Temperature management after cardiac arrest - IngentaConnect

REVIEW URRENT C OPINION

Temperature management after cardiac arrest Niklas Nielsen and Hans Friberg

Purpose of review Temperature management for patients comatose after cardiac arrest has been an integral component of postcardiac arrest care for the last decade. In this review, we present recent findings and discuss implications for future trials. Recent findings The two largest trials on temperature management after cardiac arrest were recently presented. The first investigated prehospital induction of hypothermia using ice-cold intravenous saline in 1364 patients. The intervention gave a significant reduction in time from return of circulation to start of hypothermia and lower body temperature on admission to hospital. There was no difference in survival or neurological function between the study groups, but there were indications of possible harm in the group that received saline. The second trial investigated two actively controlled temperatures provided in intensive care units, randomizing 950 unconscious patients suffering out-of-hospital cardiac arrest of a presumed cardiac cause to targeted temperature management at 33 and 368C. There was no difference in survival until end of trial or neurological function at 180 days. Summary Prehospital hypothermia induced by cold crystalloid infusion does not benefit cardiac arrest patients. For patients treated in an intensive care unit targeting a temperature of 368C provides similar results as targeting 338C. Keywords cardiac arrest, outcome, postresuscitation care, targeted temperature management, therapeutic hypothermia

INTRODUCTION For those patients with an out-of-hospital cardiac arrest wherein a resuscitation is attempted at the scene, survival to hospital discharge has been very low at around 5–10% [1,2]. Fortunately, some regions recently reported a doubling of their survival rates [3,4 ]. The explanation for this observation is unclear, but is most likely multifactorial and may include improved prehospital care and attention to detail in the postcardiac arrest period [5 ,6 ]. Cardiac arrest patients belong to the group with the highest mortality rate of all diagnoses in critical care. Among those admitted to intensive care units less than half survive to follow-up [7]. In contrast to the dismal survival rate, patients discharged alive have a good neurological function in nine out of 10 cases, and their quality of life is within the normal range [7,8,9 ]. Thus, the outcome is more or less binary – either death, or survival with a favorable functional status compatible with independent living. Poor survival associated with cardiac arrest has spurred researchers to find a therapeutic intervention to lower mortality and further increase the chance &

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of a good functional outcome. Pharmaceutical interventions have so far proved disappointing and basic organ support was, until the turn of the last century, the only therapy offered to patients unresponsive and comatose following a cardiac arrest. Results from animal models demonstrating a neuroprotective effect of hypothermia led to clinical investigations and in 2002 two trials were published indicating a clear benefit of hypothermia of 32–348C induced for 12–24 h for out-of-hospital cardiac arrest of presumed cardiac cause with initial shockable rhythms [10,11]. Hypothermia was soon advocated in an advisory statement from the International Liaison Committee on Resuscitation (ILCOR) [12] and recommended in guidelines for advanced life support in 2005 and 2010 [13,14]. The

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Department of Clinical Sciences, Section of Anesthesiology and Intensive Care, Lund University, Lund, Sweden Correspondence to Niklas Nielsen, MD, PhD, Intensive Care Unit, Helsingborg Hospital, S Vallgatan 5, 251 87 Helsingborg, Sweden. E-mail: [email protected] Curr Opin Crit Care 2015, 21:202–208 DOI:10.1097/MCC.0000000000000203 Volume 21 Number 3 June 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Temperature management after cardiac arrest Nielsen and Friberg

KEY POINTS Recent trials have shown no effect of early hypothermia induced prehospitally with ice-cold intravenous fluids for patients suffering out-of-hospital cardiac arrest.

latter part of 2013, we saw the results from the two largest trials so far on temperature management in cardiac arrest, investigating timing of hypothermia (prehospital versus in-hospital cooling) and depth (hypothermia to 338C versus a milder temperature at 368C) [24 ,25 ]. This article will describe these trials in context, but also try to define some thoughts on how to advance this area of postcardiac arrest care. &&

There is no difference in mortality or neurological function whether temperature management for comatose cardiac arrest patients is targeted at 33 or 368C. A systematic review of animal studies on hypothermia and targeted temperature management in cardiac arrest is lacking. The overall quality of evidence for targeted temperature management is on a low level and a sufficiently powered trial investigating the concept should be performed.

