Letters

Author Affiliations: Division of Pulmonary and Critical Care, University of Washington, Seattle (Curtis, Engelberg); Department of Medicine, University of Washington, Seattle (Back). Corresponding Author: J. Randall Curtis, MD, MPH, University of Washington, 325 Ninth Ave, Seattle, WA 98104 ([email protected]).

We believe that new studies that are large enough to avoid any imbalance in important confounders should be conducted to evaluate the effect of hypothermia induced by techniques that do not rely on fluid administration.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Curtis and Engelberg reported receiving grants from the National Institutes of Health. No other disclosures were reported.

Romain Pirracchio, MD, PhD Didier Journois, MD, PhD

1. Weeks JC, Catalano PJ, Cronin A, et al. Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med. 2012;367(17):1616-1625.

Author Affiliations: Department of Anesthesiology and Critical Care Medicine, Hôpital Européen Georges Pompidou, Paris, France.

2. Bays AM, Engelberg RA, Back AL, et al. Interprofessional communication skills training for serious illness: evaluation of a small-group, simulated patient intervention. J Palliat Med. 2014;17(2):159-166.

Corresponding Author: Romain Pirracchio, MD, PhD, Hôpital Européen Georges Pompidou, 20 Rue Leblanc, Paris 75015, France (romainpirracchio @yahoo.fr).

3. Chi J, Verghese A. Improving communication with patients: learning by doing. JAMA. 2013;310(21):2257-2258.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Hypothermia for Bacterial Meningitis To the Editor Although we acknowledge the importance and the quality of the study by Dr Mourvillier and colleagues,1 we have some reservations about the authors’ conclusions. They stated that moderate hypothermia does not improve the outcome in patients with severe bacterial meningitis and may even be harmful. For several reasons, we think that this conclusion is not fully supported by the data. First, the treatment evaluated was not moderate hypothermia but early fluid loading using cold saline. The effect of hypothermia alone would have been tested only if both groups had received comparable amounts of fluid. The induction of hypothermia required a median volume of cold saline of 2401 mL; the amount of fluid received in the control group was not reported. Fluid management, especially for chloride solutions, is important in this clinical context because fluid overload may be deleterious at the early stage of a cerebral insult.2 In addition, massive chloride loading may increase the risk of kidney injury.3 Hence, hypothermia using cold fluid administration could have harmed the treatment group for reasons unrelated to any potential detrimental effect of hypothermia. Second, the study had noncomparable groups, especially with respect to the prevalence of septic shock (37% in the treatment group and 20% in the control group). This imbalance could have contributed to the results in the treatment group. The cause of death was systemic in 44% of the patients in the treatment group vs 38% in the control group. In a multivariable analysis, no association was found between hypothermia and mortality (hazard ratio [HR], 1.76; 95% CI, 0.89-3.45), but septic shock was associated with greater mortality (HR, 2.54; 95% CI, 1.31-4.94). Third, the difference in the proportion of patients reaching a Glasgow Outcome Scale (GOS) score of 5 may be explained by the higher mortality rate in the treatment group. However, among survivors, a larger proportion of patients reached a GOS score of 4 in the treatment group (20% in the treatment group vs 12% in the control group) and fewer patients had a GOS score of 3 (14% vs 31%, respectively). Hence, we conjecture that hypothermia might be associated with better neurological outcomes.

1. Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: a randomized clinical trial. JAMA. 2013;310(20):2174-2183. 2. Ichai C, Payen J-F, Orban J-C, et al. Half-molar sodium lactate infusion to prevent intracranial hypertensive episodes in severe traumatic brain injured patients: a randomized controlled trial. Intensive Care Med. 2013;39(8):14131422. 3. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566-1572.

To the Editor In the randomized clinical trial by Dr Mourvillier and colleagues,1 the authors found that induced hypothermia in adults with severe community-acquired bacterial meningitis did not improve the outcome and may even be harmful. Furthermore, the authors stated that such results could have important implications for future trials on hypothermia in such patients. The results of this trial are in contrast with experimental studies and recent observations in case series.2,3 Therefore, several important issues regarding the recruitment and methods of this trial should be discussed. First, recruitment at each of the participating centers was low (1 patient per center for 3 years). Although severe bacterial meningitis is a rare disease, we would have expected the number of recruited patients from the 49 centers to be much higher. Therefore, a possibility of selection bias is evident. Second, the baseline characteristics of patients revealed a high proportion with septic shock and who were deeply comatose at admission (median Glasgow Coma Scale score of 7 [interquartile range, 4-8] in the hypothermia group). Furthermore, the presence of septic shock at admission was determined to be a significant predictor for adverse outcome (HR, 2.54; 95% CI, 1.31-4.94). Data regarding the duration of the disease, antibiotic timing according to the disease onset, associated serious comorbidities, and results of blood cultures were not shown. Third, therapeutic hypothermia was arbitrarily conducted for 48 hours without any measurements to show whether hypothermia itself was beneficial or harmful. We agree with the authors that early stopping of the clinical trial precluded firm conclusions about the effects of therapeutic hypothermia in bacterial meningitis. Further trials in-

