Resuscitation 84 (2013) 10111012

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Resuscitation
journal homepage: www.elsevier.com/locate/resuscitation

Editorial

Fever after therapeutic hypothermia Does rebound pyrexia matter?

Fever has been consistently associated with lower survival rates and worse outcomes after different forms of brain injury1 including hypoxic-ischaemic encephalopathy after cardiac arrest.2 However, controversy remains as to whether increased body temperature causes brain injury directly or merely acts as a surrogate marker for more severely damaged patients. A systemic inammatory response is the common pathophysiological denominator after cardiac arrest and may be an important factor for the early increase in body temperature found in animals subjected to forebrain ischemia3 and cardiac arrest patients who have not been treated with hypothermia.4 Infectious diseases, mainly pneumonia, become prevalent during the following days after arrest and may act as an additional cause of fever, a phenomenon that may be more common in hypothermia treated patients.5 The pathophysiological chain of events following global brain ischaemia and reperfusion has been extensively characterized in animal models. Virtually all pathophysiological processes are aggravated by fever and mitigated by hypothermia.6 Major events such as loss of ion homeostasis, excessive glutamate release and free radical production are initiated during ischaemia and accelerate during the rst hours after reperfusion. Evidence of neuronal necrosis can also be seen in humans as early as 5 h after arrest, but programmed cell death apoptosis continues over several days.7 In a recent rodent study it was found that the increase in survival and good neurological outcome seen with hypothermia was lost if cooling was delayed beyond 4 h after a global ischaemic event. Surprisingly, at a histological level, the protective effect on hippocampal neuronal cells was maintained with cooling started as late as 8 h after ischaemia and this protection increased further if hypothermia was prolonged from 24 to 48 h.8 Experimentally induced fever, on the other hand, may aggravate neuronal damage after global ischaemia even when it is induced as late as 24 h after the initial insult.9 Also, the spontaneous rebound pyrexia occurring during the rst days after experimental global ischaemia and hypothermia may be suppressed pharmacologically leading to an increased neuronal survival.3 Thus, it appears that in small animal models, temperature control to normo- or hypothermia should ideally last several days to provide maximal neuronal protection. In this issue of Resuscitation, there are two studies from the United States concerning the effects of pyrexia during the rst 48 h after cardiac arrest.10,11 Gebhardt and associates compared patients treated with or without therapeutic hypothermia during 20052010 in one academic centre while Leary and coworkers report on 236 patients treated with hypothermia at 11 institutions collaborating in a registry. Leary and colleagues compare outcome
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between hypothermia treated patients who develop hyperthermia after rewarming (rebound pyrexia) and those who do not. Gebhardt and co-investigators take a broader perspective with a population of both hypothermia and non-hypothermia treated patients and the development of fever during the rst days after cardiac arrest. The authors discuss several relevant limitations. Both studies are retrospective and observational which provides only associative data and no information on any possible effect of increased temperature. Further, both in and out-of-hospital cardiac arrests are included, which may have implications on the interpretation of the results, since we know that the in-hospital cardiac arrest patient more likely sustains multi-organ dysfunction (and thus have fever of other causes) and die of a non-brain injury related cause. The background demographics for patients treated with hypothermia are similar in the two studies and both excluded patients dying during the period when fever development was studied (48 h after cardiac arrest and 24 h after the end of the intervention period respectively). The low overall survival in both studies should be acknowledged in the light of a fairly low proportion of initially shockable rhythms and long periods before return of spontaneous circulation. Although the survival rates are similar for hypothermia-treated patients in the two studies, survival with good outcome was less common in the Gebhardt-study, which may reect the different denitions of good outcome used. The main results of the two studies are convergent. Fever frequency was approximately the same, developing in around 40% of the patients. Among patients treated with therapeutic hypothermia, fever occuring after rewarming is not consistently associated with an adverse outcome. The study by Gebhardt and coworkers conrms earlier observations that any fever is associated with worse outcome in non-hypothermia treated patients.2 However, this association was not evident in the hypothermia treated group, and the authors speculate that this may result from a delayed onset of fever by hypothermia. On the contrary, their results in a multivariate model give signals that any fever burden may be associated with a better neurological outcome. In contrast, the study by Leary and colleagues does not show any difference in mortality or neurological function between those who develop any fever and those who do not, but they found a worse neurological outcome for patients developing a high fever (above 38.7 C). These discrepancies call for different interpretations. It might be that the actual gure matters and that there is a relationship between higher temperature and increased severity of brain damage, or that there is a threshold temperature above which the signal is picked up. To get closer to the answer, a multivariate modelling with temperature introduced as a continuous non-linear variable would be a possible next step. We

