Key Papers from the Most Recent Literature Relevant to Anesthesiologists
The primary outcome is positive—is that good enough? N Engl J Med 2016; 375:971–9.
This paper extends the debate surrounding use of metrics, such as P values or journal impact factors, when publishing high-quality clinical trials. In a recent issue of the New England Journal of Medicine, the authors focused on the natural tendency to simplify the findings of a clinical trial into a binary conclusion: “Was there a positive outcome or not?” By examining examples of clinical trials with positive primary outcomes, they reasoned that a more nuanced interpretation through examination of the totality of the evidence, including secondary endpoints, safety issues, and the size and quality of the trial, might be more realistic. They propose a strategy for presenting trials in which the primary outcome is positive. This paper represents a means that will allow physicians to better interpret the medical information contained in clinical trials and translate new findings to clinical practice.
Take home message: Clinical trials with a positive primary outcome should include a more nuanced examination of the entirety of the evidence to allow clinicians to better translate new findings into clinical practice.
Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med 2016; 375:1231–41.
The addition of azithromycin to standard regimens for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. In this randomized controlled trial, 2,013 women who had a singleton pregnancy with a gestation of 24 weeks or more and who were undergoing cesarean delivery during labor or after membrane rupture were randomly allocated to receive 500 mg of intravenous azithromycin or placebo in addition to standard antibiotic prophylaxis. The primary outcome was a composite of endometritis, wound infection, or other infection occurring within 6 weeks. The primary outcome occurred in 62 women (6.1%) who received azithromycin and in 119 (12.0%) who received placebo (relative risk, 0.51; 95% CI, 0.38 to 0.68; P < 0.001). There were also significant differences between the azithromycin group and the placebo group in rates of endometritis (3.8% vs. 6.1%, P = 0.02), wound infection (2.4% vs. 6.6%, P < 0.001), and serious maternal adverse events (1.5% vs. 2.9%, P = 0.03).
Take home message: Among women undergoing nonelective cesarean delivery and receiving standard antibiotic prophylaxis, addition of azithromycin was more effective than placebo in reducing the risk of postoperative infection.
Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med 2016; 375:1033–43.
The optimal target for the systolic blood pressure when treating acute hypertensive response in patients with intracerebral hemorrhage remains uncertain. In this randomized controlled trial, 1,000 patients with a mean (SD) systolic blood pressure of 201 (27) mmHg at baseline and intracerebral hemorrhage (volume < 60 cm3, Glasgow Coma Scale [GCS] score > 4) were allocated to a systolic blood-pressure target of 110 to 139 mmHg (intensive treatment) or 140 to 179 mmHg (standard treatment). Intravenous nicardipine was administered to lower blood pressure within 4.5 h after symptom onset. The primary outcome was death or disability at 3 months after randomization. The primary outcome of death or disability adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage was observed in 38.7% of the participants (186 of 481) in the intensive treatment group and in 37.7% (181 of 480) in the standard treatment group (relative risk, 1.04; 95% CI, 0.85 to 1.27). The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive treatment group than in the standard treatment group (9.0% vs. 4.0%, P = 0.002).
Take home message: In patients with intracerebral hemorrhage, a strategy aimed at achieving a target systolic blood pressure of 110 to 139 mmHg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mmHg.
Does tranexamic acid improve outcomes in traumatic brain injury? BMJ 2016; 354:i4814.
The effectiveness and safety of tranexamic acid in reducing blood loss in trauma patients is supported by randomized controlled trials, yet its role after traumatic brain injury remains uncertain. Tranexamic acid could reduce intracranial bleeding but might increase the risk of cerebral thrombosis and ischemia. A systematic review published in 2015 identified two relevant completed randomized trials; neither was large enough to answer the question definitively. Here, the authors report their critical analysis on this issue after having updated a broad and relevant literature search. They identified two randomized trials, a meta-analysis, which indicated that statistically significant reduction in intracranial hemorrhage was observed with tranexamic acid, but because the confidence intervals were wide, the quality of this evidence was low. The authors are confident that three ongoing trials will address the uncertainty of whether tranexamic acid improves outcomes in patients with traumatic brain injury. For now, they recommend that patients with isolated traumatic brain injury should not receive tranexamic acid outside the context of a randomized trial until uncertainty is resolved.
Take home message: Patients with isolated traumatic brain injury should not receive tranexamic acid outside the context of a randomized trial until uncertainty on the risk/benefit balance is resolved.
