Childhood Epilepsy, Febrile Seizures, and Subsequent Risk of ADHD

OBJECTIVES:

Epilepsy, febrile seizures, and attention-deficit/hyperactivity disorder (ADHD) are disorders of the central nervous system and share common risk factors. Our goal was to examine the association in a nationwide cohort study with prospective follow-up and adjustment for selected confounders. We hypothesized that epilepsy and febrile seizures were associated with subsequent ADHD.

METHODS:

A population-based cohort of all children born in Denmark from 1990 through 2007 was followed up until 2012. Incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) for ADHD were estimated by using Cox regression analysis, comparing children with epilepsy and febrile seizure with those without these disorders, adjusted for socioeconomic and perinatal risk factors, as well as family history of neurologic and psychiatric disorders.

RESULTS:

A total of 906 379 individuals were followed up for 22 years (∼10 million person-years of observation); 21 079 individuals developed ADHD. Children with epilepsy had a fully adjusted IRR of ADHD of 2.72 (95% CI, 2.53–2.91) compared with children without epilepsy. Similarly, in children with febrile seizure, the fully adjusted IRR of ADHD was 1.28 (95% CI, 1.20–1.35). In individuals with both epilepsy and febrile seizure, the fully adjusted IRR of ADHD was 3.22 (95% CI, 2.72–3.83).

CONCLUSIONS:

Our findings indicate a strong association between epilepsy in childhood and, to a lesser extent, febrile seizure and subsequent development of ADHD, even after adjusting for socioeconomic and perinatal risk factors, and family history of epilepsy, febrile seizures, or psychiatric disorders.

(Elin Næs Bertelsen, et al. Pediatrics. 2016 Aug;138(2). pii: e20154654).

Congenital Hypothyroidism Diagnosis Often Delayed

Diagnosis of congenital primary hypothyroidism (CPH) is delayed in an alarming percentage of newborns, leaving them inadequately treated and therefore potentially exposed to unnecessary neurocognitive losses, according to a new study of a large birth cohort in Utah.

"Utah has a very [well-run] infrastructure, and my concern is that if we are missing the diagnosis in this many babies in Utah, I think we have a significant problem nationwide, and it just hasn't been looked at," first author Joel Ehrenkranz, MD, director of diabetes and endocrinology in the department of medicine, Intermountain Healthcare, Salt Lake City, Utah, said when presenting the findings here at the American Thyroid Association (ATA) 2016 Annual Meeting.

His data show that almost half of the infants they identified as having CPH had delayed diagnosis and a similar number had potentially inadequate treatment in the first few weeks of life.

Alex Stagnaro-Green, MD, regional dean of the University of Illinois College of Medicine at Rockford, who comoderated the session at the ATA meeting, commented that Dr Ehrenkranz's findings were "disquieting."

"The whole idea for having the screening is to make sure the newborn will develop normally, especially in terms of their neurocognitive abilities," he told Medscape Medical News.

"So to hear that there are issues where the screening is identifying children later than should be expected and where the treatment may also not have been to the extent recommended is worrisome.

"Our goal as physicians is to treat patients to make sure they have the ability to live up to their potential, so this is clearly something that needs to be pursued so we can make sure that this screening is effective," he concluded.

CPH Is an "Endocrine Emergency"

Under the guidelines of the American Academy of Pediatrics (AAP), congenital primary hypothyroidism — defined as a serum thyroid-stimulating hormone (TSH) level of 20 mIU/L or higher — should be diagnosed no later than the 14th day of life, and by 6 weeks, children should be biochemically euthyroid, with a serum TSH level below 5 mIU/L.

To evaluate compliance with these guidelines, Dr Ehrenkranz and his colleagues analyzed data on serum TSH assays of 4394 children under the age of 2 who had been referred for such testing at Intermountain Healthcare in Utah between 2006 and 2015.

Among the infants in the study, 98 (2%) were identified as having serum TSH samples that were above 20 mIU/L, including 82 (84%) that represented the initial TSH samples taken.

Nearly half of the 82 (39; 48%) had delayed diagnoses, with initial TSH samples that had not been taken in the first 14 days of life.

In terms of treatment follow-up, 12 of the 82 (15%) infants were not retested and 28 (34%) achieved goals of TSH levels of 5 mIU/L or lower within 28 days of the initial test; however, 42 (51%) showed one or more subsequent TSH values higher than 5 mIU/L 1 month or more after the initial TSH, indicative of inadequate treatment.

The consequences of delayed or inadequately treated CPH are potentially significant, Dr Ehrenkranz said.

"CPH is an endocrine emergency, because if untreated, a newborn baby can have irreversible losses of up to one-half an IQ point a day," he said.

The data also showed that 16 infants with TSH levels below 20 mIU/L on initial screening subsequently went on to develop elevated levels after 1 month of age, between the ages of 92 and 690 days.

Dr Ehrenkranz said those findings were perplexing.

"I don't know what this represents, but I think this is a very interesting cohort of patients with congenital hypothyroidism, which I refer to as 'late onset,' " he observed. "It is notable that of the 16 patients, three had multiple TSH tests that were greater than 20 mIU/L."

"A Bigger Problem Than We Thought"

Dr Ehrenkranz said he was prompted to look into the issue after observing that anecdotal reports of CPH are common.

"If you talk to pediatricians and hospitalists, they will tell you that it is not at all uncommon to see an infant 6 months or 9 months of age with CPH, so that piqued my interest."

"In the course of looking at data for the US Food and Drug Administration [FDA] to establish normal thyroid levels in newborns, we observed that a lot of the newborns had elevated levels of TSH, so we realized this is a bigger problem than we thought."

He added that some hospitals have published results indicating that they missed diagnoses as much as 10% of the time, "and that's probably an underestimate."

With screening and treatment, severe CPH, previously known as cretinism and associated with severe mental retardation, has been eradicated in the developed world; however, newborns can still suffer effects from delayed diagnosis or treatment, Dr Ehrenkranz told Medscape Medical News.

"In the first 3 months of life, when most of the neurogenesis is going on, it's very important that children have the appropriate amount of thyroid hormone," he said.

"I think people just assume the process works perfectly because we don't see true cretinism anymore, but you do see children who may not have been able to reach their cognitive potential."

A separate study underscores the potential cognitive risks to infants who are not properly screened [Lancet Diabetes Endocrinol. 2016; 4:756–765], with its results, from an Australian cohort, showing poor educational and developmental outcomes among infants with neonatal TSH concentrations in the highest percentiles.