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vestigating hypothermia treatment in bacterial meningitis should include more precise inclusion criteria such as objective intracranial pressure status. Marko Kutleša, MD, PhD Dragan Lepur, MD, PhD Bruno Baršić, MD, PhD Author Affiliations: Department of Intensive Care Medicine and Neuroinfectology, University Hospital for Infectious Diseases “Dr Fran Mihaljević,” Zagreb, Croatia. Corresponding Author: Marko Kutleša, MD, PhD, University Hospital for Infectious Diseases “Dr Fran Mihaljević,” Mirogojska 8, Zagreb 10000, Croatia ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: a randomized clinical trial. JAMA. 2013;310(20):2174-2183. 2. Irazuzta JE, Pretzlaff R, Rowin M, Milam K, Zemlan FP, Zingarelli B. Hypothermia as an adjunctive treatment for severe bacterial meningitis. Brain Res. 2000;881(1):88-97. 3. Lepur D, Kutleša M, Baršić B. Induced hypothermia in adult community-acquired bacterial meningitis—more than just a possibility? J Infect. 2011;62(2):172-177.

In Reply Therapeutic hypothermia always includes an induction phase and a maintenance phase.1 In our study, induction was obtained by infusion of cold saline. This technique was proven to be safe in several types of cerebral injuries.2 Because all centers did not use the same hypothermia technique, we tried to obtain a uniform and quick induction phase in the hypothermia group. Moreover, there are no data in the literature supporting a restrictive fluid policy for bacterial meningitis.3 Although we do not have fluid data for the control group, we found no association between the amount of fluid and mortality (t test P = .34) in the hypothermia group. We agree with Drs Pirracchio and Journois that there was an imbalance between groups concerning septic shock. Nevertheless, futility analysis showed that there was a very low probability of demonstrating any beneficial effect of therapeutic hypothermia. We believe that the results of our study do not support that mild hypothermia is associated with better neurological outcome. We disagree that higher mortality may affect only the proportion of patients with a GOS score of 5. When we compared the proportion of patients with GOS scores of 4 and 5 with those with a GOS score of 3 in each group, we found no beneficial effect of therapeutic hypothermia (odds ratio, 1.90 [95% CI, 0.56-6.91], P = .38). A higher number of patients died because life support was withdrawn due to poor neurological outcome in the hypothermia group. Dr Kutleša and colleagues point out the low recruitment at each participating center. Enrolling the 49 centers took 14 months, so some centers were active during a shorter period than the total inclusion period. Among the 49 centers, only 34 actively enrolled patients, with a median of 1 patient per center. Bacterial meningitis is a rare disease4 and only the most severe patients met all of the inclusion criteria. We agree that 1358

the inclusion rate was low, but it was homogenous among all active centers, excluding selection bias. The duration of the disease is almost impossible to assess because timing of the infection is unknown. Nevertheless, once patients were referred to the hospital, we found no significant difference in time from door to first dose of antibiotics. Knaus chronic health status score and McCabe classification were also similar in the 2 groups. We acknowledge that the chosen duration (48 hours) of therapeutic hypothermia was arbitrary. This period corresponds to the maximum inflammatory response into the cerebrospinal fluid. Monitoring intracranial pressure could have helped to guide the hypothermia duration. Nevertheless, the use of this technique could have precluded external validation of the results because most hospitals do not measure intracranial pressure. Moreover, inserting a device to measure intracranial pressure could have delayed the onset of therapeutic hypothermia at a time when cerebral inflammation is maximal. Bruno Mourvillier, MD Michel Wolff, MD Author Affiliations: Réanimation Médicale et Infectieuse, Groupe Hospitalier Bichat-Claude Bernard, Paris, France. Corresponding Author: Bruno Mourvillier, MD, Réanimation Médicale et Infectieuse, Groupe Hospitalier Bichat-Claude Bernard, 46 Rue Henri Huchard, 75018 Paris, France ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Nielsen N, Wetterslev J, Cronberg T, et al; TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206. 2. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid. Crit Care Med. 2005;33(12):2744-2751. 3. Maconochie I, Baumer H, Stewart ME. Fluid therapy for acute bacterial meningitis. Cochrane Database Syst Rev. 2008;(1):CD004786. 4. Thigpen MC, Whitney CG, Messonnier NE, et al; Emerging Infections Programs Network. Bacterial meningitis in the United States, 1998-2007. N Engl J Med. 2011;364(21):2016-2025.

Basic Science Content in the USMLE Step 1 To the Editor When discussing changes to the United States Medical Licensing Examination (USMLE) Step 1, Dr Haist and colleagues1 concluded that “many medical students prepared for Step 1 with a ‘binge and purge’ mentality; because students failed to recognize the value of the basic sciences in medical practice, many memorized information for shortterm retention.” Haist et al1 used this position as a rationale for “planned changes to emphasize basic sciences throughout [the] USMLE.” The Viewpoint neglected to consider the alternative hypothesis that students take a binge and purge mentality not because they fail to recognize the value of basic science in medicine, but because they believe the focus of Step 1 is on clinically irrelevant minutiae that have little value in patient care. For instance, Step 1 commonly tests students on their ability to analyze various bacterial growth plates and media to de-

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Hypothermia for bacterial meningitis.

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