Association between therapeutic hypothermia and survival after in-hospital cardiac arrest. JAMA 2016; 316:1375–82.
Therapeutic hypothermia is used for patients following both out-of-hospital and in-hospital cardiac arrest. However, comparative effectiveness data are limited. In this cohort study, 26,183 patients successfully resuscitated from an in-hospital cardiac arrest between March 1, 2002, and December 31, 2014, and either treated or not treated with hypothermia at 355 U.S. hospitals were included. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic recovery. Comparisons were performed using a matched propensity score analysis. Therapeutic hypothermia was associated with lower in-hospital survival (27.4% vs. 29.2%; adjusted relative risk = 0.88 [95% CI, 0.80 to 0.97]; risk difference = −3.6% [95%CI, −6.3% to −0.9%]; P = .01), and this association was similar for nonshockable cardiac arrest rhythms. Therapeutic hypothermia was also associated with lower rates of favorable neurologic recovery for the overall cohort. These observational findings warrant a randomized clinical trial to assess efficacy of therapeutic hypothermia for in-hospital cardiac arrest.
Take home message: In patients with in-hospital cardiac arrest, use of therapeutic hypothermia compared with usual care was associated with lower survival to hospital discharge and poorer neurologic outcome.
Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med 2016; 375:1119–30. Editorial: Intracranial pressure rescued by decompressive surgery after traumatic brain injury. N Engl J Med 2016; 375:1183–4.
The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear. In this trial, 408 patients, ages 10 to 65 yr, with traumatic brain injury and refractory elevated intracranial pressure (>25 mmHg), were randomly assigned to undergo either decompressive craniectomy or ongoing medical care. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOS-E) (an 8-point scale, ranging from death to “upper good recovery” [no injury-related problems]) at 6 months. It was found that the GOS-E distribution differed between the two groups (P < 0.001). Surgical patients had fewer hours than medical patients with intracranial pressure above 25 mmHg after randomization (median, 5.0 vs. 17.0 h; P < 0.001) but had a higher rate of adverse events (16.3% vs. 9.2%, P = 0.03). Decompressive craniectomy resulted in lower mortality but higher rates of vegetative state, lower severe disability, and upper severe disability than medical care. The rates of moderate disability and good recovery were similar in the two groups.
Take home message: The findings of this trial argue for more investigation into the nuances of selecting patients for decompressive craniectomy after traumatic brain injury and emphasize the importance of a case-by-case discussion of therapeutic options.
Structure-based discovery of opioid analgesics with reduced side effects. Nature 2016; 537:185–90.
A long-standing goal of analgesic pharmacology has been to discover opioids that offer high levels of analgesia with reduced side effects. Recent advancements with so-called “biased opioid agonists” move us closer to that goal. In principal these drugs activate G-protein mediated pathways linked to analgesia while minimally activating β-arrestin pathways linked to common side effects. In this paper, the authors describe a structure-based search strategy followed by synthetic chemistry that resulted in the testing of a compound named PZM21. This molecule was then demonstrated to provide high levels of analgesia in animal experiments while causing little respiratory depression or constipation. In addition, it appeared to have little abuse potential. These properties were similar to those of TRV130, a drug now in advanced stages of clinical testing. Results like these suggest that we may soon have opioid-like drugs with much-improved side effect and safety profiles.
Take home message: A structure-based search strategy followed by synthetic chemistry identified opioid-like drugs with much-improved side effect and safety profiles.
Breaking the silence: Time to talk about race and racism. Acad Med 2016 Sep 20. [Epub ahead of print].
Teaching and learning is classically characterized as encompassing three domains: cognitive, psychomotor, and affective. As educators, anesthesiologists teach content and skills with great facility. Do we teach the components of the affective domain, i.e., attitudes, feelings, and the emotions, as well? The stark answer is no! The authors place this deficiency before the eyes of medical educators in a timely commentary in Academic Medicine. Racism has plagued the world from time immemorial and it continues to pervade all of society, including medical care. The authors highlight racism as not only a problem, but also an opportunity for enhanced education. They point out that, as is so often the case, medical teachers are ill-equipped and devoid of the skills necessary to confront racism and teach physicians how to recognize and deal with its presence to establish better relationships with patients. The opening quote of this commentary speaks to medical educators about what they must add to the curriculum for faculty development and physician education.
Take home message: As educators, anesthesiologists teach content and skills with great facility, but components of the affective domain, including race and racism, should also be essential educational objectives.
