By Kathryn Radigan, MD, MSc

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: In unconscious survivors of out-of-hospital cardiac arrest who are admitted to the ICU, targeted temperature management at 33°C for 48 hours failed to significantly improve neurologic outcomes at six months when compared to 24 hours.

SOURCE: Kirkegaard H, Søreide E2, de Haas I, et al. Targeted temperature management for 48 vs. 24 hours and neurologic outcome after out-of-hospital cardiac arrest: A randomized clinical trial. JAMA 2017;318:341-350.

Although the most recent international resuscitation guidelines recommend targeted temperature management (TTM) at 33°C-36°C for at least 24 hours in unconscious patients who experience out-of-hospital cardiac arrest, there remains controversy over the optimal duration of TTM. To better understand this, Kirkegaard et al conducted a randomized, clinical trial across 10 ICUs at 10 university hospitals in six European countries from Feb. 16, 2013, to June 1, 2016. The researchers randomized 355 unconscious adults with out-of-hospital cardiac arrest to TTM (33 ± 1°C) for 48 hours (n = 176) or 24 hours (n = 179), followed by gradual rewarming of 0.5°C per hour until reaching 37°C. The primary outcome was six-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to delineate a favorable outcome. A score in this range would be described as a functional status of at least moderate cerebral disability or better (e.g., sufficient cerebral function for independent activities of life).

Out of the 355 patients who were randomized, 351 patients completed the trial. There was no significant difference in favorable functional neurologic outcome at six months for patients treated for 24 hours (n = 176; 64% with favorable outcome) vs. 48 hours (n = 175; 69% with favorable outcome) of TTM (difference, 5%; 95% confidence interval [CI], -5% to 14.8%). There was no difference in six-month mortality or time to mortality (hazard ratio, 0.79; 95% CI, 0.54-1.15; P = 0.22). Although there was no significant difference in overall hospital stay (11 vs. 12 days; P = 0.50), the median length of ICU stay was longer in the 48-hour group than in the 24-hour group (151 vs. 117 hours, respectively; P < 0.001). Adverse events were more common in the 48-hour group than in the 24-hour group. Although there were no significant differences in the rates of pneumonia or bleeding between the two groups, there was significantly more hypotension in the 48-hour group than the 24-hour group (62% vs. 49%, respectively; P = 0.013). Despite no significant differences in overall incidence of bleeding, severe bleeding was more common in the 24-hour group compared to the 48-hour group.

COMMENTARY

In 2015, 347,000 adults received emergency medical services-assessed, out-of-hospital cardiac arrest, and 209,000 individuals experienced in-hospital cardiac arrest.1 Unfortunately, neurologic injury is the major cause of morbidity and mortality after cardiac arrest. Hypothermia is one of the major advances that has improved neurological outcomes after cardiac arrest. Although hypothermia as a medical treatment dates to the time of Hippocrates, the study of hypothermia has been a challenge as most trials are limited by number of participants. Despite these limitations, the American Heart Association guidelines call for starting all comatose adult patients with return of spontaneous circulation after cardiac arrest on TTM with a target temperature between 32°C and 36°C maintained for at least 24 hours.2 Nielsen et al explored the range of temperature from 32°C and 36°C. Their work showed there was no significant difference in mortality or poor neurological outcomes when comparing a targeted temperature of 33°C to 36°C in unconscious survivors of out-of-hospital cardiac arrest undergoing TTM.3

Although Kirkegaard et al found no significant difference between the 24-hour and 48-hour groups in the TTM trial, the sample size calculation using a 15% absolute difference in the primary outcome may have increased the risk of a type II error, leading to the conclusion that there is no difference between groups when there may be a difference. The 95% CI between -5% to 14.8% suggests that a true difference is unlikely to lie outside this range. Even a 5% higher rate of six-month favorable neurologic outcome in the prolonged-cooling group may be clinically relevant. This potential benefit should be considered for patients who may necessitate a particular goal based on the response of the individual patient. For instance, an ICU patient with significant cerebral edema may continue at a lower temperature until intracranial pressure (ICP) is optimized and then rewarmed slowly with close monitoring of ICP. Unfortunately, further studies to prove clinical relevancy would require an enrollment at least eight times the numbers seen in this particular study.

Kirkegaard et al may have revealed a trend toward benefit in the patients with 48-hour TTM, but their results also must be put in the context of an increased rate of adverse events in the 48-hour group (97%) vs. the 24-hour group (91%) (difference 5.6%; 95% CI, 0.6-10.6%; relative risk, 1.06; 95% CI, 1.01-1.12; P = 0.04). The adverse events included higher rates of hypotension in the 48-hour group compared to the 24-hour group (62% vs. 49%; P = 0.013). Of course, the hypotension did not affect overall mortality or length of hospital stay even though it may have affected the ICU length of stay (151 hours, interquartile range [IQR], 127-178 hours for the 48-hour group vs. 117 hours, IQR, 99-138 hours for the 24-hour group; P < 0.001). Despite experiencing more severe bleeding in the 24-hour group compared to the 48-hour group (4% vs. 1%; P = 0.03), there were no significant differences in the rates of severe arrhythmias, pneumonia, or overall bleeding between the two groups. The reason for more severe bleeding in the 24-hour group remains unclear. As expected, more patients were rewarmed to 36°C before TTM was completed in the 48-hour group compared with the 24-hour group.

Unconscious survivors of out-of-hospital cardiac arrest who were admitted to the ICU with TTM at 33°C for 48 hours experienced no significant benefit in six-month neurologic outcome compared to patients treated with 24 hours of TTM. The findings revealed no significant difference, but this study may have been limited in the power to detect clinically important differences. Further studies are warranted to learn more. Regardless of the results of this or any future study, it is always ideal for clinicians to titrate temperature to a particular goal, which should be based on the response of individual patients within the context of each clinical scenario.

REFERENCES

  1. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 2017;135:e146-e603.
  2. Callaway CW, Donnino MW, Fink EL, et al. Part 8: Post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132:S465-S482.
  3. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med 2013;369:2197-2206.