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Editorial / Resuscitation 84 (2013) 10111012 2. Zeiner A, Holzer M, Sterz F, Schorkhuber W, Eisenburger P, Havel C, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Int Med 2001;161:200712. 3. Coimbra C, Drake M, Boris-Mller F, Wieloch T. Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inammatory/antipyretic drug, evidence for chronic encephalopathic processes following ischemia. Stroke 1996;27:157885. 4. Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, Fitting C, et al. Successful cardiopulmonary resuscitation after cardiac arrest as a sepsis-like syndrome. Circulation 2002;106:5628. 5. Mongardon N, Perbet S, Lemiale V, Dumas F, Poupet H, Charpentier J, et al. Infectious complications in out-of-hospital cardiac arrest patients in the therapeutic hypothermia era. Crit Care Med 2011;39:135964. 6. Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371:195569. 7. Horn M, Schlote W. Delayed neuronal death and delayed neuronal recovery in the human brain following global ischemia. Acta Neuropathol 1992;85: 7987. 8. Che D, Li L, Kopil CM, Liu Z, Guo W, Neumar RW. Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest. Crit Care Med 2011;39:142330. 9. Baena RC, Busto R, Dietrich WD, Globus MY, Ginsberg MD. Hyperthermia delayed by 24 h aggravates neuronal damage in rat hippocampus following global ischemia. Neurology 1997;48:76873. 10. Leary M, Grossetreuer AV, Iannacone S, Gonzalez M, Shofer F, Povey C, et al. Pyrexia and neurologic outcomes after therapeutic hypothermia for cardiac arrest. Resuscitation 2013;84:105661. 11. Gebhardt K, Guyette FX, Doshi AA, Callaway CW, Rittenberger JC. Prevalence and effect of fever on outcome following resuscitation. Resuscitation 2013;84:10627. 12. Haugk M, Testori C, Sterz F, Uranitsch M, Holzer M, Behringer W, et al. Relationship between time to target temperature and outcome in patients treated with therapeutic hypothermia after cardiac arrest. Crit Care 2011;15: R101. 13. Nielsen N, Hovdenes J, Nilsson F, Rubertsson S, Stammet P, Sunde K, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-ofhospital cardiac arrest. Acta Anaesthesiol Scand 2009;53:92634. 14. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:55763. 15. HACA-trial group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:54956. 16. Deakin CD, Nolan JP, Soar J, Sunde K, Koster RW, Smith GB, et al. European resuscitation council guidelines for resuscitation 2010 section 4. Adult advanced life support. Resuscitation 2010;81:130552. 17. Nielsen N, Wetterslev J, Al-Subaie N, Andersson B, Bro-Jeppesen J, Bishop G, et al. Target temperature management after out-of-hospital cardiac arrest a randomized, parallel-group, assessor-blinded clinical trial-rationale and design. Am Heart J 2012;163:5418.

do not know whether these signals indicate that higher fever per se is detrimental to neuronal survival or is just a marker of a more severely injured brain. As discussed by Gebhardt and co-workers, the relationship between any fever burden and a good neurological outcome may be because a less injured brain is more able to thermoregulate and generate a fever in comparison with a severely injured brain that has lost thermoregulatory function. It has been speculated that this mechanism accounts for the lack of evidence for a better neurological outcome with shorter time to achieving the target temperature in hypothermia-treated patients the less injured patient has retained thermoregulation and may ght the attempt to reduce body temperature.12,13 Another interesting aspect not investigated in the current studies is the fact that many patients with a subsequent good outcome wake up close to the end of the intervention period, and any rebound pyrexia should ideally be investigated in the light of the patients state of consciousness; would a possible therapeutic effect of temperature control in the post-intervention phase be restricted only to those who remain comatose? The pivotal studies by Bernard et al.14 and the HACA-group15 indicated a benecial effect of induced hypothermia to 33 C for 12 and 24 h after cardiac arrest respectively, leading to the recommendation and implementation of hypothermia as a neuroprotective treatment for comatose cardiac arrest survivors.16 In the HACA trial, many in the control group had a fever very much in keeping with the non-hypothermia treated patients in the Gebhardt study. The optimal target temperature for a general cardiac arrest population, balancing any benet with possible harm, is still not dened. Strict controlled normothermia, avoiding fever, may still be an option and is currently being tested in an on-going trial.17 The two current studies by Leary and Gebhart indicate that additive neuroprotective effects of prolonged cooling beyond the initial 2436 h may be limited and that a large study sample will be needed to answer this question. Prolonged temperature control for 48 or 72 h has not yet been tested in clinical trials in adults, but one study in children with hypoxic ischaemic encephalopathy is under way, comparing hypothermia of 33 C for 24 versus 72 h (NCT00797680). This strategy would also be the next logical step in adult cardiac arrest patients, when we can be more condent about the optimal target temperature. Conict of interest statement Tobias Cronberg is responsible for neurological prognostication and follow-up and Niklas Nielsen is chief investigator in the Target Temperature Management after Out-of-hospital Cardiac Arrest trial (NCT01020916). References
1. Greer DM, Funk SE, Reaven NL, Ouzounelli M, Uman GC. Impact of fever on outcome in patients with stroke and neurologic injury: a comprehensive metaanalysis. Stroke 2008;39:302935.

Tobias Cronberg Lund University Hospital, Lund, Sweden Niklas Nielsen Lund University, Helsingborgs Hospital, Helsingborgs, Sweden
Corresponding author. E-mail address: Tobias.Cronberg@skane.se (T. Cronberg)

8 May 2013