Dr Ehrenkranz is the inventor of a TSH point-of-care immunoassay and of smartphone/tablet point-of-care diagnostics. He notes that the study was subject to independent review of all data. Dr Stagnaro-Green had no relevant financial relationships. (From Medscape Medical News © 2016 WebMD, LLC )

Efficacy and Tolerability of Zolmitriptan Nasal Spray for the Treatment of Acute Migraine

Results of a Randomized, Double-blind, Multi-center, Parallel-group Study (TEENZ)

Objective.

The primary objective of the TEENZ Study (NCT01211145) was to assess the efficacy of zolmitriptan nasal spray in the acute treatment of adolescent migraine patients (ages 12 to 17 years), as measured by the primary outcome variable of pain-free status at 2 hours post-treatment.

Methods.

This randomized, double-blind, placebo-controlled, four-arm parallel group study compared zolmitriptan nasal spray with placebo in the treatment of a single episode of adolescent migraine. Patients completed a 30-day run-in period to treat a single migraine attack with single-blind placebo nasal spray. Eligible patients, who had not responded to placebo, were randomized to one of three zolmitriptan nasal spray doses (5, 2.5, or 0.5 mg) or placebo in a ratio of 5:3:3:5 according to a computer-generated randomization scheme. Patients completed diaries for 24 hours after treatment, recording headache pain scores, adverse events (AEs), and medications taken.

Results.

In an interim futility analysis, zolmitriptan nasal spray doses of 0.5 and 2.5 mg were declared futile relative to placebo and further randomization to these treatment arms was discontinued. Of 1653 patients enrolled into the study, 855 patients failed to meet study eligibility criteria and were considered screen failures. The most common reason for screen failure was response to placebo challenge (325 patients [38.0%]). Of the 798 patients who were randomized to treatment, 721 (90.4%) completed the study period. Of these, 657 (82.3%) treated a migraine within the study period and contributed data for analysis. Zolmitriptan nasal spray 5 mg was significantly more effective than placebo in achieving pain-free status at 2 hours after treatment (P < .001), with 30% of patients achieving pain-free status at 2 hours vs 17% of placebo-treated patients (OR 2.18; 95% CI 1.40, 3.39). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving pain-free status at 3 and 4 hours post-treatment (45 vs 24%, and 56 vs 39%; both P < .001). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving headache response at 2, 3, and 4 hours after treatment (51 vs 39%, 61 vs 48%, and 69 vs 57%, respectively; all P ≤ .011). Zolmitriptan nasal spray was well-tolerated at all doses. Dysgeusia was the most frequently reported AE, with greater frequencies reported in active treatment groups versus placebo. No serious AEs or AEs leading to discontinuation were reported. Most AEs were mild or moderate in severity, and consistent with the known profile of zolmitriptan in adult and adolescent populations.

Conclusion.

Zolmitriptan nasal spray was well-tolerated in the acute treatment of adolescent (ages 12 to 17 years) migraine. Zolmitriptan 5 mg nasal spray demonstrated superior efficacy compared with placebo for the primary efficacy endpoint of pain-free status 2 hours after treatment and the efficacy of the 5 mg dose was supported by the majority of secondary efficacy endpoints.

(Source: Headache. 2016;56(7):1107-1119).

FDA Warns Against Homeopathic Teething Tablets, Gels

Homeopathic teething tablets and gels, used by some parents to relieve teething pain and symptoms, may pose risks to infants and children, the FDA says.

The agency issued a warning late last month on the tablets and gels, which are sold in stores and online.

The FDA said it is investigating reports of side effects in children, including seizures in some, and is testing product samples. The agency previously issued a safety alert on the products in 2010, according to the statement.

However, one manufacturer of teething tablets, Hyland's, says it is "confident" its product is safe.

"We are fully cooperating with FDA's inquiry and we're providing them with all the data we have," Hyland's says in a statement posted on its website. "We also hope to learn from FDA what facts, if any, the agency has based its action on."

Homeopathic medicines are regulated as drugs by the FDA, but the agency notes in its warning that the products are not evaluated or approved by the FDA for safety or how well they work.

"The agency is also not aware of any proven health benefit of the products," the FDA says.

The warning advises parents to stop using the tablets and gels and dispose of them. They should "seek medical care immediately if their child experiences seizures, difficulty breathing, lethargy, excessive sleepiness, muscle weakness, skin flushing, constipation, difficulty urinating, or agitation after using homeopathic teething tables or gels."

The FDA did not offer details on what might be causing the side effects.

Side effects or reactions can be reported to the FDA online.

Hyland's says its homeopathic medicines "are made in facilities that follow current good manufacturing practices and are inspected by the FDA in the same way as other OTC drugs are. You may use them with confidence."

- Ashley Hayes, In MedScape Pediatrics, October 07, 2016

Gluten-Free Diet Does Not Repair Intestinal Damage in Some Children With Celiac Disease

Despite following a gluten-free diet for a year, nearly 20% of children with celiac disease continue to show signs of intestinal damage on repeat biopsies, according to a new study.

The findings point to the need for revisiting the criteria for monitoring mucosal recovery and managing pediatric celiac disease, Maureen M. Leonard, MD, clinical director at the Center for Celiac Research & Treatment at Massachusetts General Hospital for Children in Boston, and colleagues write in a report published online November 3 in the Journal of Pediatric Gastroenterology and Nutrition.

In recent years, IgA tissue transglutaminase antibody (tTG) serologic testing has replaced routine follow-up biopsies to monitor intestinal healing in children with celiac disease who have been placed on a gluten-free diet. Although current guidelines endorse and recommend serology as a marker of dietary adherence and mucosal recovery, the evidence supporting their use for that purpose is lacking, the authors write.

In light of the growing body evidence suggesting that adults with celiac disease have persistent enteropathy despite being symptom-free and having normal IgA tTG levels, the current study was designed to evaluate the rate of mucosal recovery in children with celiac disease on a gluten-free diet and to assess whether a correlation exists between tTG levels and mucosal damage.

The researchers reviewed the medical records of children and adolescents with celiac disease who received treatment at one of two medical centers between January 2012 and March 2015 or between January 2008 and December 2013. Patients were included in the study if they had a diagnosis of celiac disease confirmed by the presence of Marsh 3 lesions on diagnostic endoscopy and if they underwent a repeat endoscopy with duodenal biopsy at least 12 months after initiating a gluten-free diet.

