Intensive care with endovascular catheter rewarming for accidental severe hypothermia (ICE-CRASH II): a protocol for a randomised controlled study

Abstract

Introduction

Accidental hypothermia (AH) can occur in mild-to-severe cases; however, its management is crucial in severe cases as it can cause ventricular fibrillation and lead to death. Among various rewarming therapies for AH, endovascular catheter rewarming has been the focus of recent studies as a minimally invasive alternative to invasive internal rewarming, such as extracorporeal membrane oxygenation (ECMO). However, no study has demonstrated the efficacy and safety of endovascular catheter rewarming therapy. This study aimed to validate the efficacy and safety of endovascular catheter rewarming for patients with AH.

Methods and analyses

The intensive care with endovascular catheter rewarming in accidental severe hypothermia (ICE-CRASH II) study is a multicentre, randomised study of patients with AH. This study will include patients with AH (age ≥65 years, core temperature <30°C) with preserved circulation and a target sample size of 88. Patients with cardiac arrest (CA), those who have undergone hospital transfers, and those in whom a central venous catheter could not be accessed through the femoral vein will be excluded from the study. Patients will be assigned to either the endovascular catheter plus conventional rewarming group or the conventional rewarming group based on stratified-substitution block randomisation. Patients will be followed up for 30 days after the initiation of the intervention or until discharge. The primary outcome will be to compare the percentage of patients achieving a rewarming rate ≥1.5°C/hour between the endovascular catheter plus conventional rewarming group and the conventional rewarming group.

Ethics and dissemination

This study was approved by the Hokkaido University Certified Review Board (approval number: 024-00013). Written informed consent will be obtained from all the participants or their legally acceptable representatives. The results will be disseminated through publications and presentations.

Trial registration number

Japan Registry of Clinical Trials (jRCT1012240051).

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is a randomised controlled study, providing evidence about both the efficacy and safety of endovascular catheter rewarming for patients with accidental hypothermia (AH) (age ≥65 years, core temperature <30°C).

• A limitation of this study is the unblinded design due to the nature of the study.

• Due to the limited study sample size, it was not possible to include facilities in the stratification factor, a limitation that does not eliminate the possibility of bias.

• The study included older adult patients with AH in Japan; therefore, it may not be generalisable to patients with AH in other countries.

Introduction

Accidental hypothermia (AH) is defined as a decreased core temperature <35°C.¹ AH is often classified classically as mild, moderate and severe with core temperatures of 32–35°C, 28–32°C and less than 28°C, respectively.² Treatment of severe AH is clinically important owing to the risk of developing ventricular fibrillation, a life-threatening condition. For patients with moderate-to-severe AH, active external rewarming (electric blankets, forced air surface rewarming and heating pads) and active internal rewarming (thoracic lavage, gastric lavage, haemodialysis, endovascular catheter and extracorporeal membrane oxygenation (ECMO)) are clinically employed.^{3 4} Active external rewarming carries the risk of rewarming shock, in which peripheral vasodilation in response to active external rewarming may cause venous pooling and a drop in blood pressure. In contrast, active internal rewarming, through rewarming the body from the inside, has a lower risk of rewarming shock. In general, active internal rewarming, which has a faster rewarming rate than active external rewarming, is employed in patients in whom sufficient rewarming cannot be achieved by external rewarming. Several studies have shown that the rewarming rate is associated with prognosis and that the optimal rewarming rate is between 1.5 and 5.0°C/hour.⁵,⁷

The ECMO rewarming approach has the fastest rewarming rate compared with other internal and external rewarming therapies.⁸ The use of ECMO for patients with AH with cardiac arrest (CA) showed good efficacy with survival rates as high as 47–63%¹ and is strongly recommended in several clinical guidelines.^{3 9} In our previous multicentre prospective observational study (ICE-CRASH study), which evaluated ECMO effectiveness for AH, significantly improved survival was demonstrated in patients with AH with CA in the ECMO group compared with that in the patients in the non-ECMO group (58.3% vs 21.2%, respectively).¹⁰ No significant difference was observed in the patients with non-CA between the ECMO and non-ECMO groups, but there was an increase in haemorrhagic complications in the ECMO group. The mean age of patients in this study was 81 years, suggesting that the use of ECMO in older patients with AH may be excessively invasive. Extracorporeal Life Support Organisation has reported that the use of ECMO in older patients is associated with increased mortality and complications.¹¹ In Japan, more than 80% of patients with AH are aged ≥65 years and have comorbidities¹²; therefore, less invasive rewarming therapy is warranted.