recommendation was also extended to include outof-hospital cardiac arrests of nonshockable rhythms, of noncardiac cause and cardiac arrests occurring in hospitalized patients. The recommendation to cool cardiac arrests of other origins and occurring in-hospital was not based on the results of additional clinical studies, merely on extrapolation of the results of the initial trials. The latest summary of the evidence behind the guideline recommendations and Cochrane analyses gave a high level of evidence for hypothermia after cardiac arrest per se, but indicated knowledge gaps in aspects of how hypothermia was delivered, with regards to timing, duration and depth of temperature management [15–17]. There have been some proponents of a more conservative interpretation of the strength of the evidence in support of hypothermia after cardiac arrest [18–21]. We undertook a systematic review including GRADE-methodology and trial sequential analysis and came to the conclusion that the quality of evidence rather was on a low leading to clinical equipoise for continued investigation of hypothermia as a neuroprotective therapy in cardiac arrest patients [22]. Four years ago, we also expressed our concern with the evidence evaluation process performed by the large international societies, and called for a more objective assessment process and recommendations involving a clear message of knowledge gaps [23]. The new guideline process for advanced life support, including temperature management after cardiac arrest, is ongoing and will be published in October 2015. This process will again assess the evidence that was fundamental to earlier guidelines, and synthesize this with the results from trials that have emerged during the last 5 years. During the

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TIMING OF HYPOTHERMIA The rationale for earlier initiation of hypothermia to improve outcome originates from experiments in rodents, where the relationship between time to cooling and extent of brain injury has been demonstrated [26]. In clinical practice, it has been difficult to initiate hypothermia earlier than 1–1.5 hours after the cardiac arrest, and in an attempt to provide the intervention as soon as possible after return of circulation, prehospital cooling by an ambulance team has been introduced and tested. Several pilot studies indicated the feasibility of lowering body temperature significantly by intravenous infusion of cold crystalloid solutions [27], but two randomized trials by Bernard et al. [28,29] performed in Australia and presented in 2010 and 2012 did not show any benefit of this strategy on relevant patient outcomes. The largest trial so far was performed by the emergency medical service system in the Seattle area, well known for its high-quality cardiac arrest program, and randomized 1364 unconscious, adult patients with out-of-hospital cardiac arrest to either standard care or rapid infusion of 2000 ml 48C normal saline along with muscle paralysis and sedation [24 ]. There was a significant difference of more than 18C between the admission temperatures of the two groups, but in spite of a clear separation of temperatures between the groups, there was no difference in neurological outcome or survival (Fig. 1) [24 ]. Importantly, the intervention group had more re-arrests and a higher frequency of pulmonary edema, indicating possible harm with hypothermia induced by rapid infusion of cold saline. Both the Australian trials and the large Seattle trial have been criticized, mainly because a proportion of patients did not retain their target temperatures after admission to hospital, but the bottom line is that no signal of benefit was detected with an early cooling approach. In summary, there seems to be compelling evidence for abstaining from administrating cold crystalloid infusion in the field to lower body temperature. Moreover, metaanalyses, not including the large Kim trial, also came to the conclusion that no benefit could be demonstrated with this intervention [30,31 ]. &&

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FIGURE 1. The proportion of comatose patients achieving either death without awakening or awakening as a function of days after cardiac arrest for enrolled patients [24 ]. The area between the two curves represents the proportion of patients who remain comatose. All patients at time ¼ 0 are comatose and over time either awaken or die without awakening. (a) There were 568 patients with ventricular fibrillation and known event times (284 in intervention group and 284 in control group). For patients with initial rhythm of ventricular fibrillation at 7 days, 157 patients died without awakening (28%), 355 had awakened (62%) and 56 were still comatose (10%). At 30 days, 34 more patients died without awakening, 14 more had awakened and 8 patients remained comatose. (b) There were 771 patients without ventricular fibrillations but with known event times (395 in the intervention group and 376 in the control group). At 7 days, 566 patients died without awakening (73%), 138 had awakened (18%) and 67 were still comatose (9%). At 30 days, 46 more patients died without awakening, 8 more had awakened and 13 patients remained comatose. &&

In observational reports, some single-center studies have indicated benefit of earlier initiation of hypothermia [32], but larger registry data have not been able to reproduce this finding [7,33,34 ]. There are nevertheless other interventions currently being tested where hypothermia is administrated before return of spontaneous circulation, which has a pathophysiological rationale as the proposed neuroprotective temperatures are achieved before the injurious reperfusion cascade starts. The pilot PRINCE trial randomizing 200 patients to nasopharyngeal cooling with aerosolized fluorocarbon or standard care did not show a difference in outcome, but the investigators identified a subgroup of patients with shockable rhythms and short times to cardiopulmonary resuscitation who might benefit [35]. This led to the ongoing PRINCESS trial designed to investigate survival effects of intra-arrest cooling in this select patient group [36]. &

