Critical Care Alert: Duration of Device-Based Fever Prevention After Cardiac Arrest

ARTICLE
Hassager C, Schmidt H, Møller JE, et al. Duration of Device-Based Fever Prevention after Cardiac Arrest. N Engl J Med. 2023;388(10):888-897. 

OBJECTIVE
To determine whether undergoing 36 versus 72 total hours of device-based fever prevention after an initial 24 hours of targeted temperature management (TTM) in comatose patients who suffered a cardiac arrest results in a lower mortality from all causes or hospital discharge with a Cerebral Performance Category (CPC) of 3 or 4 within 90 days (Table 1).

BACKGROUND
Current guidelines recommend 72 hours of active fever prevention in comatose patients who have achieved sustained return of spontaneous circulation (ROSC) after an out-of-hospital cardiac arrest (OHCA). The goal of fever prevention is to mitigate the harmful effects of hypoperfusion during a cardiac arrest and reduce sequelae of reperfusion injury after ROSC.1 In 2002 the Advanced Life Support (ALS) Task Force of the International Liaison Committee on Resuscitation (ILCOR) first introduced the recommendations for TTM at 32° to 34°C for 12 to 24 hours for unconscious adult patients who achieved ROSC after an OHCA.2 Data for the prevention of fevers beyond 12 to 24 hours is less robust, however, based primarily on animal studies and observational data suggesting there is increased morbidity and mortality associated with fever beyond this period.3 While there have been multiple trials investigating the specific temperature to target during the initial 12-24 hour post-arrest period, they include fever prevention after rewarming in both the intervention and control groups for the 72 hours after the arrest4. The goal of this trial was to compare outcomes of 2 different durations (36 hours versus 72 hours) of fever prevention after 24 hours of TTM in comatose patients who have been resuscitated after an OHCA. 

DESIGN
Randomization was performed with the use of a web-based system; random permuted blocks of 2, 4, and 6 participants; and stratification according to the participating site. All patients in the trial underwent cooling to 36°C in the first 24 hours in accordance with international guidelines at the time of the design and initiation of the trial.

Patients received mechanical ventilation and were kept sedated to a Richmond Agitation Sedation Scale of -4 during the period of temperature control at 36°C and during the subsequent rewarming period. The target core body temperature was controlled by means of commercially available surface cooling (CritiCool and Allon, Belmont Medical Technologies) at one participating site (286 patients) and by means of intravenous cooling (Thermogard XP and Cool Line Catheter, Zoll) at the other participating site (503 patients).

After the 24-hour maintenance period at 36°C, the core temperature was gradually increased by 0.5°C per hour to 37°C for a total duration of 36 hours or 72 hours. Patients were then maintained at 37°C for the randomly assigned interval with the same type of device that had been used for the initial 24 hours. Non–device-based treatment of fever (temperature >37.5°C) was done by pharmacologic means (acetaminophen), by uncovering the patient’s body, or both depending on the discretion of the treating physician. Ice packs or pads were not used. Device-based cooling was terminated if the patient awakened at any point. 

INCLUSION CRITERIA

• Age ≥ 18 years
• OHCA of presumed cardiac cause
• Sustained ROSC: when chest compressions have been not required for 20 consecutive minutes and signs of circulation persist
• Unconsciousness (GCS < 8) (patients not able to obey verbal commands) after sustained ROSC

EXCLUSION CRITERIA

• Conscious patients (obeying verbal commands)
• Females of childbearing potential (unless a negative HCG test can rule out pregnancy within the inclusion window)
• In-hospital cardiac arrest
• OHCA of presumed non-cardiac cause (eg, after trauma or dissection/rupture of major artery) or cardiac arrest caused by initial hypoxia (eg, drowning, suffocation, hanging)
• Known bleeding diathesis (being on warfarin, DOAC, or antiplatelet therapy did not exclude the patient)
• Suspected or confirmed intracranial bleeding or acute stroke
• Unwitnessed asystole
• Known limitations in therapy and DNR status
• Known disease making 180 day survival unlikely or known pre-arrest CPC of 4
• > 4 hours from ROSC to screening
• SBP < 80 mmHg despite fluid loading, vasopressor and/or inotropic support, or mechanical circulatory support device (eg, intra-aortic balloon pump/axial flow device)
• Temperature on admission < 30°C

PRIMARY OUTCOME

• Death from any cause within 90 days
• Discharge from hospital with a Cerebral Performance Category score of 3 or 4 (indicating severe disability or coma or vegetative state) within 90 days

SECONDARY OUTCOMES

• Death from any cause at 3 months
• Montreal Cognitive Assessment score at 3 months 
• (Range 0-30, higher score indicating better cognitive ability)
• Modified Rankin score at 3 months 
• (Range 0-6, 0 being no symptoms, 6 being death)
• Cerebral Performance Category at 3 months

KEY RESULTS
802 patients were enrolled from March 2017-December 2021. The intention-to-treat population consisted of 789 patients, 393 patients were assigned to 36 hours and 396 patients were assigned to 72 hours of device-based-temperature control. 

Primary outcome
Death from any cause or CPC score of 3 or 4 at discharge occurred in 127 of 393 patients (32.3%) in the 36-hour group and 113 of 396 patients (33.6%) in the 72-hour group. Active device-based fever prevention for either 36 or 72 hours after cardiac arrest did not result in a significantly different percentage of patients dying or having severe disability (hazard ratio 0.99; 95% CI 0.77-1.26). These results were consistent in the subgroup populations. 

Secondary outcomes
Death from any cause within 90 days occurred in 116 patients (29.5%) and 120 patients (30.3%) in the 36 and 72-hour group respectively which was not statistically significant. The median CPC was 1 and modified Rankin scale score 1 in both groups. The median Montreal Cognitive Assessment score was 26 and 27 for the 36 and 72-hour group respectively.  

LIMITATIONS

• Intervention group was not masked
• This trial involved a cohort of patients with a relatively good prognosis (eg, > 85% of included patients had an initial shockable rhythm and received bystander CPR) which may be less generalizable to patients with higher risk of more severe brain injury
• Number of follow-up visits and cognitive evaluations were lower than expected due to COVID-19 pandemic

EM TAKE-AWAYS
While fever prevention for 72 hours after cardiac arrest has been endorsed by international guidelines since 2005, there is a lack of randomized control trial (RCT) generated data supporting this after the initial 24 hours of temperature control. The authors of this RCT found that active device-based fever prevention for 36 or 72 hours after cardiac arrest did not result in significant different percentages of patients dying or having severe disability or coma within 90 days. 

Table 1

Cerebral Performance Category Scale (Adult)⁵

REFERENCES

1. Sandroni C, Nolan JP, Andersen LW, et al. ERC-ESICM guidelines on temperature control after cardiac arrest in adults. Intensive Care Med. 2022;48(3):261-269.
2. Nolan JP, Morley PT, Vanden Hoek TL, et al. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation. 2003;108(1):118-121. 
3. Zeiner A, Holzer M, Sterz F, et al. (2001). Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med. 2001;161(16):2007-2012. 
4. Fernando SM, Di Santo P, Sadeghirad B, et al. Targeted temperature management following out-of-hospital cardiac arrest: a systematic review and network meta-analysis of temperature targets. Intensive Care Med. 2021;47(10):1078-1088. 
5. Table: cerebral performance category scale (Adult)*. Merck Manuals Professional Edition.