Of 103 children included, 92 (89%) were IgA tTG positive at diagnosis. Eleven patients had a negative tTG test result at diagnosis, including 2 who were asymptomatic but at high genetic risk at diagnosis.

Despite excellent adherence to a gluten-free diet for most (91%) patients, 43% experienced persistent symptoms, 27% had new gastrointestinal symptoms, and 34% had persistently elevated serology at the time of repeat endoscopy and biopsy. Only 33% of the patients were asymptomatic at the time of repeat endoscopy.

The reasons for the repeat biopsy in the absence of celiac symptoms varied but included follow-up for another disease, persistently elevated serology, and "to assess for mucosal recovery and confirm the diagnosis of celiac disease in the setting of seronegative [celiac disease]."

Overall, 19% of patients showed persistent enteropathy consistent with a Marsh 3 lesion at the repeat endoscopy.

The authors note that the endoscopy results could not be predicted by the presence of symptoms or by IgA tTG. Of the patients with evidence of persistent enteropathy, 45% were asymptomatic at the time of repeat endoscopy.

"In practice, IgA tTG was a poor predictor of Marsh 3 histology at repeat biopsy as sensitivity was 43%, specificity was 68%, the positive predictive value (PPV) was 25%, and the negative predictive value (NPV) was 83%," the authors explained. They note that the poor predictability was not influenced by symptom status or the duration of the gluten-free diet.

Furthermore, IgA tTG was not an accurate measure of mucosal recovery in this population. The NPV was highest (87%) in patients following a gluten-free diet for more than 2 years, but the PPV was only 36% "Additionally, the NPV of tTG was not improved when correlated with the presence or absence of symptoms at the repeat endoscopy," the authors write.

The findings demonstrate that neither the presence of symptoms nor a positive tTG result was a reliable measure of mucosal recovery in the study population. For example, tTG was elevated in 43% of patients with persistent enteropathy and in 32% of those with mucosal healing. In contrast, 84% of patients with mucosal recovery on repeat biopsy were symptomatic at the time of the repeat endoscopy, as were 55% with persistent enteropathy.

The findings "raise concerns" about using serologic tests as markers in pediatric celiac disease patients, the authors write. "Despite the clinical practice and endorsement of using serological tests as markers of dietary adherence and mucosal recovery in pediatric patients with [celiac disease] on a [gluten-free diet], these serology tests have not been validated for this purpose."

Although current practice guidelines — which were drafted more than 25 years ago and don't reflect the transformation in clinical presentation of the disease over the past decades — do not recommend repeat endoscopy to assess mucosal recovery, it is currently the only objective way to confirm that enteropathy has resolved.

"These findings suggest the need not only for a baseline endoscopy to confirm the diagnosis of celiac disease but also consideration of a repeat biopsy to evaluate for remission," the authors write.

The long-term consequences of suboptimal mucosal healing in children with celiac disease are unclear. "However, malabsorption and ongoing inflammation in children may have negative repercussions on physical and cognitive development"…[P]ersistent enteropathy in adults has been associated with an increased risk of lymphoma, low bone density, and fracture," they note.

Additional studies should be pursued to improve understanding of the intestinal response to the gluten-free diet in children and adolescents, the authors stress. "Furthermore, identifying minimally invasive accurate surrogate endpoints for patients is of utmost importance to identify patients who may benefit from potential for new therapeutic agents that may serve as adjuvant medications to the [gluten free diet]."

Study coauthor Dr Alessio Fasano disclosed financial relationships with Alba Therapeutics, Mead Johnson Nutrition, Inova Diagnostics, Regeneron, and Pfizer. No other authors have disclosed any relevant financial relationships. (Citation: J Pediatr Gastroenterol Nutrition. Published online November 3, 2016).

Infection, Not Antibiotics, in Infancy Tied to Later Obesity

Veronica Hackethal, MD

November 03, 2016

Untreated infections during infancy, not antibiotics, may increase the risk of childhood obesity, according to results from a large Kaiser Permanente study published online November 1 in Lancet Diabetes & Endocrinology.

"Although our results do not necessarily rule out that antibiotics, if used in the absence of infection, could still increase the risk of obesity, early-life efforts to prevent childhood obesity should focus on reducing infections in infancy," write De-Kun Li, MD, reproductive and perinatal epidemiologist at the Kaiser Permanente Division of Research in Oakland, California, and colleagues.

"The use of antibiotics should always be judicious, but treatment of common infections with antibiotics in infancy is unlikely to be a main contributor to childhood obesity," they add.

The new results run counter to findings from past studies, which have linked antibiotic use during infancy to childhood obesity. However, both infection and antibiotics have the potential to alter gut microbial composition, which in turn may have an impact on the immune system and the regulation of metabolism.

Past studies, however, could not separate antibiotic use from underlying infections, making it impossible to weed out whether the increased obesity risk was due to antibiotics, infection, or both.

What's new about the Kaiser study is that researchers were able to evaluate these two factors separately.

"Our study is one of the largest analyses of the interplay among infections, antibiotic use, and childhood obesity and adds important evidence to a small but growing body of research on how the microbiome, or gut bacteria, may be affecting children's development," Dr Li said in a press release.

In the study, researchers analyzed data on 260,556 individuals born at Kaiser Permanente Northern California facilities between January 1997 and March 2013. Using electronic medical records, they obtained information on antibiotic use, infections during the first 12 months, body mass index (BMI), and obesity in children starting from birth to 18 years of age.

Researchers also did a separate analysis in 547 same-sex twins who had different exposures to antibiotics and infection.

After researchers controlled for maternal age, race/ethnicity, prepregnancy BMI, preterm delivery, low birth weight, maternal antibiotic use, and infection during pregnancy, analyses suggest that children who had an infection that went untreated without antibiotics during the first year of life had 25% higher risk of childhood obesity than those who did not have an infection (odds ratio [OR], 1.25; 95% CI, 1.20–1.29).

Results also suggest a dose-response relationship: children with more infections had a significantly increased risk of childhood obesity (P for trend < .0001).

On the other hand, children who received antibiotics during the first year of life did not have increased risk of childhood obesity, compared with those with untreated infections (OR, 1.01; 95% CI, 0.98–1.04).

