A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.
Despite a lack of clinical data supporting their superiority, 4-factor PCCs have been universally accepted as the intervention of choice for the reversal of Warfarin induced bleeding. While PCCs have demonstrated rapid normalization of INR values, they have yet to show any added value over FFP in true clinically relevant endpoints. In the largest RCT to date, 4-factor PCC corrected INR values far faster than FFP but with a mortality rate that was almost double that of the FFP group. In a recent small RCT published in American Journal of Emergency Medicine, Karaca et al attempted to demonstrate that 4-factor PCCs provide more than just surrogate benefits when treating Warfarin induced gastrointestinal hemorrhage.
In this small unblinded trial, 40 patients with clinically suspected upper GI bleeds were randomized to have their coagulopathy reversed by either FFP or Cofact, a 4-factor PCC. The outcomes examined by the authors were INR values at 2 and 6 hours, time-to-endoscopy, and percentage of patients with active hemorrhage at time of endoscopy (based on the Forrest Classification). Patients were required to have their INR level reach 2.1 before undergoing definitive endoscopic interventions. As is typical in FFP vs PCC trials, the dose of FFP used was bordering on a straw man dose at 10-15 cc/kg.
To what should be no one’s surprise, 4-factor PCC reduced INR levels significantly faster than FFP, and thus patients in the PCC group underwent endoscopy earlier than their FFP counterparts. Patients in the PCC group received their endoscopy on average at 8 hours after admission, while the FFP group underwent endoscopy closer to the 12 hour mark. Endoscopy revealed more patients with active hemorrhage (Forrest Classification 1a or 1b) in the FFP group (7 patients vs 0) and sclerotherapy was performed in 10 patients in the FFP group, with 1 in the PCC group. Furthermore 3 patients in the FFP group required further therapy due to rebleeding, while no events of rebleeding occurred in the PCC group.
These superiorities in surrogate and pseudo-surrogate endpoints did not translate into the patient oriented endpoint of mortality, which was equivalent (one patient in each group). As far as the dreaded complication of “thrombolic events” that has been associated with PCC use it is somewhat unclear. One patient in the PCC group experienced a fatal IVC thrombosis but authors claim this condition was a presenting malady rather than an adverse event due to the administration of PCC.
Once again PCC has found success upon examination of soft endpoints. In an unblinded trial with surrogate and subjective endpoints, it is unclear if the PCC group’s performance was due to the medication’s efficacy or simply random chance and a small cohort. Until superiority in concrete clinically relevant outcomes is demonstrated, we should be wary of the crown of supremacy PCCs currently flaunt.
“Use and effectiveness of PCC vs FFP in gastrointestinal hemorrhage due to warfarin usage in the emergency department”
www.ajemjournal.com/article/S0735-6757%2814%2900107-7/abstract
Month: March 2014
Dexamethasone. Think About It.
Many aspects of medicine are simply based on momentum and routine. One of those routines, in my anecdotal experience, is the use of 5-day courses of steroids for mild/moderate asthma exacerbations. However, why give multiple doses when one will suffice? Why not dexamethasone?
Unfortunately, this meta-analysis doesn’t really bring any new knowledge into play. These authors attempt to pool the results from all the pediatric randomized trials comparing dexamethasone vs. short-course prednisone for the outpatient management of asthma with exacerbation. No included individual trial showed a relapse rate with dexamethasone significantly worse than prednisone – and, unsurprisingly, the pooled results reflect that same finding. The only recorded adverse effect – vomiting in the ED or at home – was seen less frequently with dexamethasone, although the overall incidence in both arms was minimal.
But, there are only six trials, most of which are fewer than 100 patients. These trials are also a mix of oral and intramuscular, single and multiple dose, and dose ranges from 0.3 mg/kg to 1.7 mg/kg (“max 36 mg”!). There were also methodologic problems with blinding, allocation, and other outcomes issues with each included study.
