses of small RCTs examining dexamethasone in the treatment of acute asthma exacerbations show that it is equivalent to prednisone/prednisolone in symptomatic improvement and risk of revisit, and possibly superior with regard to the risk of vomiting.
Citations: Meyer JS, Riese J, Biondi E. Is dexamethasone an effective alternative to oral prednisone in the treatment of pediatric asthma exacerbations? Hosp Pediatr. 2014;4(3):172-180. Keeney GE, Gray MP, Morrison AK. Dexamethasone for acute asthma exacerbations in children: a meta-analysis. Pediatrics. 2014;133(3):493-499.
Reviewed by Pediatric Editor Weijen Chang, MD, SFHM, FAAP, associate clinical professor of medicine and pediatrics at the University of California at San Diego School of Medicine, and a hospitalist at both UCSD Medical Center and Rady Children’s Hospital.
Higher Mean Arterial Pressure in Septic Shock Patients Doesn’t Decrease Mortality
Clinical question: Does targeting a higher mean arterial pressure (MAP) in patients with septic shock lead to decreased mortality compared with targeting a more typical MAP range?
Background: The ideal blood pressure target for patients with septic shock is not currently known. There is some clinical evidence that patients with chronic arterial hypertension may require higher blood pressure to sustain kidney function.
Study design: Multicenter, randomized, stratified, open-label clinical trial.
Setting: ICUs at 29 centers in France
Synopsis: Researchers randomized 776 patients with septic shock to receive vasopressor treatment to maintain a MAP of 80-85 mmHg (high-target group) or 65-70 mmHg (low-target group). There was no significant difference between groups in the primary outcome of death at 28 days (HR in the high target group 1.07; 95% CI 0.84-1.38; P=0.57).
In patients with chronic arterial hypertension, those who were randomized to the high-target group had a reduced risk of doubling of plasma creatinine or need for renal-replacement therapy from days one to seven. Patients in the high-target group received larger amounts of vasopressors and for a longer period of time. There was no difference between the groups in the overall incidence of serious adverse events, though significantly more patients in the high-target group (6.7%) developed new onset atrial fibrillation compared with those in the low-target group (2.8%).
Bottom line: Mortality at 28 days was not significantly different in patients with septic shock who were randomized to a higher MAP target compared to patients who had a lower MAP target; this lower target encompasses the 65 mmHg target that is listed in the Surviving Sepsis Campaign guidelines.
Citation: Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593.
Clinical question: Does targeting a higher mean arterial pressure (MAP) in patients with septic shock lead to decreased mortality compared with targeting a more typical MAP range?
Background: The ideal blood pressure target for patients with septic shock is not currently known. There is some clinical evidence that patients with chronic arterial hypertension may require higher blood pressure to sustain kidney function.
Study design: Multicenter, randomized, stratified, open-label clinical trial.
Setting: ICUs at 29 centers in France
Synopsis: Researchers randomized 776 patients with septic shock to receive vasopressor treatment to maintain a MAP of 80-85 mmHg (high-target group) or 65-70 mmHg (low-target group). There was no significant difference between groups in the primary outcome of death at 28 days (HR in the high target group 1.07; 95% CI 0.84-1.38; P=0.57).
In patients with chronic arterial hypertension, those who were randomized to the high-target group had a reduced risk of doubling of plasma creatinine or need for renal-replacement therapy from days one to seven. Patients in the high-target group received larger amounts of vasopressors and for a longer period of time. There was no difference between the groups in the overall incidence of serious adverse events, though significantly more patients in the high-target group (6.7%) developed new onset atrial fibrillation compared with those in the low-target group (2.8%).
Bottom line: Mortality at 28 days was not significantly different in patients with septic shock who were randomized to a higher MAP target compared to patients who had a lower MAP target; this lower target encompasses the 65 mmHg target that is listed in the Surviving Sepsis Campaign guidelines.
Citation: Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593.
Clinical question: Does targeting a higher mean arterial pressure (MAP) in patients with septic shock lead to decreased mortality compared with targeting a more typical MAP range?
Background: The ideal blood pressure target for patients with septic shock is not currently known. There is some clinical evidence that patients with chronic arterial hypertension may require higher blood pressure to sustain kidney function.
Study design: Multicenter, randomized, stratified, open-label clinical trial.
Setting: ICUs at 29 centers in France
Synopsis: Researchers randomized 776 patients with septic shock to receive vasopressor treatment to maintain a MAP of 80-85 mmHg (high-target group) or 65-70 mmHg (low-target group). There was no significant difference between groups in the primary outcome of death at 28 days (HR in the high target group 1.07; 95% CI 0.84-1.38; P=0.57).
In patients with chronic arterial hypertension, those who were randomized to the high-target group had a reduced risk of doubling of plasma creatinine or need for renal-replacement therapy from days one to seven. Patients in the high-target group received larger amounts of vasopressors and for a longer period of time. There was no difference between the groups in the overall incidence of serious adverse events, though significantly more patients in the high-target group (6.7%) developed new onset atrial fibrillation compared with those in the low-target group (2.8%).