The use of broad- and narrow-spectrum antibiotics also showed no significant association with childhood obesity.

The analysis of twin pairs showed similar results, the authors note.

"This study adds an important aspect in the field of childhood-obesity research," Dr Antti Saari, MD, PhD, of Kuopio University Hospital, Finland, commented in an email to Medscape Medical News.

Although the results are "interesting" and "convincing," they are limited by the study's design, he added. As a retrospective register study, the results can reveal only associations, not whether antibiotics or infections have a direct effect on childhood obesity.

"There might be some unknown factors that are actually related to both increased risk for infections and obesity," he pointed out.

Although the study could not differentiate between various types of infections, (such as viral vs bacterial or local vs systemic), gastrointestinal infection, in particular, may "potently affect the microbiome," Herbert Tilg, MD, of the Medical University Innsbruck, Austria, pointed out in an email to Medscape Medical News.

"Still, we have to accept that the microbiota at best might control 10% of body weight, but of course over the years this could still be sufficient to lead to obesity," he added.

One caveat: children in developing countries have a much higher rate of childhood infections than those in Westernized countries.

"Of course children in developing countries consume much less food, so the effect might only take place if food consumption is in excess, as in Western societies," he concluded.

Other researchers, however, are more skeptical of the findings. Writing in an accompanying editorial, Christopher B Forrest, MD, professor of pediatrics and health care management at the University of Pennsylvania and Children's Hospital of Philadelphia, and colleagues note that a link between growth and antibiotic use has been known in animals for decades, and a growing body of evidences suggests the link exists in humans as well.

Given the consistency of those data, and no obvious mechanistic link between infection and subsequent obesity, Dr Forrest and colleagues suggest selection bias or other confounding could be at play in the new study.

"Future studies should attempt to replicate Li and colleagues' findings and assess a longer period of antibiotic exposure, with special emphasis on repeated use of antibiotics," they write. "Establishing the reproducibility of these findings is essential before the claim can be accepted that infections, rather than antibiotics, affect children's growth."

The study was funded by Kaiser Permanente Center for Effectiveness & Safety Research. The authors and editorialists report no relevant financial relationships, nor do Drs Saari and Tilg.

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Lancet Diabetes Endocrinol. Published online November 1, 2016. Abstract, Editorial

Kawasaki Disease: Add Corticosteroids to Initial IVIG

Diana Swift

October 21, 2016

Pediatric patients with Kawasaki disease (KD), especially those resistant to intravenous immunoglobulin (IVIG), appear to benefit from early adjunctive corticosteroids, according to a small meta-analysis published online October 17 in JAMA Pediatrics.

"Corticosteroids combined with IVIG as an initial therapy showed a more protective effect compared with conventional IVIG therapy, and the efficacy was more pronounced in high-risk patients at the initiation of intervention, indicating that an early and aggressive initial anti-inflammation therapy for high-risk patients may be beneficial to improve coronary outcomes," the researchers write.

The findings point to the role of prompt adjunctive treatment in preventing potential coronary artery abnormalities (CAA) such as aneurysm and ectasia, researchers Shaojie Chen, MD, MM, PhD, a cardiologist at Shanghai General Hospital in China, and colleagues write.

Adding corticosteroids to IVIG, either as initial or rescue therapy, was associated with an overall relative risk reduction of 58% in the rate of CAA compared with IVIG alone (odds ratio [OR], 0.424; 95% confidence interval [CI], 0.270 - 0.665; P < .001).

The effect was more pronounced in patients deemed at high risk for IVIG resistance at baseline, with a relative risk reduction of 76% vs IVIG alone (OR, 0.240; 95% CI, 0.123 - 0.467, P < .001).

"Corticosteroid therapy strategy was also correlated with a more rapid resolution of fever, and the merit of corticosteroids was conferred without an increased risk of adverse events as relative to IVIG therapy," the researchers write.

KD, an acute febrile vasculitis of unknown etiology, is estimated to affect as many as 3500 US children annually. As a common cause of acquired heart disease in children, KD has serious public health implications, the authors note.

Their analysis involved 16 moderately heterogeneous studies, conducted mainly by Japanese researchers from 1999 to 2013 and including a total of 2746 children ranging in age from 2.2 to 5.4 years. More than half the patients were male. There were 1885 participants in the IVIG-only group and 861 in the adjunctive corticosteroid group. Meta-regression based on known patient variables found that the overall efficacy of corticosteroids was negatively correlated with longer duration of illness before therapy (P < .001).

In subgroup analysis, initial adjunctive therapy was also more effective than IVIG alone for CAA prevention (OR, 0.320; 95% CI, 0.183 - 0.560; P < .001), which was a benefit not observed in a subgroup of studies that administered corticosteroids as rescue therapy.

The authors note that 30% to 50% of patients in the meta-analysis developed transient coronary artery dilatation in the acute stage, and about a quarter subsequently developed serious abnormalities such as aneurysm and ectasia. Untreated CAAs carry a risk for thrombus, stenosis, myocardial infarction, and sudden death years after the acute illness, they write.

"Should all patients with KD receive corticosteroids as a part of initial treatment, or only a selected group of patients with high risk of poor prognosis?" the authors ask, referring to the superior benefit seen in patients deemed high risk for IVIG resistance. If the latter, "further questions one might raise are how best to early identify patients who are at high risk for IVIG resistance and what the strong risk factors are for the development of CAA," the researchers write.

Current risk-scoring systems for IVIG resistance need to be improved, they write, adding, "A more efficient diagnosis and treatment system is urgently needed by both clinicians and patients."

In an accompanying editorial, Robert Sundel, MD, a pediatric rheumatologist at Boston Children's Hospital in Massachusetts, outlines the changing attitudes over time to corticosteroids in KD, with sentiment fluctuating "between the extremes, from indispensable to proscribed, even as the roles of [IVIG] and aspirin have been defined."

Dr Sundel notes that steroids were long considered contraindicated in KD, a view based largely on a small 1979 observational study that reported a higher incidence of coronary artery aneurysm in patients receiving corticosteroids vs no treatment.

Recent studies, however, "are finally lending some clarity to when steroids can be beneficial in KD," he writes. Among these, "the meta-analysis of Chen et al does an excellent job of bringing together the most important KD clinical trials involving corticosteroids and of highlighting the actionable findings."

