n e w e ng l a n d j o u r na l

have also shown that subgroup effects are often spurious and that specialized patient populations generally follow the same trend as that in the general population.4 In the era of shrinking research budgets, it is even more important to strategically focus research in areas that will have the greatest clinical effect. Another trial evaluating the duration of red-cell storage would not meet that target. Aaron A.R. Tobian, M.D., Ph.D. Paul M. Ness, M.D. Johns Hopkins University Baltimore, MD [email protected]​­jhmi​.­edu


m e dic i n e

Since publication of their editorial, the authors report no further potential conflict of interest. 1. Rapido F, Brittenham GM, Bandyopadhyay S, et al. Pro-

longed red cell storage before transfusion increases extravascular hemolysis. J Clin Invest 2017;​127:​375-82. 2. Goel R, Johnson DJ, Scott AV, et al. Red blood cells stored 35 days or more are associated with adverse outcomes in high-risk patients. Transfusion 2016;​56:​1690-8. 3. Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage. JAMA 2016;​316:​2025-35. 4. Sun X, Ioannidis JP, Agoritsas T, Alba AC, Guyatt G. How to use a subgroup analysis: users’ guide to the medical literature. JAMA 2014;​311:​405-11. DOI: 10.1056/NEJMc1700464

Hypothermia for Convulsive Status Epilepticus To the Editor: In the HYBERNATUS (Hypothermia for Brain Enhancement Recovery by Neuroprotective and Anticonvulsivant Action after Convulsive Status Epilepticus) trial, Legriel et al. (Dec. 22 issue)1 did not find a beneficial effect of induced hypothermia on functional outcomes at 90 days among patients with convulsive status epilepticus. These results should be revisited with regard to the three potential benefits of induced hypothermia: neuroprotection, seizure treatment,2 and lowering of intracranial pressure.3 The neuroprotective effect of hypothermia was not significant, but the trial showed a clear antiepileptic benefit, in that hypothermia lowered the rate of progression to electroencephalogram (EEG)–confirmed status epilepticus. Although 25% of the patients had refractory status epilepticus at randomization, the majority had probably stopped seizing at the time of induction of hypothermia. Thus, the primary outcome pools the results of postseizure neuroprotection with those of successful treatment of refractory status epilepticus. Lowering of intracranial pressure, the third potential benefit of hypothermia, may have biased the results for the 26% of patients who had potential mass lesions (hemorrhage, tumor, thrombosis, infection, or trauma). We think that the HYBERNATUS trial still has much to teach us, most notably through separate analyses for patients with or without ongoing seizures.


Nicolas Engrand, M.D. Stéphane Welschbillig, M.D. Vera Dinkelacker, M.D., Ph.D. Fondation Ophtalmologique Rothschild Paris, France [email protected]​­for​.­paris No potential conflict of interest relevant to this letter was reported. 1. Legriel S, Lemiale V, Schenck M, et al. Hypothermia for neu-

roprotection in convulsive status epilepticus. N Engl J Med 2016;​ 375:​2457-67. 2. Schmitt FC, Buchheim K, Meierkord H, Holtkamp M. Anticonvulsant properties of hypothermia in experimental status epilepticus. Neurobiol Dis 2006;​23:​689-96. 3. Vigué B, Ract C, Zlotine N, Leblanc PE, Samii K, Bissonnette B. Relationship between intracranial pressure, mild hypothermia and temperature-corrected PaCO2 in patients with traumatic brain injury. Intensive Care Med 2000;​26:​722-8. DOI: 10.1056/NEJMc1700535

To the Editor: We noted some clinically relevant issues in the report by Legriel et al. First, the participants were patients in the intensive care unit (ICU), and body-mass index (BMI) was not taken into consideration when patients were assigned to the treatment groups, nor was there a post hoc analysis of outcomes according to BMI. In studies involving other cohorts of patients in the ICU, in-hospital mortality rates have been found to be lower among patients with a high BMI.1 Second, in our clinical practice, patients undergoing hypothermic treatment have been prone to pneumonia, and pneumonia related to hypothermia has been prolonged and hard to

n engl j med 376;11  March 16, 2017

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treat. It may be useful for the investigators to take into account the severity of pneumonia among their patients. Furthermore, most of the participants (93%) were intubated, and this could be one reason for high rates of pneumonia. Haifeng Wang, M.D. Daming Wang, M.D. Beijing Hospital Beijing, China [email protected]​­263​.­net No potential conflict of interest relevant to this letter was reported. 1. Hutagalung R, Marques J, Kobylka K, et al. The obesity para-

dox in surgical intensive care unit patients. Intensive Care Med 2011;​37:​1793-9. DOI: 10.1056/NEJMc1700535

intracranial pressure. Because the underlying lesions that may have caused intracranial hypertension, to which Engrand et al. refer, were more frequent among patients receiving hypothermia, we cannot exclude the possibility that elevations in intracranial pressure may have altered the trial results.2 Wang and Wang emphasize the potential effect of BMI on mortality among critically ill patients. Although randomization was not stratified according to BMI (the weight in kilograms divided by the square of the height in meters), these data were collected prospectively, and the median values were 23.8 (interquartile range, 21.5 to 26.5) in the hypothermia group and 24.2 (interquartile range, 21.6 to 27.7) in the control group. There was no significant interaction with BMI in an analysis of subgroups (BMI

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