Hypothermia for the Treatment of Acute Respiratory Distress Syndrome? Cool It*

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Acute respiratory distress syndrome (ARDS) has been a defining illness for critical care over the last 50 years. The search for effective ARDS treatments has yielded lung-protective ventilation (which saves lives), conservative fluid management (which shortens the duration of ventilation), and neuromuscular blockade, prone positioning, and extracorporeal membrane oxygenation (for which additional research to confirm benefit is ongoing). Innumerable other therapies have fallen short, and ARDS mortality remains unacceptably high.
Hypothermia as a therapy for acute illness predates even ARDS. First proposed as treatment for cancer in the 1930s (1), hypothermia attained widespread use following its introduction into the field of cardiac surgery in the 1950s (2). The recognition that mild therapeutic hypothermia to 32–34°C or targeted temperature management at 36°C might retain the benefits of deeper hypothermia with fewer side effects (3) led to trials in a wide array of critical illnesses including cardiac arrest (4), myocardial infarction (5), traumatic brain injury (6), stroke (7), seizure (8), pneumococcal meningitis (9), and septic shock (10).
In this issue of Critical Care Medicine, Slack et al (11) unite one of critical care’s oldest therapies with one of critical care’s landmark diseases, examining hypothermia as a treatment for patients with ARDS. Prior experimental models of acute lung injury have demonstrated that mild hypothermia attenuates inflammation by decreasing pulmonary vascular permeability, decreasing the production of free radicals and proinflammatory cytokines, decreasing neutrophil adhesion and activation, and down-regulating the expression of toll-like receptors, tumor necrosis factor alpha, and mitogen-activated protein kinases (12). Hypothermia also reduces metabolic rate, diminishing both carbon dioxide production (which may decrease minute ventilation and prevent ventilator-induced lung injury) and oxygen consumption (improving PaO2/FIO2 ratio at a given level of respiratory support). Despite these promising preclinical data, only two prior prospective trials have evaluated nonpharmacologic temperature management in patients with ARDS: 1) a trial of hypothermia among 19 ARDS patients in the era prior to lung-protective ventilation (13) and 2) a randomized trial among 200 patients with septic shock, nearly half of whom had ARDS, in which fever reduction for 48 hours reduced 14-day mortality (10).
In this context, Slack et al (11) present the results of a pilot study examining the feasibility of therapeutic hypothermia among patients receiving neuromuscular blockade for moderate-to-severe ARDS (PaO2/FIO2 < 150). The authors enrolled eight ARDS patients, externally cooled them to a target of 34–36°C for 48 hours, and then rewarmed them at 0.33°C per hour. No fever suppression after rewarming was performed. These eight patients were compared with a retrospective cohort of 58 patients identified via a pharmacy database to have received continuous neuromuscular blockade for ARDS during the prior 3 years. The hypothermia intervention achieved target temperature a median of 4 hours after initiation, was continued for a median of 43 hours, and achieved a median temperature significantly lower than the retrospective control group (34.4°C vs 36.7°C). There was significant overlap between study groups, however, with almost 40% of the retrospective cohort spending at least 6 hours at temperatures less than 36°C. The reported rates of bleeding, pneumonia, hypokalemia, and symptomatic bradycardia among the eight patients treated with hypothermia were similar to rates in the retrospective control group and in prior randomized trials of temperature management for cardiac arrest. The authors conclude that, among ventilated patients receiving neuromuscular blockade for ARDS, the administration of mild therapeutic hypothermia seems feasible and safe.
Slack et al (11) are to be commended for this pilot, which provides important information for the design of future studies of hypothermia in ARDS. Nonetheless, there are important limitations. Delivery of the intervention is a key focus for pilot trials (14).

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