Based on this low-quality evidence, it would be reasonable to say dexamethasone use is not adequately described in the literature. It would, likewise, be reasonable to go ahead and make use of dexamethasone in this setting, with the recognition of these limitations. Personally, I fall on the dexamethasone side of the argument – for children, as well as adults. When feasible, I use an approximately prednisone-equivalent oral dosing at 0.15 mg/kg up to a maximum dose of 12mg in both populations.
And I would love to see a high-quality trial to settle matter, once and for all.
“Dexamethasone for Acute Asthma Exacerbations in Children: A Meta-analysis”
http://www.ncbi.nlm.nih.gov/pubmed/24515516
Blood Pressure and ICH: The Beat Goes On….
A guest post by William Paolo (@paolomd1), the Program Director of Emergency Medicine at SUNY Upstate.
Spontaneous intracerebral hemorrhage (ICH) continues to carry a great deal of morbidity and mortality, with little hyperacute emergent patient interventions available to the treating physician. For these reasons multiple avenues to alter patient prognosis have been explored, from continuous ICP monitoring to decompressive craniectomies, with little demonstrable patient benefit. Elevations in blood pressure (BP) in all forms of measurement (SBP, DBP, MAP) have long been associated with worse outcomes in individuals with spontaneous ICH. At issue is the nature of the association between ICH and a rise in BP, as it is not entirely clear that the subsequent elevation is directly responsible for causative harm rather than correlated poor outcomes. As BP is a simple empirical data point, multiple studies have attempted to define the relationship between poor outcomes and BP to determine if acute BP lowering will result in net patient benefit. It should be noted that the theoretical benefit of BP lowering in the face of ICH is counterbalanced by the potential for harm if elevations of MAP are in fact adaptive to allow for adequate cerebral and penumbral perfusion in the face of rising ICP.
In June of 2013 the New England Journal of Medicine published the INTERACT2 study in which individuals with spontaneous ICH were randomized into intensive BP lowering versus current guidelines based lowering. The study assessed the proportion with poor outcomes (a composite of death and major disability) as its primary outcome, and a secondary outcome consisting of multiple measures of quality of life and death. INTERACT2 found no difference in the primary outcome and discovered no difference between the hematoma growth across cohorts. Only after conducting an ordinal analysis did the authors report a better functional primary outcome in the intensive BP lowering group, a result not fully supported by a principal analysis of the study’s raw findings.
Continuing this work, The Lancet Neurology has published a post-hoc analysis of the INTERACT2 database in which it is hypothesized that variability in BP is predictive of poor outcomes in addition to total BP elevation. The authors reanalyzed the INTERACT2 raw data looking for the association between variation in BP and patient outcomes. Given multiple statistical assumptions and parsing of the initial data, the study determines that there is indeed an association between BP variation and poor outcomes. The study concludes that the findings are in fact relevant to practice and should cause the provider not only to lower the BP acutely in ICH, but to aim for a smooth reduction in BP with little variability. Unfortunately it is difficult to endorse the study’s findings given its multiple limitations and assumptions. The entire INTERACT2 database was examined as a single cohort, lumping in together both treatment arms into a single evaluative group. The authors posit that this demonstrates the robustness of the association, however it may in fact prove the opposite. While it may be true that variability is predictive independent of treatment, it may also be true, given the grouped analysis, that treatment does not affect outcomes, and that BP across treatment groups predicts poor outcomes without the ability to positively intervene to change net patient results. Further, the study is a post-hoc analysis in which a hypothesis is generated prior to the generation of data allowing only the demonstration of association. No matter how robust the findings, clinical practice changes should not be recommended based on a study whose design can only generate new hypotheses from their discovered correlations to be confirmed with prospective evaluations. Unfortunately, the debate will continue regarding BP management in ICH, as this study does not alter clinical practice nor change the negative findings of the INTERACT2 trial.
“Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial.”
Splicing Up PECARN
The PECARN study is the largest of the prospective evaluations of children with minor head injury for clinically important traumatic brain injury. The derived prediction instruments, for children aged <2 years of age and for children aged 2 to 18 years, generate “very low risk” cohorts whose incidence of important injury is negligible. However, the overall incidence of cTBI was quite low in the entire study – meaning each positive predictor still only raises the risk of cTBI from negligible to tiny.