In Dr Sundel's view, although the pooled data argue strongly for the initial use of adjuvant corticosteroids in high-risk children, he cautioned that the study excluded the bulk of published reports on the grounds of low quality. Hence, "the data are not adequate to answer questions about other situations in which steroids may be effective," he said. "Analyzing the same deficient information, no matter how carefully or creatively, will not answer the numerous questions that remain."

Addressing timing of administration and initial vs rescue corticosteroid therapy, Dr Sundel took issue with the authors' view that corticosteroids are probably most beneficial when started at KD diagnosis, rather than at IVIG failure. "This conclusion is based on six studies involving 383 patients, only 167 of whom were treated with steroids, and using widely disparate therapeutic protocols," he writes. "Is this really sufficient experimental evidence to obviate late treatment with steroids when no clear alternatives are available?"

He doubts whether the findings warrant precluding steroid salvage therapy when initial therapy fails. "This is where the small number of evaluable studies (16 in all) and the heterogeneity between treatment groups impose intractable limitations on the ability of a meta-analysis to extend our knowledge," Dr Sundel writes. As in other inflammatory diseases, early steroids are better than late, he concedes, but "this does not preclude the possibility that salvage therapy with steroids might have some benefit."

He cites the need for research to identify the characteristics of IVIG-resistant children of various ethnic groups who are likely to respond to initial adjunctive therapy. Clinical trials or comparative effectiveness studies are needed to determine optimal dose, formulation, and a circumstance-appropriate regimen.

"Chen et al move us forward, but although they confirm 1 important indication for steroids in KD, they do not define the full extent or limitations of their role," Dr Sundel writes.

The authors and the editorial commentator have disclosed no relevant financial relationships.

JAMA Pediatr. Published online October 17, 2016. Article full text, Editorial full text

New Guideline for the Treatment of Prolonged Seizures in Children, Adults

The American Epilepsy Society (AES) has released a new guideline to help physicians, hospitals, and health systems treat patients with status epilepticus effectively.

The guideline, published in the January/February issue of Epilepsy Currents, focuses on convulsive status epilepticus in particular because it is the most common type of status epilepticus and is associated with substantial mortality.

“This is a valuable new guideline for both children and adults that could change the approach many clinicians take in treating these seizure emergencies,” said guideline author Tracy Glauser, MD, Cincinnati Children’s Hospital Medical Center’s Comprehensive Epilepsy Center, Cincinnati, Ohio. “The goal of therapy is the rapid termination of the seizure activity to reduce neurological injuries and deaths.”

Despite recognition of the need to address status epilepticus as a critical care emergency, current treatment approaches vary dramatically. Some therapies focus on reducing, rather than ending, the seizures and use inefficient therapies such as sedatives and paralytics or insufficient doses of anticonvulsants.

The guideline, which reviewed all available adult and paediatric evidence, provides a treatment algorithm that comprises 3 phases of treatment and 1 phase where there is not clear evidence to guide therapy:

• Stabilisation phase (0-5 minutes of seizure activity), includes standard initial first aid for seizures and initial assessments and monitoring.
• Initial therapy phase (5-20 minutes of seizure activity) when it is clear the seizure requires medical intervention, a benzodiazepine (specifically intramuscular midazolam, IV lorazepam, or IV diazepam) is recommended as the initial therapy of choice, given its demonstrated efficacy, safety, and tolerability.
• Second therapy phase (20-40 minutes of seizure activity) when response (or lack of response) to the initial therapy should be apparent. Reasonable options include fosphenytoin, valproic acid and levetiracetam. There is no clear evidence that any one of these options is better than the others. Because of adverse events, IV phenobarbital is a reasonable second therapy alternative if none of the other 3 recommended therapies are available.
• Third therapy phase (≥40 minutes of seizure activity). There is no clear evidence to guide therapy in this phase. The guideline found strong evidence that initial second therapy is often less effective than initial therapy, and the third therapy is substantially less effective than initial therapy. Thus, if second therapy fails to stop the seizures, treatment considerations should include repeating second-line therapy or anaesthetic doses of thiopental, midazolam, pentobarbital, or propofol (all with continuous EEG monitoring).

The guideline also found evidence that depending on the causes or severity of the seizure, clinicians may go through the phases faster or even skip the second phase and move rapidly to the third phase, especially in sick patients or patients in the intensive care unit.

“In treating status epilepticus there is an overriding urgency to stop seizures before the 30-minute mark when seizure-associated neurologic injury can occur,” said guideline co-author Shlomo Shinnar, MD, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York. “This guideline supports an aggressive approach to treating status epilepticus and seeks to bring some structure to what can often be a chaotic and dire medical situation.”

The guideline was endorsed by the Epilepsy Foundation, Child Neurology Society, the Association of Child Neurology Nurses, the American College of Emergency Physicians, and the American Association of Neuroscience Nurses.

SOURCE: American Epilepsy Society. Available from: http://dgnews.docguide.com/new-guideline-treatment-prolonged-seizures-children-adults?overlay=2&nl_ref=newsletter&pk_campaign=newsletter

Physiotherapy Relieves Constipation in Children

Diana Phillips

September 26, 2016

The use of physiotherapy to retrain the pelvic floor musculature reduces functional constipation in children above and beyond standard medical treatment, according to results from a multicenter randomized controlled trial.

"This study found that children receiving [pelvic physiotherapy] had significant improvements in symptom reduction, reduced [polyethylene glycol (PEG)] use and improved quality of life compared to children receiving [standard medical care] only. These results suggest that [pelvic physiotherapy] might be a valuable treatment option for [functional constipation] in children, aged 5-16 years, and an early intervention may prevent chronicity," write Marieke L. van Engelenburg-van Lonkhuyzen, from the Department of Epidemiology, School for Public Health and Primary Care, Maastricht University Medical Centre, the Netherlands, and colleagues.

The researchers report their results in an article published online September 17 in Gastroenterology.

Although previous studies have demonstrated the effectiveness of pelvic physiology as an adjunct to routine constipation management in adults, evidence of its effectiveness in constipated children "has been scarce," the authors write.

For the current study, the researchers randomly assigned 53 children, aged 5 to 16 years, either to pediatrician-provided standard medical care (n=26), which consisted of education, toilet training, and laxatives, or to standard care plus specific physiotherapeutic interventions (n=27) administered by a pelvic physiotherapist. All participants had been diagnosed with functional constipation according to Rome III criteria at hospitals in the Netherlands between December 2009 and May 2014.