Bottom line: Mortality at 28 days was not significantly different in patients with septic shock who were randomized to a higher MAP target compared to patients who had a lower MAP target; this lower target encompasses the 65 mmHg target that is listed in the Surviving Sepsis Campaign guidelines.
Citation: Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593.
Infection Risk Decreases With Lower Red Blood Cell Transfusion Thresholds
Clinical question: Do different thresholds for red blood cell (RBC) transfusion influence the risk of infection, and does leukocyte reduction also influence the risk of infection?
Background: RBC transfusion is a common and costly medical intervention performed across U.S. hospitals. Scientists suspect that RBC transfusion may have immunomodulatory properties and may affect a patient’s risk of acquiring various infections.
Study design: Meta-analysis and systematic review.
Setting: International adult, pediatric, obstetric medical and surgical wards, and ICUs.
Synopsis: Eighteen studies performed were included in the meta-analysis of published randomized trials comparing restrictive to liberal RBC transfusion strategies in which infectious outcomes were reported. Patient enrollment spanned from 1994 to 2012. Six of the trials included pediatric patients. For adult patients, the restrictive RBC transfusion threshold ranged from 6.4–9.7 g/dL, while the liberal target ranged from 9-11.3 g/dL in included trials.
The overall pooled risk ratio for the association of restrictive vs. liberal transfusion threshold with infection was 0.99 (95% CI, 0.78-0.99; P=0.033). A decreased risk of infection with the use of a restrictive transfusion compared with a liberal threshold persisted in studies of leukocyte-reduced blood products.
Bottom line: Restrictive RBC transfusion thresholds are associated with a decreased risk of acquiring healthcare-associated infections compared with liberal transfusion thresholds.
Citation: Rohde JM, Dimcheff DE, Blumberg N, et al. Health care-associated infection after red blood cell transfusion: A systematic review and meta-analysis. JAMA. 2014;311(13):1317-1326.
Clinical question: Do different thresholds for red blood cell (RBC) transfusion influence the risk of infection, and does leukocyte reduction also influence the risk of infection?
Background: RBC transfusion is a common and costly medical intervention performed across U.S. hospitals. Scientists suspect that RBC transfusion may have immunomodulatory properties and may affect a patient’s risk of acquiring various infections.
Study design: Meta-analysis and systematic review.
Setting: International adult, pediatric, obstetric medical and surgical wards, and ICUs.
Synopsis: Eighteen studies performed were included in the meta-analysis of published randomized trials comparing restrictive to liberal RBC transfusion strategies in which infectious outcomes were reported. Patient enrollment spanned from 1994 to 2012. Six of the trials included pediatric patients. For adult patients, the restrictive RBC transfusion threshold ranged from 6.4–9.7 g/dL, while the liberal target ranged from 9-11.3 g/dL in included trials.
The overall pooled risk ratio for the association of restrictive vs. liberal transfusion threshold with infection was 0.99 (95% CI, 0.78-0.99; P=0.033). A decreased risk of infection with the use of a restrictive transfusion compared with a liberal threshold persisted in studies of leukocyte-reduced blood products.
Bottom line: Restrictive RBC transfusion thresholds are associated with a decreased risk of acquiring healthcare-associated infections compared with liberal transfusion thresholds.
Citation: Rohde JM, Dimcheff DE, Blumberg N, et al. Health care-associated infection after red blood cell transfusion: A systematic review and meta-analysis. JAMA. 2014;311(13):1317-1326.
Clinical question: Do different thresholds for red blood cell (RBC) transfusion influence the risk of infection, and does leukocyte reduction also influence the risk of infection?
Background: RBC transfusion is a common and costly medical intervention performed across U.S. hospitals. Scientists suspect that RBC transfusion may have immunomodulatory properties and may affect a patient’s risk of acquiring various infections.
Study design: Meta-analysis and systematic review.
Setting: International adult, pediatric, obstetric medical and surgical wards, and ICUs.
Synopsis: Eighteen studies performed were included in the meta-analysis of published randomized trials comparing restrictive to liberal RBC transfusion strategies in which infectious outcomes were reported. Patient enrollment spanned from 1994 to 2012. Six of the trials included pediatric patients. For adult patients, the restrictive RBC transfusion threshold ranged from 6.4–9.7 g/dL, while the liberal target ranged from 9-11.3 g/dL in included trials.
The overall pooled risk ratio for the association of restrictive vs. liberal transfusion threshold with infection was 0.99 (95% CI, 0.78-0.99; P=0.033). A decreased risk of infection with the use of a restrictive transfusion compared with a liberal threshold persisted in studies of leukocyte-reduced blood products.
Bottom line: Restrictive RBC transfusion thresholds are associated with a decreased risk of acquiring healthcare-associated infections compared with liberal transfusion thresholds.