One of the predictors, vomiting, is an element in the decision instrument for children aged 2 to 18 years. The management recommendation for patients with vomiting, then, defaults to “do as is your wont” – and studies suggest most folks are going ahead with CT, rather than using the “observation” option.
This study goes back and looks specifically at the vomiting component – and tries to tease out whether “isolated” or “non-isolated” prior to enrollment provided additional information. Of the 5,392 enrolled patients with complete data, 815 had a single episode of vomiting – with 0.2% having cTBI. The remaining 4,577 with non-isolated vomiting had a 2.5% incidence of cTBI. The article goes further into the details of the data set, noting patients with vomiting who received CT were more likely to have cTBI – but also had other concomitant comorbid injury.
This is, unfortunately, not terribly profound – and of debatable utility. The joy – what there is – of PECARN is its use as a decision-instrument with which to simplify medical decsion-making. Mining the details of individual +LR and -LR provides more patient-specific information, but increases the complexity of knowledge translation – and ultimately decreases the contextual acceptability of the product. The cTBI is heterogeneously distributed throughout the PECARN set – but the existing rule cannot be improved upon until better tools emerge to offload the cognitive demand required for for precision medicine-type applications.
“Association of Traumatic Brain Injuries With Vomiting in Children With Blunt Head Trauma”
http://www.ncbi.nlm.nih.gov/pubmed/24559605
Still Muddling Through Massive Hemorrhage
The last few years have given way to a paradigm shift in the resuscitation of traumatic hemorrhage. Using observational data from military settings, resuscitation strategies utilizing reactive correction of coagulopathy have given way to strategies mimicking whole blood transfusion. Limited evidence suggests PRBC:FFP:Platelet ratios nearing 1:1:1 may be beneficial in resuscitation from traumatic hemorrhage.
This observational study of trauma patients followed lactate levels and measures of coagulopathy during the acute resuscitative phase from major trauma. 106 patients with median Injury Severity Score of 34 received a median of 8 units of PRBCs, 6 units of FFP, and a smattering of platelets and cryoprecipitate transfusions. Lactate levels, as compared by median and IQR, did not significantly normalize following the initial transfusion, requiring a full day of therapeutic intervention to improve. Likewise, measures of coagulopathy did not reflect improvement in the acute phase, tending to normalize only after a full day. It did not matter whether patients received a small, moderate, or large amount of resuscitation.
This study only comments on surrogate outcomes – serum lactate, markers of coagulopathy – and not patient-oriented outcomes, but it serves as a reminder the science is clearly not settled regarding the optimal, cost-effective fashion to resuscitate patients from traumatic hemorrhage. While many centers have fully adopted whole blood-style resuscitation strategies, it would be incorrect to conclude we have any sort of certainty in the matter.
“Hemostatic resuscitation is neither hemostatic nor resuscitative in trauma hemorrhage”
http://www.ncbi.nlm.nih.gov/pubmed/24553520
Kids with Tubes and Otitis Media Get Drops not Pills
A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.
Over the last decade, researchers have sought to determine the usefulness, or lack there of, for systemic antibiotics in a number of infectious etiologies previously thought to require antibiotics for resolution. This includes strep throat, sinusitis, bronchitis and, more recently, diverticulitis. Acute otitis media (AOM) has long been a target for such studies and recently, the guidelines have changed. The American Academy of Pediatrics now endorses a “wait and see” approach for many children with AOM while also recommending a more stringent definition of the disease.
Over the last decade, researchers have sought to determine the usefulness, or lack there of, for systemic antibiotics in a number of infectious etiologies previously thought to require antibiotics for resolution. This includes strep throat, sinusitis, bronchitis and, more recently, diverticulitis. Acute otitis media (AOM) has long been a target for such studies and recently, the guidelines have changed. The American Academy of Pediatrics now endorses a “wait and see” approach for many children with AOM while also recommending a more stringent definition of the disease.
What about for patients with tympanostomy tubes who present with signs of AOM? These patients typically present with otorrhea (pus from the tympanostomy tube). Is the presence of drainage adequate to treat or should these patients be placed on oral or topical antibiotics? Small trials have shown good efficacy of topical antibiotics but Pediatricians and Emergency Physicians continue to prescribe oral antibiotics in the face of inadequate evidence.