Children and parents in the standard care group received education and dietary advice. Further, "[t]o normalize toilet behavior, the children were told not to withhold stools when they felt the urge to defecate, and they were instructed to sit on the toilet in a relaxed manner for at least five minutes after the three main meals, carefully squeezing, when necessary, using a toilet seat or footstool," the authors report. The pediatricians also discussed the standardized bladder and bowel diary and prescribed a PEG laxative when needed.

The intervention group received standard care and specific physiotherapeutic interventions, as per the Dutch Pelvic Physiotherapy Protocol, including:

balance and stability training for effective toileting posture;
instruction on proper abdominal breathing, effective straining, and relaxation of muscles;
sensory processing techniques to achieve awareness of a filled bowel and the urge to defecate; and
specific abdominal and pelvic floor muscle training to improve awareness, relaxation, and proper muscle functions.

During the 6-month study period, patients had as many as six treatment sessions, although fewer sessions were allowed at pediatrician discretion, "provided that all predefined treatment goals were achieved," the authors explain.

The clinical characteristics of children in both treatment groups were similar at baseline: 41.5% children defecated fewer than three times per week, 56.6% had fecal incontinence, 60.4% had hard stools or painful defecations, 50.9% had large amounts of stools, 45.3% were postponing defecation, and 26.4% had palpable fecaloma.

Of the 53 children, all but one was prescribed PEG, and 47 had been constipated for 6 months or longer.

After 6 months of treatment, 24 (92.3%) of the children in the pelvic physiotherapy group and 17 (63.0%) of the standard care–only group were no longer functionally constipated, as per Rome III criteria (adjusted odds ratio [OR], 11.7; 95% confidence interval [CI], 1.8 - 78.3; P = .011), which was the primary end point of the trial. The absence of all six Rome III criteria was similarly reported in 24 of the physiotherapy patients, whereas only 12 (44.4%) of the standard care group achieved that outcome (adjusted OR, 21.0; 95% CI, 3.6 - 122.3; P = .001), the authors report.

In addition, 65.4% of children in the combined therapy group were no longer using the laxative medication compared with 37.0% of the standard care group (adjusted OR, 6.5; 95% CI, 1.6 - 26.4; P = .009).

Although all the children had a reduction in Rome II criteria from baseline to postintervention, reductions in two of the criteria — hard stools and/or painful bowel movements, and a large amount of stools that may obstruct the toilet — were significantly greater in the physiotherapy group.

With respect to patient-reported secondary outcomes, improvements were greater in the physiotherapy group across all measures except the strengths and difficulties questionnaire, which showed no between-group differences.

No adverse events were reported by either children or parents.

Previous randomized controlled trials comparing standard care alone with standard care with the addition of specific biofeedback training delivered by medical physicians did not demonstrate a benefit to the adjunct therapy. However, the latter approach differs from the comprehensive musculoskeletal approach of pelvic physiotherapy delivered by physiotherapists, according to the authors.

In addition to the motor relearning elements that appear to contribute to the effectiveness of pelvic physiotherapy, "[p]ossibly, the children's growing awareness of their bodily sensations, while learning to recognize and resolve abnormal functions (as muscular over activity), or to prevent fecal incontinence, [plays] a role," the authors write.

The authors acknowledge that the study findings may not be readily generalizable to clinical practice, given the study's small size and the fact that the Dutch pelvic physiotherapy quality requirements do not apply worldwide. In addition, the study design did not allow the researchers to identify the most effective elements of the physiotherapy treatment because it was offered as a package.

The authors have disclosed no relevant financial relationships.

Gastroenterology. Published online September 17, 2016. Abstract

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Reuters Health Information

Propranolol Safe for Infantile Hemangioma, Systematic Review Confirms

By Megan Brooks

September 30, 2016

Oral propranolol is safe for the treatment of infantile hemangioma (IH), according to what is believed to be the largest systematic review on the topic.

"Since 2008, we have many reports concerning the efficacy of propranolol, however a systematic review on safety was lacking," said Dr. Christine Léauté-Labrèze of Pellegrin Children's Hospital in Bordeaux, France.

"In pediatrics we are very concerned by the safety of drugs, especially the drugs used in vulnerable populations such as infants less than one year of age," she told Reuters Health by email.

The new results show that propranolol "can be used safely to treat complicated infantile haemangiomas, provided appropriate pre-treatment assessments to exclude patients with cardiologic contraindications; and appropriate monitoring to minimize serious side-effects, mainly bronchospasm and hypoglycemia, during treatment," Dr. Léauté-Labrèze said.

The findings are based on more than 5,800 patients with IH treated with propranolol. The safety profile in this sample confirms that oral propranolol for IH has "a similar profile to that observed in cardiologic indications in the pediatric population," the researchers report in Pediatrics, online September 29.

No unexpected side effects emerged.

The most common propranolol-related events (sleep disorders, diarrhea, peripheral coldness, and agitation) are transient, manageable and not serious, according to the researchers.

"Serious risks in certain cases can be avoided with appropriate screening and exclusion and in others can be minimized and managed with appropriate monitoring, caregiver education, and discontinuation of propranolol when necessary," they write.

Current recommendations for pretreatment screening call for obtaining a cardiovascular and pulmonary history and doing a clinical examination to identify patients at risk of heart block, arrhythmia, or pulmonary abnormalities or reactive airway diseases, they point out. Routine echocardiography and ECG are not considered necessary unless there are abnormal clinical findings.

With appropriate screening and monitoring, "oral propranolol treatment at a dose of up to 3 mg/kg per day, taken 2 or 3 times daily, for an average of 6 months (and up to 36 months) appears to be well tolerated," the team concludes.

They add, "The results of this review provide extensive data on the safety of oral propranolol in pediatric patients with IH and will assist health care providers in understanding the pretreatment assessments required and within-treatment monitoring necessary when treating patients with IH. This review also contributes to the overall safety profile of oral propranolol in pediatric patients, which has previously been less well defined than for adults."

The study was funded by Pierre Fabre Dermatologie, which markets the pediatric formulation of oral propranolol (Hemangiol/Hemangeol). Several authors disclosed financial relationships with the company.

SOURCE: http://bit.ly/2dnaYhJ

Pediatrics 2016.

Physiotherapy Relieves Constipation in Children

Diana Phillips

September 26, 2016

The researchers report their results in an article published online September 17 in Gastroenterology.

