Critical Care Alert: ICE-CRASH Study

ARTICLE:Takauji S, Hayakawa M, Yamada D, et al. Outcome of extracorporeal membrane oxygenation use in severe accidental hypothermia with cardiac arrest and circulatory instability: A multicentre, prospective, observational study in Japan (ICE-CRASH study). Resuscitation. 2023;182:109663.

OBJECTIVE
To compare the 28-day survival and favorable neurological outcomes at discharge between patients with severe hypothermia who received extracorporeal membrane oxygenation (ECMO) support versus those who just received standard therapy (non-ECMO).

BACKGROUND
Hypothermia is an involuntary drop in body temperature below 35°C and can be further classified as mild, moderate, or severe.¹ Severe accidental hypothermia (AH) has a mortality rate as high as 29% and often causes ventricular fibrillation (VF) and cardiac arrest (CA), resulting in the need for both circulatory support and rewarming.² Prior studies have suggested a benefit for veno-arterial ECMO (VA-ECMO) in these situations.³ This is because VA-ECMO withdraws deoxygenated blood from the venous system, pumps it through a membrane lung, and returns it to the arterial circulation, thus bypassing the native cardiopulmonary system which is compromised in a patient with severe AH.

The current resuscitation guidelines from the European Resuscitation Council (ERC) recommended the use of ECMO in AH patients with CA or circulatory instability.⁴ However, few studies exist to evaluate the effectiveness of ECMO given the scarcity of eligible patients as well as the ethical implications of randomizing patients to receive this treatment modality. In addition, it is unclear whether ECMO would benefit patients with severe AH who have not yet reached the point of CA. This study was thus designed as a prospective observational study to further evaluate the survival benefits as well as the complications of initiating ECMO for patients with severe AH.

DESIGN

• Prospective, multicenter, observational study of AH patients from December 2019 to March 2022
• A total of 36 tertiary emergency medical facilities in Japan participated in this study
• Severe AH was defined in this study based on meeting any of the following criteria: 1) CA on arrival at the hospital or transition to CA in the ED or 2) unmeasurable blood pressure or systolic blood pressure of 60 mmHg or less, or heart rate of 50 bpm or less on arrival at the hospital.
• Patients who received ECMO were allocated to the ECMO group, and those who received other methods of rewarming were allocated to the non-ECMO group. Cases wherein more than one method of rewarming was applied, of which one of them was ECMO, were included in the ECMO group.
• Rewarming methods were divided into active external rewarming (eg, warmed blanket and warmed bath) and active internal rewarming (eg, warmed fluid infusion, body cavity lavage, hemodialysis, intravascular temperature system, and ECMO). The specific rewarming method was decided by the attending physician.

INCLUSION CRITERIA

• Age >18
• Presented to ED with body temperature <32°C

EXCLUSION CRITERIA

• Age <18
• Patients with CA who were deemed not eligible for resuscitation (according to the judgment of the emergency room physician)

PRIMARY OUTCOME

• Survival at 28 days after admission

SECONDARY OUTCOMES

• Favorable neurologic status (CPC score 1 or 2) at discharge
• The incidence of complications (bleeding, thrombosis, pneumonia, acute pancreatitis, lower limb ischemia, acute kidney injury) at 28 days after admission
• Event-free days (ICU-, ventilator-, RRT-, and catecholamine administration-free days) at 28 days after admission

KEY RESULTS
The ICE-CRASH study enrolled a total of 499 AH patients, 242 of which had severe AH and were included in the main analysis. Of these, 57 had CA on arrival or transitioned to CA in the ED whereas 185 had circulatory instability without CA. These patients were then divided into the ECMO group (N = 41) and the non-ECMO group (N = 201). The median (IQR) age of patients with AH was 81, with the incidence of indoor AH (79.8%) higher than that of outdoor AH (20.2%). The mean body temperature was 27.7°C. 

Primary outcome
There were no differences in 28-day survival between the ECMO (65.9%) and non-ECMO (64.7%) groups (odds ratio [OR] 1.08, 95% CI: 0.53-2.21) in overall severe AH. However, in patients with both severe AH and CA, survival at 28 days was significantly higher in the ECMO group (58.3%) than in the non-ECMO group (21.2%) (OR 0.19, 95%CI: 0.06–0.62). No significant difference in survival was seen between the two groups (ECMO 76.5%, non-ECMO 75.9%) in patients without CA (OR 1.02, 95%CI: 0.31-3.3).

Secondary outcomes

• There were no significant differences in favorable neurological outcomes at discharge between the ECMO (53.7%) and non-ECMO (52.2%) groups (OR 0.95, 95%CI: 0.48–1.85) in overall severe AH. In patients with severe AH and CA, however, the ECMO group (41.7%) had a significantly better neurological outcome than the non-ECMO group (15.2%) (OR 0.95, 95%CI: 0.48–1.85).
• The incidence of bleeding occurred significantly more frequently in the ECMO group (73.2%) than in the non-ECMO group (21.9%).
• In patients with CA, the number of ICU-, ventricular-, RRT-, and catecholamine administration-free days at 28 days after admission were significantly higher in the ECMO group than in the non-ECMO group (see Table 3 for specific p-values).

LIMITATIONS

• This was not a randomized study and thus subject to selection bias; patients receiving ECMO versus those who didn’t was up to the discretion of the emergency physician.
• There was a low incidence of accidental hypothermia during this 2 year enrollment period, thus the target number of patients in the ECMO group (as previously calculated)⁵ could not be achieved.
• Most AH patients in Japan were elderly and had underlying comorbidities resulting in high mortality. This may have attenuated the beneficial effects of ECMO rewarming in AH patients without AH. Additionally, these results may not be generalizable to patients in the U.S who may have different baseline characteristics.

EM TAKE-AWAYS

• Consider initiating ECMO for patients with severe accidental hypothermia who present in cardiac arrest, as this was the only subgroup that had a statistically significant survival benefit and improved neurological outcomes.
• Use caution with initiating ECMO in non-cardiac arrest patients with severe hypothermia as it can decrease the number of “event-free” (ICU-, ventilator-, and catecholamine administration-) days and increase the frequency of bleeding complications without improving survival or neurological outcomes.

REFERENCES

1. Duong H, Patel G. Hypothermia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan.
2. Takauji S, Hifumi T, Saijo Y, et al. Accidental hypothermia: characteristics, outcomes, and prognostic factors—A nationwide observational study in Japan (Hypothermia study 2018 and 2019). Acute Med Surg. 2021;8:e694.
3. Dunne B, Christou E, Duff O, Merry C. Extracorporeal-assisted rewarming in the management of accidental deep hypothermic cardiac arrest: a systematic review of the literature. Heart Lung Circ. 2014;23(11): 1029-1035.
4. Lott C, Truhlar A, Alfonzo A, et al. European Resuscitation Council Guidelines 2021: Cardiac arrest in special circumstances. Resuscitation. 2021;161:152–219.
5. Takauji S, Hayakawa M. Intensive care with extracorporeal membrane oxygenation rewarming in accident severe hypothermia (ICE-CRASH) study: a protocol for a multicentre prospective, observational study in Japan. BMJ Open. 2021;11(10):e052200.