The researchers here attempt to answer this question. They performed a fairly large study of 230 children who were randomized to either observation, oral antibiotics or topical antibiotic-glucocortocoid drops in an open-label fashion. The primary endpoint was resolution of otorrhea at 2 weeks. The results are surprising. Resolution was seen in 95% in the group given drops, 56% in the oral antibiotic group and 45% in the observation group. These numbers yield a miniscule NNT = 3 for resolution of otorrhea with topical antibiotics-glucocortocoids vs. oral antibiotics.
A couple of notes are important. All of the patients had otorrhea for up to 7 days prior to entering the study and the presence of a fever excluded them from the study. Additionally, tubes couldn’t be recently placed (< 2 weeks) there couldn’t be recent antibiotic use (< 2 weeks) or otorrhea (< 4 weeks).
As evidence mounts to the harms of inappropriate and unnecessary systemic antibiotic use, it’s important to tailor therapy based on the available literature. Many patients with tympanostomy tubes that develop otorrhea will resolve with simple observation. However, treatment with topical antibiotic-glucocortocoid drops should be the first line treatment as they are superior to oral antibiotics with fewer side effects.
“A trial of treatment for acute otorrhea in children with tympanostomy tubes.”
Sources of Nonmedical Opiates
Making an even three consecutive posts on opiate abuse makes a week of it; this ought to be the last, unless further profound insights are hot-off-the-presses.
This study – actually a minor Research Letter in JAMA Internal Medicine – evaluates self-reported behavioral patterns in nonmedical drug use in the United States. This accompanies another study looking at the risk factors for unintentional opiate-related deaths, which, helpfully, adds a little context.
This survey extrapolates out to approximately 12 million nonmedical opiate users aged greater than 12 years in the United States. A slight majority of users were male, and most had annual incomes less than USD$50,000. Most interesting, however, is Table 2, which describes how the source of opiates varies with increasing frequency of use. Individuals who reported nonmedical use of opiates fewer than 30 days out of the year received their opiates predominantly for free from a friend or relative. As frequency of use increased, opiates were less frequently received from a friend for free – and more likely to be received from a physician or purchased from friends, family, or drug dealers. As the accompanying study notes, increasing prescription and increasing mean daily use of opiates were associated with increased risk of death – so it would appear the population at highest risk of death also has the greatest extent of physician contact for opiates.
But, just as important as it may be to evaluate an individual risk for opiate misuse when prescribing, it is also important to note the majority of nonmedical use was obtained via diversion activities. Every opiate prescribed enters an ecosystem of illicit exchange – presumably under-recognized by physicians, else I would expect far fewer prescriptions. Judicious – and sparing – use of opiates is far more likely to benefit society than harm.
“Sources of Prescription Opioid Pain Relievers by Frequency of Past-Year Nonmedical Use: United States, 2008-2011”
http://archinte.jamanetwork.com/article.aspx?articleid=1840031
Nonsensical Opiate Overuse in Adolescent Headache
The title says it all.
This is an observational cohort analysis of linked medical and pharmacy records for commercially insured patients across 14 health plans. Patients were identified by age 13-17 with, allegedly, new-onset atraumatic headache from claims database abstraction – limited, of course, by the nature of querying such a database. 8,373 patients were identified from their two year study period as meeting these criteria.
And 46% were prescribed opiates.
52% of those received more than one prescription for opiates, including 11% who received 5 or more prescriptions for opiates during the study period.
This study came about because the insurer contacted the American Academy of Pediatrics with a query regarding the appropriate frequency of use of opiates for headache. The answer ought to be a tiny fraction, as third-line or rescue therapy.
Considering all the problems this country has with prescription opiate abuse, it is maddening to see physicians inoculating such a vulnerable population with medication whose harms almost certainly outweigh the benefits.
“Opioid Use Among Adolescent Patients Treated for Headache”
http://www.jahonline.org/article/S1054-139X(13)00834-3/abstract