The intervention group received standard care and specific physiotherapeutic interventions, as per the Dutch Pelvic Physiotherapy Protocol, including:

balance and stability training for effective toileting posture;
instruction on proper abdominal breathing, effective straining, and relaxation of muscles;
sensory processing techniques to achieve awareness of a filled bowel and the urge to defecate; and
specific abdominal and pelvic floor muscle training to improve awareness, relaxation, and proper muscle functions.

Of the 53 children, all but one was prescribed PEG, and 47 had been constipated for 6 months or longer.

No adverse events were reported by either children or parents.

The authors have disclosed no relevant financial relationships.

Gastroenterology. Published online September 17, 2016. Abstract

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Reuters Health Information

Propranolol Safe for Infantile Hemangioma, Systematic Review Confirms

By Megan Brooks

September 30, 2016

Oral propranolol is safe for the treatment of infantile hemangioma (IH), according to what is believed to be the largest systematic review on the topic.

"In pediatrics we are very concerned by the safety of drugs, especially the drugs used in vulnerable populations such as infants less than one year of age," she told Reuters Health by email.

No unexpected side effects emerged.

The most common propranolol-related events (sleep disorders, diarrhea, peripheral coldness, and agitation) are transient, manageable and not serious, according to the researchers.

SOURCE: http://bit.ly/2dnaYhJ

Pediatrics 2016.

The Safety of LABAs in Teen/Adult Asthma

Is Combination Asthma Controller Therapy Safe?

The US Food and Drug Administration (FDA) has published concerns about the safety of long-acting beta-agonists (LABAs), after trials of salmeterol as an asthma controller raised concern about increased asthma events and even increased asthma-related deaths in salmeterol-treated patients.^[1] The FDA requested that each of the LABA manufacturers conduct trials to evaluate whether the medications were safe when used in combination with inhaled glucocorticoids—something that had not been part of the two large previous trials.^[2]

Study: Fluticasone/Salmeterol vs Fluticasone Alone

Stempel and colleagues^[3] conducted an industry-sponsored multicenter, randomized, double-blind trial in Australia to evaluate whether serious asthma-related events were more common among patients with moderate to severe asthma treated for at least 26 weeks with a combination inhaled product that contains salmeterol and inhaled steroid (fluticasone) vs inhaled steroid alone. The patients (aged ≥ 12 years) were enrolled from 2011 to 2015 in 33 different countries.

The primary safety outcome of interest was what the investigators termed a "serious asthma-related event," which included endotracheal intubation, hospitalization, or death. The main efficacy endpoint was the first serious asthma exacerbation, defined as the use of systemic steroids for at least 3 days, an asthma-related hospitalization, or an asthma-related emergency department visit that also resulted in systemic steroid use.

More than 11,000 patients were randomized and included in this report, with an adherence rate of approximately 95%. In the group who received steroid plus LABA, 34 patients experienced a serious asthma-related event compared with 33 patients in the steroid-only group (hazard ratio, 1.03; 95% confidence interval, 0.64-1.66]). The preset upper bound of the CI for determining noninferiority was 2.0; therefore, the investigators concluded that the steroid-LABA preparation was not inferior to steroid alone.

No asthma-related deaths occurred during the study. An equal number of patients in each group experienced asthma-related hospitalization. Withdrawal as a result of adverse events occurred in 3% of the patients in each group, and serious adverse events occurred equally in the groups, at 2%. Severe asthma exacerbations occurred slightly less often in the steroid/LABA group than in the steroid-only group (8% vs 10%), a difference that was statistically significant.

The investigators concluded that patients using LABAs in a fixed-dose combination with an inhaled steroid do not appear to be at greater risk for serious asthma-related events compared with those using inhaled steroids alone. Moreover, the patients on combination therapy experienced fewer severe asthma exacerbations.

Viewpoint: The Data Reassure

These are very important data that should provide some reassurance to both patients and providers. The previous randomized controlled trials that contributed to the concern that use of LABAs would control asthma symptoms overall but increase the risk for asthma-related death were trials of LABA monotherapy. These new data show that patients receiving steroid/LABA controller medication seem to do very well and are not at increased risk for adverse outcomes. Furthermore, combination-treated patients did better on at least one outcome measure.

The high adherence to therapy among the patients and the fact that this was a clinical trial mean that "real world" efficacy may be lower, and clinicians will still want to focus on the fact that combination products containing LABAs are very good drugs when used properly. However, making sure that patients and parents understand the proper use of these medications is paramount.

References

1. US Food and Drug Administration. FDA announces new safety controls for long-acting beta agonists, medications used to treat asthma. February 18, 2010.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm200931.htm Accessed July 26, 2016.

2. US Food and Drug Administration. FDA Drug Safety Communication: FDA requires post-market safety trials for long-acting beta-agonists (LABAs). April 15, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm251512.htm Accessed July 26, 2016.

3. Stempel DA, Raphiou IH, Kral KM, et al; AUSTRI Investigators. Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med. 2016;374:1822-1830.

Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine

Scott W. Powers, et al. N Engl J Med. 2016 Oct 27. [Epub ahead of print]

October 27, 2016DOI: 10.1056/NEJMoa1610384

BACKGROUND

Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established.

Full Text of Background...

METHODS

We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment.

Full Text of Methods...

RESULTS

A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt.

Full Text of Results...

CONCLUSIONS

There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281).

Use of H1-Antihistamines in Children Is Not Based on Good Evidence

Only limited evidence supports use of commonly used first-generation antihistamines, which may have adverse side effects.

First-generation antihistamines are marketed for a number of allergic and nonallergic indications in children. Investigators from Belgium reviewed the literature from four major publication databases to assess evidence supporting use of three of these antihistamines — alimemazine, cyproheptadine, and dimethindene maleate — and to identify potential adverse drug reactions.

For alimemazine, licensed in some European countries for various indications in children, randomized, controlled trials examining efficacy for sleep disorders showed conflicting results. No randomized, placebo-controlled trials examined the use of alimemazine for pruritus. One randomized, controlled trial in children found benefit for reducing post-fundoplication emesis. For cyproheptadine, used to treat allergic rhinitis, cold urticaria, pruritus, migraine, and appetite stimulation, only one small randomized, controlled trial was found, which did not show benefit over comparators. For dimethindene maleate, used for pruritus treatment, only one randomized, controlled trial was identified and showed a reduction in the severity of itching. Use of these three classes of antihistamines for all indications was associated with adverse drug reactions, sedation being the most common.