An endovascular catheter is a minimally invasive and active internal rewarming therapy that uses the same technique as central venous catheter insertion while being less invasive than thoracic lavage, gastric lavage and ECMO. It has already been used clinically for targeted temperature management in patients with subarachnoid haemorrhage,¹³ brain injury,¹⁴ heat stroke¹⁵ and post-CA syndrome.¹⁶ Recently, the use of endovascular catheters for rewarming therapy in patients with AH has demonstrated potential benefits.¹⁷ Furthermore, in patients with AH with CA, a combination of mechanical chest compressions and rewarming with an endovascular catheter was found to be effective, leading to successful recovery without neurological sequelae.¹⁸ Recently, endovascular catheters have been used in 6–7% of patients with moderate-to-severe AH in the USA, and their use has increased since 2014.¹⁹ The review of AH also describes endovascular catheters as an important rewarming therapy⁸; however, no studies have evaluated their efficacy in a multicentre setting, where the reports are limited to case reports²⁰,²⁴ and single-centre retrospective studies.¹⁷ The previous retrospective study¹⁷ showed that endovascular catheter rewarming was performed in 49 of 102 patients with AH with a core temperature <32°C. The rewarming rate was not statistically significantly different between the endovascular catheter rewarming group and other rewarming groups (1.3°C/hour vs 1.0°C/hour, respectively; difference 95% CI 0 to 0.6°C), and the survival rate was not significantly different between the two groups (70% vs 71%, respectively; 95% CI −17% to 20%). Although this study was unable to demonstrate that the use of endovascular catheters was statistically effective in increasing the rewarming rate, it demonstrated the feasibility and safety of endovascular catheter use in patients with AH. Thus, the present study will aim to clarify the efficacy and safety of employing endovascular catheter rewarming therapy in patients with severe AH and preserved circulation.

Methods and analysis

Study design and setting

The intensive care with endovascular catheter rewarming in accidental severe hypothermia (ICE-CRASH II) study is a multicentre, randomised study of patients with severe AH. The inclusion of patients started in December 2024, with a planned 2-year patient recruitment period. The ICE-CRASH II study is being conducted in 26 tertiary care centres, including academic and community hospitals (table 1).

Table 1. List of hospitals participating in the present study.

1	Hokkaido University Hospital
2	Nippon Medical School
3	Tokyo Metropolitan Tama Medical Center
4	Kansai Medical University Medical Center
5	Osaka University Graduate School
6	Hyogo Emergency Medical Center
7	Osaka Saiseikai Senri Hospital
8	Nara Medical University
9	Hirosaki University
10	Nayoro City General Hospital
11	Kushiro City General Hospital
12	Sapporo Medical University
13	St Luke’s International Hospital
14	Juntendo University Urayasu Hospital
15	Toho University Omori Medical Center
16	Japanese Red Cross Akita Hospital
17	Yodogawa Christian Hospital
18	St Mary's Hospital
19	Kishiwada Tokushukai Hospital
20	Kansai Medical University
21	Hiratsuka City Hospital
22	Asahikawa Medical University Hospital
23	Saiseikai Utsunomiya Hospital
24	Tohoku University Hospital
25	Chiba Emergency and Psychiatric Medical Center
26	Tottori Prefectural Central Hospital

Patients and interventions

A flowchart of the patient enrolment process is presented in figure 1. The inclusion criteria for patients are as follows: (1) age ≥65 years at the time of emergency transport; (2) core temperature measured in the emergency room is <30°C, and patients diagnosed with AH having preserved circulation and (3) informed consent obtained from patients or their relatives. The exclusion criteria are as follows: patients (1) with CA before and on arrival at hospital; (2) transferred from another hospital; (3) in whom an endovascular catheter cannot be inserted for rewarming in the femoral vein; (4) who are unable to undergo core temperature monitoring due to trauma or other reasons; (5) with hypersensitivity reactions to heparin; (6) with severe coagulation disorders worsened by AH and (7) other patients who are judged to be inadequate as research participants by the investigator.

Figure 1. Flowchart of the enrolment process for the patients. AH, accidental hypothermia; CA, cardiac arrest.

The research participants in this study are patients with severe AH who have impaired consciousness at the time of arrival at the emergency department and have difficulty giving consent of their own free will. The investigator will provide an informed consent document approved by the certified review board (CRB) to potential surrogates on behalf of the research participant, provide sufficient written and oral explanations, and obtain consent in writing of free will. If it is difficult to contact the surrogate immediately, the CRB committee will approve participation in the study, even in the absence of explanation and written consent from the surrogate. Even in such cases, explanation and consent from the research participants or their surrogates are essential until discharge from the hospital, and written consent will be obtained later. Participants whose consent could not be obtained during the above period will not be included in this study.