DEPTH OF HYPOTHERMIA Contrary to the guidelines and the Cochrane summaries, our systematic review from 2011 led to the conclusion that there was a lack of robust evidence for hypothermia after cardiac arrest, also for the most studied patient group: out-of-hospital cardiac arrest of a presumed cardiac cause with initial shockable rhythm. However, it was also evident that the optimal target temperature was not thoroughly 204


investigated [22]. The proposed temperature range of 32–348C was used in initial trials based on animal research performed on young healthy animals. We hypothesized that the balance between possible harm and benefit might not be within that temperature range in elderly humans with significant comorbidities. Also, it was not established whether the suggested effect in the Hypothermia after Cardiac Arrest (HACA) trial, where the control group developed fever, was an effect of lowering body temperature to hypothermic ranges or an effect of avoiding fever. We therefore designed the independently funded and investigator-initiated Target Temperature Management after Out-of-hospital Cardiac Arrest (TTM) trial. The TTM trial randomized 950 patients at 36 hospitals in 10 countries to targeted temperature management at 33 and 368C during 26 months between 2010 and 2013 [37]. Both groups were sedated and mechanically ventilated throughout the 36-h intervention period and both groups targeted the set temperature with the use of feedback-control devices, providing either intravascular or surface cooling. As opposed to what was reported in the previous trials, a strict protocol for neuroprognostication and decisions on level of care (including withdrawal of life supporting therapies) was used [37]. Not doing so may impact a trial with inherent problems of blinding of the intervention allocation for the immediate caregivers, as it is difficult to conceal body temperature and the Volume 21 Number 3 June 2015



physiological response to cooling. The outcome assessors and the physicians performing neurological prognostication were blinded to the intervention. Primary outcome was survival until the end of trial and secondary outcomes included neurological function using both the cerebral performance category scale and the modified Rankin scale. The result of the TTM trial was neutral, with no benefit of either temperature in any outcome measure, including adverse events [25 ] (Fig. 2). It is important to emphasize that we cannot draw the conclusion from the TTM trial that cooling is not necessary, as both treatment arms received active temperature control to ranges below normal body temperature (Fig. 3). At the same time, it is equally important to realize that the TTM trial does not add to the evidence that active temperature control is of benefit, as there was no untreated control group. It is reasonable to believe, however, that both intense (338C) and less intense (368C) temperatures provide similar results. There has been criticism of the TTM trial, mainly on the precision of temperature control and time to reaching target temperature in the 338C group, but also that the whole trial cohort was less ill than in previous trials, owing to a high proportion of bystander cardiopulmonary resuscitation and a short time to start of basic life support [38,39]. Regarding timing and precision, additional reports from the TTM trial have shown that temperature &&

Kaplan-Meier estimates for time to death in TTM trial intervention groups P = 0.51

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was tightly controlled and that the time to reaching below 348C was faster than in the HACA trial [40]. With respect to severity of illness, it is correct that more patients had bystander resuscitation performed (3/4 in TTM versus 1/2 in HACA), in line with reports on improvement in prehospital care that has been seen between the contemporary TTM trial and previous trials [3]. Nevertheless, the overall mortality rate of 50%, the time to return of spontaneous circulation of a median of 25 min and the low motor-Glasgow Coma Score at admission, would definitely vouch for a patient group with a very substantial risk of ischemic brain injury.

WHAT TO DO WITH THIS NEW INFORMATION? What can we conclude from these new trials? Regarding prehospital cooling, it seems uncontroversial to not provide this intervention unless as part of a clinical trial protocol. For targeted temperature management as a concept, and the specific optimal temperature range, it is not as clear-cut. As a consequence of the neutral results of the TTM trial, all sites involved in the trial moved to 368C. In support of the change to 368C were the point estimates, which were all in favor of 368C, and in an adjusted analysis of the main outcome the point-estimate moved even more in favor of 368C. Moreover, the subgroup analysis did not indicate signals in favor of selecting any specific group for a target of 338C. Lastly, 368C is closer to the normal body temperature and must therefore be considered less invasive. There are as yet no observational publications of how temperature management is provided after the publication of the TTM trial, but it is likely that many hospitals across the globe have reached a similar conclusion. At the same time, there are definitely sites that continue to provide the guideline-recommended temperature range of 32–348C, as there were no differences detected in the TTM trial (no benefit of 368C) and due to the results of the Bernard and HACA trial from 2002.