Comment

First-generation antihistamines are often used in children, and some formulations are available over the counter without a prescription; yet, as findings of this literature review show, their use is generally not supported by clinical trial data. The authors cite a suggestion by two pediatric allergists that first-generation antihistamines be limited to severe pruritus or as adjunctive therapy with epinephrine for prophylaxis of anaphylaxis. Clearly, if being used, parents should be made aware of the lack of evidence for efficacy as well as potential adverse side effects.

Citation: De Bruyne P et al. Are antihistamines effective in children? A review of the evidence. Arch Dis Child 2016 Jun 22; [e-pub]. (http://dx.doi.org/10.1136/archdischild-2015-310416)

Vitamin D may be 'useless'!

Those who pop vitamin D pills regularly, may be better off simply spending cash on fruit and vegetables as a recent study has suggested that the supplements give no protection against diseases.

Those who pop vitamin D pills regularly, may be better off simply spending cash on fruit and vegetables as a recent study has suggested that the supplements give no protection against diseases.

The vital nutrient that comes with the sun's rays is widely seen as an important element to good health. Many people place strong belief in its potential benefits in treating a number of medical conditions, such as depression or Multiple Sclerosis, and feel a need to supplement their vitamin D intake. But according to lead author Michael Allan, much of that belief isn't validated by science.

"Wouldn't it be great if there was a single thing that you or I could do to be healthy that was as simple as taking a vitamin, which seems benign, every day? There is an appeal to it. There is a simplicity to it. But for the average person, they don't need it." says Allan.

The study examined the evidence for 10 common beliefs about vitamin D. The beliefs range from the ability of vitamin D to reduce falls and fractures, improve depression and mental well-being, prevent rheumatoid arthritis, treat Multiple Sclerosis, and lessen incidences of cancer and mortality. The review finds little evidence though that supplementation with this vitamin has much of an effect at all.

According to Allan, only a few of the 10 beliefs the team looked into seemed to exhibit some scientific proof. Strongest among them, vitamin D was shown to have a minor impact in reducing the number of falls among the elderly and reducing fractures.

Allan says other possible benefits of vitamin D covered in the review were not borne out or are still unproven. He is quick to point out that much of the existing research around vitamin D was poorly executed and consists of poor quality evidence. While he welcomes ongoing research in the area, he says moving forward it needs to consistently be of a higher caliber to be of clinical relevance. The study is published in the Journal of General Internal Medicine.

Source: Allan GM et al. J Gen Intern Med. 2016 Jul;31(7):780-91.

Worse Outcomes for Extubations Done at Night

Extubations done at night in the ICU are associated with worse outcomes than those done during the day, according to a new study.

"While we anticipated there might be an association of overnight extubation with harm (specifically, mortality) in some subgroups of patients, I was amazed by how commonly we found this to be the case," said Dr. Hayley B. Gershengorn from Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

"We saw an association of overnight extubation with mortality in both patients with longer and shorter durations of mechanical ventilation as well as in many of the smaller patient subgroups we studied. And we did not identify one subgroup within our cohort in which overnight extubation was associated with improved outcomes," she told Reuters Health by email.

Little is known about the frequency, safety, and effectiveness of overnight extubations.

Dr. Gershengorn's team used data from the Project IMPACT database to investigate the frequency of overnight extubations and to assess the association between overnight extubations and clinical outcomes.

One-fifth of the more 97,000 adults with mechanical ventilation admitted to one of 165 U.S. ICUs underwent overnight extubation, with the percentage decreasing from 23.3% in 2000 to 2001 to 18.8% in 2009, the reserachers report in JAMA Internal Medicine, online September 6.

Overnight extubations were more common among patients who had been mechanically ventilated for less than 12 hours (42.1%) than among those who had spent more time on mechanical ventilation (11.9%).

In a propensity-matched analysis of patients who had been on mechanical ventilation for less than 12 hours, those who underwent overnight extubation had higher ICU mortality (5.6% vs. 4.6%, p=0.03) and hospital mortality (8.3% vs. 7.0%, p=0.01).

ICU length of stay was slightly shorter for patients undergoing overnight extubation, whereas hospital length of stay and rates of reintubation were similar between the two groups.

In patients on mechanical ventilation for at least 12 hours, overnight extubation was also tied to higher ICU mortality (11.2% vs. 6.1%, p<0.001) and hospital mortality (16.0% vs. 11.1%, p<0.001), whereas length of ICU and hospital stays did not differ.

Rates of reintubation were also significantly higher for patients undergoing overnight extubation, though only among those who had been mechanically ventilated for more than 12 hours.

The researchers found no patient subgroup in which overnight extubation was associated with reduced rates of reintubation or mortality.

"Our study is retrospective in design and, as such, does not demonstrate that overnight extubation causes harm to patients in the ICU," Dr. Gershengorn said. "However, I believe that a fair general recommendation would be that providers think explicitly about each case in which overnight extubation is being considered."

"While there are likely some circumstances in which extubating patients overnight is without risk (and may even confer benefit), at present we do not know for certain which patients these are," she said. "I sometimes work overnight in a busy medical ICU, and I do continue to extubate some patients overnight, but I am much more thoughtful now about the decision to do so than I was prior to conducting this analysis."

Dr. Peter K. Moore from the University of California, San Francisco, and San Francisco VA Medical Center, who co-authored an invited commentary, said the findings suggest "that the observed mortality difference was not solely driven by postextubation respiratory failure, as we would expect the rate of reintubation to be elevated to a similar degree (regardless of ventilation duration). Thus there is no clear mechanism for the observed increase in mortality."

"In my experience, overnight extubation is generally approached with caution," he said. "It is often discussed in depth among multiple team members including the treating physicians, nurse, and respiratory therapist. While the findings in this study are by no means definitive proof of harm from extubation overnight, I think they do support being cautious and deliberate when making the decision to extubate a patient at night."

SOURCE: JAMA Intern Med 2016; http://bit.ly/2bTbsMT

Childhood Epilepsy, Febrile Seizures, and Subsequent Risk of ADHD

September 2015

October 2014

September 2013

June 2011

March 2009

December 2003

Not too little, not too much: problems of selecting oral antibiotic dose for children

IAP Advisory Committee on Vaccines & Immunization Practices

Mangla Hospital & Research Center