After inclusion, patients will be promptly assigned to either of the two groups: the endovascular catheter plus conventional rewarming group or the conventional rewarming group. Conventional rewarming therapies include forced-air surface rewarming, electric blankets and heating pads (in combination) and are defined as rewarming therapies that do not include ECMO, haemodialysis, thoracic lavage or gastric lavage. In accordance with the standard method described for each device, the core temperature should be rewarmed up to 36°C. If the temperature can be set in the mode selection of each device, select the temperature setting that allows for the fastest rewarming up to 36°C. An endovascular catheter is inserted through the femoral vein using the same technique used for the central venous catheter. The endovascular temperature management system comprises a Thermogard XP or HQ console and a Start-up Kit fitted with a Quattro or an ICY (four or three balloons) heat exchange catheter (Asahi Kasei Zoll Medical, San Jose, CA, USA). To avoid inducing arrhythmias caused by the guidewire, we will insert this catheter under ECG monitoring using abdominal ultrasonography or fluoroscopy to place the catheter in an appropriate position. If necessary, other modalities (ECMO, blood purification, thoracic perfusion, abdominal perfusion, bladder perfusion and hot bath) may be used in combination, and such datasets will be excluded from the analysis. In both groups, the patients will be rewarmed up to 36°C.

Outcome measures

The primary outcome is to compare the percentage of patients achieving a rewarming rate ≥1.5°C/hour with and without endovascular catheter rewarming therapy. The percentage of patients achieving a rewarming rate ≥1.5°C/hour in this study is defined as the average. Rewarming rate to 36°C is calculated as the time from the start of rewarming up to 36°C, as rewarming time, as shown below.

Rewarming rate (°C/hour) = (36−core temperature at start of rewarming) (°C)/rewarming time (hour)

For patients who did not achieve a temperature rewarming to 36°C, rewarming rate (°C/hour) = (core temperature at end of rewarming−core temperature at start of rewarming) (°C) / rewarming time (hour).

The secondary outcomes are as follows: (1) rewarming rate of core temperature to 36°C; (2) percentage of core temperature rewarming to 36°C achieved; (3) rewarming rate from the start of endovascular catheter rewarming (rewarming rate from the start of conventional rewarming therapy); (4) ventilator days; (5) renal replacement therapy days; (6) catecholamine administration days; (7) length of stay at ICU; (8) adverse event rates; (9) outcome at discharge and (10) Cerebral Performance Category (CPC) at discharge. If the patient remains hospitalised until day 30, the discharge outcome and CPC will be evaluated after day 30.

Randomised assignment of interventions and participant timeline

This study adopts a stratified substitution block randomisation design for patient allocation. The stratification factors will be (1) age (≥80 years vs <80 years), (2) sex and (3) core temperature (≥28°C vs <28°C). A web-based system adjusted to avoid large bias will assign the participants randomly and sequentially to each treatment group in the order of enrolment of cases and save the participant enrolment number and treatment group on the electronic data capture (EDC) system. The schedule of observations and assessments in this study is summarised in figure 2. The assessment data will be recorded using an EDC system (NorthNet, https://www.crmic-huhp.jp/northnet/edc/). Monitoring experts, who are independent of the conduct of the study, will ensure that the data reported by the investigators are accurately collected. Participants will be followed up for 30 days after intervention initiation or until discharge. Owing to the nature of the study, the participants and care providers cannot be blinded to the assigned intervention. However, we plan to perform data analysis by statisticians who are not involved in the study.

Figure 2. Time schedule of interventions and assessments of participants. Assessment data will be recorded using an electronic data capture system. Participants will be followed up for 30 days after intervention initiation or until discharge. If the participants are still hospitalised until day 30, the discharge outcome and CPC will be evaluated after day 30. *Explanation and acquiring consent from research participants or their surrogates are essential until discharge from the hospital. **Core temperature measurement site is either from the rectum, bladder or oesophagus. CPC, cerebral performance category; ED, emergency department; SOFA, Sequential Organ Failure Assessment.

