Changes in the inflammatory response following cardiac arrest: a matter of ischemia/reperfusion or induced hypothermia?

to the editor: Although induced hypothermia to reduce neurologic damage after cardiac arrest is applied in clinical practice for some time now, mechanisms of protection remain unknown. With interest we read the article in Criti cal Care Medicine, in which Bisschops and coworkers (1) describe the effect of induced hypothermia on the inflammatory response in patients after cardiac arrest. Proinflammatory cytokine interleukin-6 shows a temporal rise during hypothermia. Chemokines interleukin-8 and monocyte chemotactic protein-1 levels are high, declining during the time course of 24 hrs of hypothermia followed by rewarming. Levels of high-mobility group box-1 show a rise during rewarming in this study (1). The authors state that hypothermia does not prevent a systemic proinflammatory response and that rewarming induces a proinflammatory effect. We question whether these conclusions are substantiated by the results. The method used in this study (longitudinal observational study without a control group) does not allow distinguishing between effects of cardiac arrest and hypothermia. An increase in mediators, declining over time, may have been caused by systemic inflammatory response syndrome following cardiac arrest, as described before (2). It is possible that the rise in interleukin-6, which the authors ascribe to an intrinsic pyrogen response to low body temperature, would have been much higher when hypothermia would not have been applied. In-line with this, we previously showed a decrease in interleukin-6 during hypothermia (3). The observed rise in high-mobility group box-1 levels after 48 hrs is consistent with previous studies in mechanical ventilation and sepsis, indicating high-mobility group box-1 as a late mediator of inflammation (4). It is equally difficult to decide whether the initial increase in complement activation and decrease during hypothermia are a result of hypothermia or due to effects of cardiac arrest, as the complement system reacts to ischemia-reperfusion injury. Besides ischemia-reperfusion injury, many interventions and comorbidities may influence the rise of cytokines in the late phase of hypothermia. We applaud the effort of the authors to illuminate mechanisms of protection by hypothermia. However, we consider conclusions that hypothermia does not prevent an inflammatory response premature at this point, as well as the statement that rewarming causes proinflammatory effects and complement activation. The alternative possibility that all observed changes are due to systemic inflammatory response syndrome following cardiac arrest and not to hypothermia is underlined by the absence of difference between jugular bulb and systemic levels found in this study (1) but also by animal studies, which allow for adequate control groups (5). This study is important in trying to determine whether the inflammatory response is influenced by therapeutic hypothermia. The incomplete study design, however, hampers definite conclusions. We acknowledge that it was not possible to include a control group, due to ethical limitations. Luckily, the target temperature management trial that is currently performed, in which cardiac arrest patients are allocated to 32 or 36°C, will allow for an adequate study design to distinguish between effects of hypothermia and of systemic inflammatory response syndrome following cardiac arrest on inflammatory parameters. Results will be available within time to come. The authors have not disclosed any potential conflicts of interest.