Some of the most common practices in Emergency Medicine are only weakly tested or defined – including steroids for acute respiratory illness. What is the true minimum effective dose? How many days – 3, 5, 7, or 14? Burst or taper? Much of our practice is based on habit and mimicry, along with the general evidence that, despite ourselves, we don’t seem to be doing much harm.
This is the REDUCE trial, a multi-center, randomized, double-blind, non-inferiority comparison between a 5-day and a 14-day course of 40mg oral prednisone for acute COPD exacerbation. And…it found no difference in the primary outcome measure. So, then, all’s well.
Except, their outcome measure is utterly bizarre – re-exacerbation within six months? I cannot fathom how a 1-2 week period of steroids could have any causative association with outcomes more than a handful of half-lives after cessation of treatment. Perhaps they theorize the short-term steroid exposure is insufficient to avoid long-term damage secondary to the acute inflammation?
There are also some potentially confounding differences in baseline characteristics. There were 9% more smokers and 5% more home oxygen in the short-term treatment group – which could favor conventional treatment – but then 4% fewer were on daily steroids during the treatment period and 8% fewer received concurrent antibiotics in the conventional treatment group – which could favor the short-term treatment group. Some of these differences would have more effect on short-term outcomes, while others would affect long-term outcomes. I don’t know if there are true clues in the Kaplan-Meier curves they present – because the sample size is small enough these variations might just be occurring due to chance – but it appears there’s a possible hazard towards early re-exacerbation in the 5-day group, followed by regression towards equivalence by six months.
However, these issues aside, their conclusion is probably valid. Their predefined threshold for non-inferiority was 15% – and they easily cleared that bar. All the confounders are probably not of significant magnitude to affect the overall result at that threshold – even for shorter, more relevant follow-up time periods. Additionally, this is otherwise consistent with the other evidence that short-courses of steroids are absolutely acceptable in this context.
“Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease”
www.ncbi.nlm.nih.gov/pubmed/23695200
Month: June 2013
4-Factor PCC is Here! Yay?
The self-described “EM Nerd” Rory Spiegel from Newark Beth Israel writes in to point out a fascinating discovery – previously undiscovered clinical trial results for Kcentra, the newly available 4-Factor Prothrombin Complex Concentrate, embedded in the product labeling.
4-factor PCCs are well-known from their use in Europe – capable of rapid reversal of factor-dependent coagulopathy at the expense of increased thrombotic complications. Within the package labeling, however, two new Phase III trials are described – open-label, randomized, non-inferiority comparisons. The trials, for what they’re worth, show no significant outcome difference compared with FFP – but, yet again, no clinically relevant threshold for non-inferiority is established to drive sample size calculations. I’d like to comment more, but they only provide detailed adverse event information on one of the two trials. Perhaps we’ll see these published and peer-reviewed imminently.
It should also be noted the extensive exclusion criteria used to enroll patients in these studies – a far longer list than the few contraindications listed on the package label. These criteria may be noted on the ClinicalTrials.gov site.
Lovely to see we’ve now another costly reinvention of the wheel that will almost certainly be overutilized at the behest of Bering’s marketing army.
“Efficacy and Safety Study of BERIPLEX® P/N Compared With Plasma in Patients With Acute Major Bleeding Caused by Anticoagulant Therapy”
http://clinicaltrials.gov/ct2/show/NCT00708435
“The Sign of Four…”
http://emnerd.tumblr.com/post/50947148065/the-sign-of-four
“CSL Behring 1.14.1.3 Draft Labeling Text”
http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM350239.pdf
Bacterial Meningitis in Complex Febrile Seizure
The AAP has guidelines for simple febrile seizure – “There, there, the frightening demonic possession your child just experienced is nothing to worry about.” Complex febrile seizures, however, are offered far less conclusive guidance.
This little retrospective review from UC San Diego evaluates 193 patients presenting with complex febrile seizure. Lumbar puncture was performed in 136, and 1 patient ultimately received a diagnosis of bacterial meningitis. The authors suggest, cognizant of the limitations, that complex febrile seizures need not routinely undergo LP.
This is entirely reasonable and consistent with the prior literature. The largest retrospective review, from Boston Children’s, identified 3 cases with bacterial meningitis out of 526 children. A systematic review and meta-analysis identified 41 cases of bacterial meningitis out of 1996 children. There are additional cases of viral meningitis and encephalitis in these cohorts as well – of uncertain clinical significance – but the general implication is that otherwise well-appearing children ought not need LP absent other signs of CNS infection.
It would, of course, be fabulous if a consensus guidelines would further reinforce this evidence.
“Necessity of Lumbar Puncture in Patients Presenting with New Onset Complex Febrile Seizures”
www.ncbi.nlm.nih.gov/pubmed/23687537
“Yield of lumbar puncture among children who present with their first complex febrile seizure.”
www.ncbi.nlm.nih.gov/pubmed/20566610
“Risk of bacterial meningitis in young children with a first seizure in the context of fever: a systematic review and meta-analysis.”
www.ncbi.nlm.nih.gov/pubmed/23383133