Citation: Rohde JM, Dimcheff DE, Blumberg N, et al. Health care-associated infection after red blood cell transfusion: A systematic review and meta-analysis. JAMA. 2014;311(13):1317-1326.
Head Computed Tomography Scans Not Needed for Most Delirium Inpatients
Clinical question: Are CT scans of the head diagnostically helpful in hospitalized patients with delirium?
Background: Studies have investigated the use of head CT scans for the evaluation of delirium in the ED, but there is scant information about the utility of head CT scans in the assessment of the hospitalized patient with delirium.
Study design: Retrospective medical record review.
Setting: Large academic medical center in Massachusetts.
Synopsis: This study was designed to assess whether head CT scans obtained on patients without a history of head trauma, fall, known intracranial process, or new neurologic deficit were useful in the workup of delirium. During a two-year period, 1,714 CT scans of the head were performed, and 398 listed the indication for the scan as “delirium, altered mental status, confusion, encephalopathy, somnolence, or unresponsiveness.” Patients with the risk factors of trauma, fall, new neurologic deficit, and known intracranial process were excluded, and 220 patients’ records were reviewed.
Only six head CT scans (2.7%) revealed an acute intracranial process. Many chronic findings were noted, such as atrophy, small vessel ischemic disease, and old stroke. The authors found that the diagnostic utility was low for a head CT scan in a patient with delirium but noted no risk factors. There may be a subset of patients in whom the diagnostic yield is higher, such as those on anticoagulation or more obtunded patients.
Bottom line: In delirious inpatients without a history of head trauma, fall, known intracranial process, or new neurologic deficit, head CT scan has low diagnostic utility.
Citation: Theisen-Toupal J, Breu AC, Mattison ML, Arnaout R. Diagnostic yield of head computed tomography for the hospitalized medical patient with delirium [published online ahead of print April 15, 2014]. J Hosp Med.
Clinical question: Are CT scans of the head diagnostically helpful in hospitalized patients with delirium?
Background: Studies have investigated the use of head CT scans for the evaluation of delirium in the ED, but there is scant information about the utility of head CT scans in the assessment of the hospitalized patient with delirium.
Study design: Retrospective medical record review.
Setting: Large academic medical center in Massachusetts.
Synopsis: This study was designed to assess whether head CT scans obtained on patients without a history of head trauma, fall, known intracranial process, or new neurologic deficit were useful in the workup of delirium. During a two-year period, 1,714 CT scans of the head were performed, and 398 listed the indication for the scan as “delirium, altered mental status, confusion, encephalopathy, somnolence, or unresponsiveness.” Patients with the risk factors of trauma, fall, new neurologic deficit, and known intracranial process were excluded, and 220 patients’ records were reviewed.
Only six head CT scans (2.7%) revealed an acute intracranial process. Many chronic findings were noted, such as atrophy, small vessel ischemic disease, and old stroke. The authors found that the diagnostic utility was low for a head CT scan in a patient with delirium but noted no risk factors. There may be a subset of patients in whom the diagnostic yield is higher, such as those on anticoagulation or more obtunded patients.
Bottom line: In delirious inpatients without a history of head trauma, fall, known intracranial process, or new neurologic deficit, head CT scan has low diagnostic utility.
Citation: Theisen-Toupal J, Breu AC, Mattison ML, Arnaout R. Diagnostic yield of head computed tomography for the hospitalized medical patient with delirium [published online ahead of print April 15, 2014]. J Hosp Med.
Clinical question: Are CT scans of the head diagnostically helpful in hospitalized patients with delirium?
Background: Studies have investigated the use of head CT scans for the evaluation of delirium in the ED, but there is scant information about the utility of head CT scans in the assessment of the hospitalized patient with delirium.
Study design: Retrospective medical record review.
Setting: Large academic medical center in Massachusetts.
Synopsis: This study was designed to assess whether head CT scans obtained on patients without a history of head trauma, fall, known intracranial process, or new neurologic deficit were useful in the workup of delirium. During a two-year period, 1,714 CT scans of the head were performed, and 398 listed the indication for the scan as “delirium, altered mental status, confusion, encephalopathy, somnolence, or unresponsiveness.” Patients with the risk factors of trauma, fall, new neurologic deficit, and known intracranial process were excluded, and 220 patients’ records were reviewed.
Only six head CT scans (2.7%) revealed an acute intracranial process. Many chronic findings were noted, such as atrophy, small vessel ischemic disease, and old stroke. The authors found that the diagnostic utility was low for a head CT scan in a patient with delirium but noted no risk factors. There may be a subset of patients in whom the diagnostic yield is higher, such as those on anticoagulation or more obtunded patients.
Bottom line: In delirious inpatients without a history of head trauma, fall, known intracranial process, or new neurologic deficit, head CT scan has low diagnostic utility.
Citation: Theisen-Toupal J, Breu AC, Mattison ML, Arnaout R. Diagnostic yield of head computed tomography for the hospitalized medical patient with delirium [published online ahead of print April 15, 2014]. J Hosp Med.