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FIGURE 2. Probability of survival until end of trial [25 ]. The figure shows Kaplan–Meier estimates of the probability for survival for patients assigned to a target temperature of either 33 or 368C, and the numbers at risk for each time point. The P value was calculated by means of Cox regression with the effect of intervention group adjusted for the stratification variable of sites. &&

With this new landscape, it might be useful to reconsider all aspects of targeted temperature management after adult cardiac arrest: animal experiments, observational data and randomized trials. The concept of hypothermia for neuroprotection in clinical medicine is supported by numerous examples from the experimental animal literature [41]. Cooling of the brain before, during and immediately after ischemia has uniformly been shown to be neuroprotective in different species




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FIGURE 3. Temperature during intervention period [25 ]. The figure depicts temperature curves in the 33 and 368C groups, with bladder temperature in 8C on the y-axis and time from randomization until end of the intervention period on the x-axis. Rewarming was commenced at 28 h after randomization. The temperature curves display means 2 standard deviations (95% of the observations are within the error bars). &&

and in well tuned experimental settings. Cooling the brain with a delay after the ischemic insult has been shown to be neuroprotective in rodents, but whether this holds true for larger animals or for other tissues, like the myocardium, is less clear. Many experiments in the animal literature compare artificial cooling (hypothermia) with artificial warming (mimicking normothermia or fever), and whether this approach is relevant to mechanistically reproduce a febrile response in an injured human brain may be debatable [42,43]. There is to our knowledge no systematic review of the animal evidence, and many questions regarding extrapolation and generalizability of the results could and should be raised. A large proportion of the recommendations for temperature management rely on observational data from registries and single centers, and there are numerous before/after studies reporting risk reductions even greater and numbers needed to treat even smaller, than the very encouraging figures from the initial trials [44]. Are these reports adding to the evidence, or rather increasing confidence in a possibly erroneous risk reduction attributable to targeted temperature management? There are many compelling analogies to this in medicine. Recently two large trials could not demonstrate the proposed risk differences of several tenths of percentage indicated in the landmark trial and numerous before/after studies on early goaldirected therapy in sepsis [45–47]. We would therefore argue against using observational data as a substitute for lack of high-quality evidence from randomized trials. 206


The potential problems with the early landmark trials have already been discussed above, and they will again be evaluated in a consensus process prior to the new guidelines. Our own opinions remain with the systematic review from 2010 suggesting a low quality of the evidence, with problems of lack of generalizability, possible risk of systematic error and substantial risk of random error [22]. Our view is that the results of the TTM trial and also the Kim trial to some extent, could be regarded as providing additional arguments against the robustness of previous findings and that the results of the landmark trials from 2002 should be reinvestigated in a sufficiently powered, contemporary multicenter trial – a trial that should have been performed many years ago. Interestingly, and perhaps something to consider further when discussing future trials, is that during the TTM trial and prior to any results, its design was criticized for being unethical [48], and the trial protocol did not pass ethical review boards in some countries because of concern that the trial allocated patients to an intervention not recommended in guidelines. Recommendations which are based on insufficient evidence ought not to be a hindrance for performing clinical trials with the aim of improving that evidence.

CONCLUSION Hypothermia is a proposed intervention for neuroprotection after cardiac arrest. Initial trials have shown promising results when lowering the body temperature to 32–348C, but the quality of the Volume 21 Number 3 June 2015



collated evidence is still on a low level. A recent large trial showed no benefit on survival or neurological function of prehospital hypothermia and indicated possible harm. Another large trial has presented good evidence that targeting 33 or 368C gives similar results. In the interest of cardiac arrest patients, caregivers and healthcare systems, we believe it is time to collectively perform a large clinical trial randomizing to active temperature control or standard care without active temperature control to increase the confidence in targeted temperature management. Acknowledgements We would like to thank Drs Matt P Wise and Tobias Cronberg for valuable input on the manuscript. Financial support and sponsorship Dr Friberg and Dr Nielsen are supported by grants from the Swedish National Healthcare System (ALF). Conflicts of interest H.F. and N.N. have received speaker reimbursement from BARD Medical.

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