Statistical methods

Sample size estimation

Based on the results of our previous study,¹⁰ the percentage of patients achieving a rewarming rate ≥1.5°C/hour was estimated to be 68.8% in the group with endovascular catheter rewarming and 42.3% in the group without endovascular catheter rewarming (unpublished data). The percentage of patients achieving a rewarming rate ≥1.5°C/hour was assumed to be 70% in the group with an endovascular catheter and 40% in the group without an endovascular catheter. For a power of 70% and a type 1 error of 5%, at least 40 patients will be required in each group. Assuming that approximately 10% of patients will drop out during the process, the total number needed will be 44 patients in each group, for a total of 88 patients.

Statistical analyses

Summary statistics will be calculated for the endovascular catheter rewarming plus conventional rewarming group and the conventional rewarming group. Categorical variables will be presented as frequencies and percentages, and continuous variables will be presented as means with SD or medians with IQR (IQR; 25th–75th percentile). Intergroup comparisons will be carried out using Fisher’s exact test for categorical data and the two-sample Student’s t-test or Mann-Whitney U test for continuous data. Secondary outcomes will be compared between the groups using a model similar to that used in the primary analysis. An interim analysis will not be performed. Owing to the nature of this study, intention-to-treat analysis will not be performed; however, per-protocol analysis will be performed. In addition, we will consider carrying out a sensitivity analysis to evaluate the influence of exclusion.

Although researchers at the participating centres may conduct ancillary studies using the data obtained from this study, specific analysis methods have not been determined. Following the completion of all ancillary analyses by the trial group, the data obtained through this study may be made available to qualified researchers with a legitimate academic interest. All data sets will be deidentified and will contain no protected health information. Data release is contingent on (1) approval of the request, (2) execution of all applicable data-sharing agreements, and, where required, (3) approval by an institutional review board, (4) authorisation from the director of the participating institution and (5) confirmation that patient consent has been obtained, including via an opt-out process, when permissible.

Patient and public involvement

No patients are involved.

Ethics and dissemination

This study is conducted in accordance with the principles of the Declaration of Helsinki and the Clinical Trials Act. This study was approved by the Hokkaido University Certified Review Board (approval number: 024-00013) and registered with the Japan Registry of Clinical Trials (jRCT; 1012240051). Written informed consent to participate will be obtained from all participants or their legally acceptable representatives (see onlinesupplemental files 1 2). The data registered in the EDC system do not contain personal information. After completion of all planned analyses, the findings of the study will be presented at relevant scientific meetings and disseminated through publications in peer-reviewed journals.

Discussion

This multicentre, randomised study will evaluate the efficacy and safety of endovascular catheter rewarming therapy for patients with AH (age ≥65 years, core temperature <30°C) with preserved circulation.

Our previous ICE-CRASH study revealed that the use of ECMO as a rewarming therapy for patients with AH without CA, especially in older people, increased haemorrhagic complications and resulted in greater harm than benefit.^{10 25} In contrast, active external rewarming therapy alone is not sufficient to achieve the target rewarming rate. This study focused on endovascular catheter rewarming as a minimally invasive active internal rewarming technique that can achieve an effective rewarming rate in AH, which is common among older people in Japan, if it has not yet developed into CA.

Although the target rewarming rate is not clearly identified, a previous study revealed that the optical target rewarming rate is 1.5–5.0°C/hour.⁵,⁷ Recently, a secondary analysis of our previous study, the ICE-CRASH study (n=332), showed that the rewarming rate was significantly associated with 28-day survival in the early phase (OR 1.51 (95% CI 1.10 to 2.09), p=0.011).²⁶ Considering the aforementioned target rewarming rate, the primary outcome of this study was designated as the percentage of achieving a rewarming rate ≥1.5°C/hour. In addition, only ECMO treatment can achieve a rewarming rate of ≥5°C/hour.¹ Therefore, no additional strategy to avoid this needs to be considered in this study.

The COOL-ARREST JP study,²⁷ a clinical trial of endovascular catheters in patients with post-CA syndrome, showed no serious adverse events related to this device. However, no studies with high-quality evidence regarding endovascular catheter rewarming in patients with AH are available. In Japan, the use of endovascular catheters for patients with AH has not yet been approved by health insurance in 2025, and their use in routine clinical practice has been restricted. Therefore, we expect that endovascular catheter rewarming in combination with conventional rewarming therapy may be an effective alternative to the excessively invasive ECMO approach in patients with AH.

Trial status

The trial protocol V.1 was approved on 10 October 2024 (approval number: 024-004). The latest protocol (V.1.07) was approved on 13 March 2025, after minor revisions regarding the change of principal investigator and the addition of participating hospitals. The first patient was included on 24 December 2024. The trial is ongoing, and approximately 40 patients have been enrolled since the end of March 2025. Patients will be recruited until March 2026 and followed up thereafter.