Care at the Critical Care Medical Center is associated with improved outcomes in patients with accidental hypothermia: A report from the J-Point registry


 Background: The recommendation that patients with accidental hypothermia (AH) should be transported to specialized centers which can provide extracorporeal life support has not been validated, and the efficacy still remains unclear.Methods: This was a multicenter retrospective cohort study of patients with a body temperature of ≤35°C presenting at the emergency department of 12 hospitals in Japan between April 2011 and March 2016. We divided the patients into the two groups based on the point of care delivery: Critical Care Medical Center (CCMC) or non-CCMC. The primary outcome of this study was in-hospital death. In-hospital death was compared between AH patients at the CCMC and non-CCMC via a multivariable logistic regression analysis. Subgroup analyses were conducted according to patients with severe hypothermia (<28°C) or systolic blood pressure of <90 mmHg.Results: A total of 537 patients were included; 413 patients (76.9%) in the CCMC and 124 patients (23.1%) in the non-CCMC group. The in-hospital death rate was lower in the CCMC group than in the non-CCMC group (22.3% versus 31.5%, p<0.001). The multivariable logistic regression analysis showed that the adjusted odds ratio (AOR) of the CCMC group was 0.54 (95% confidence interval: 0.32-0.90). In subgroup analyses, patients with systolic blood pressure <90 mmHg in the CCMC group were less likely to experience in-hospital death (AOR 0.36, 95% CI 0.23-0.56). However, no such association was observed among patients with severe hypothermia (AOR 1.08, 95% CI 0.63-1.85)Conclusions: Our multicenter study indicated that Care at CCMC was associated with improved outcomes in patients with AH. Optimizing the transport of patients with AH to specialized centers is likely to be beneficial.

Accidental hypothermia (AH) is defined as an unintentional decrease in body temperature to ≤35°C.
[i] A previous study reported that AH was the leading cause of weather-related deaths. [ii] For example, the in-hospital mortality rate was around 30% in a Japanese report, and the in-hospital mortality rate among patients with moderate to severe AH was 40% in a report from the United States.
[iii] , [iv] Therefore, it is important to develop strategies for improving the prognosis of patients with AH.
Towards improving the prognosis of critical diseases, several studies have reported the effectiveness of the treatment delivered in a specialized center. [5][6][7] For example, the treatment in a specialized center improved neurological outcomes after out of hospital cardiac arrest due to acute coronary syndrome [v] and the survival rate of patients that experienced severe trauma. [vi] Moreover, a study reported that treatment within a stroke center reduced adverse outcomes associated with acute ischemic stroke.
[vii] Nowadays, some invasive and advanced treatments such as cardiopulmonary bypass or extracorporeal membrane oxygenation have attracted significant attention regarding their use for AH patients. In particular, the cardiopulmonary arrest guidelines of European resuscitation council [viii] recommended that patients with AH should be transported to specialized centers, which can provide extracorporeal life support, if the systolic blood pressure is below 90 mmHg, and there is ventricular arrhythmia, or the core temperature is <28˚C. 8 However, this recommendation has not been validated, and its efficacy remains unclear.
We performed a multicenter retrospective observational study using data obtained from the Japanese accidental hypothermia network registry (J-Point registry).
[ix] A total of 537 adult patients with AH were enrolled. Using the data from this registry, we aimed to evaluate the association between care at the Critical care medical center (CCMC), which is a specialized center for critical illness in Japan and outcomes in patients with AH.

Study design, patient, and setting
We conducted a multicenter, retrospective study of patients with AH using data from the Japanese accidental hypothermia network registry (J-Point registry). The period of this study was between April 1, 2011 and March 31, 2016. This study included hypothermic patients who were aged 18 years or older, and excluded those who did not visit the emergency department (ED), as well as those whose body temperature was unknown or over 35.0°C.

The Japanese accidental hypothermia network registry (J-Point registry)
J-Point registry aimed to obtain descriptive information about AH towards understanding its management in the EDs of Japan, to improve patient outcomes. Details of the study methodology were described previously. 9 In brief, twelve acute care hospitals with EDs including eight critical care medical centers across the Kyoto, Osaka and Shiga Prefectures in Japan joined the J-Point registry. We retrospectively enrolled eligible patients with the International Classification of Diseases, Tenth Revision (ICD-10) code for hypothermia (T68) during the study period. The ethics committee of each participating institution approved this study.

Data collection and quality control
In this registry, data on the characteristics of the participants, clinical history, presentation, laboratory findings, and treatments were collected using a predefined uniform data sheet. All chart reviewers were emergency physicians who were trained for appropriate data review by face-to-face or web meetings. The collected data were reviewed by the working group and confirmed or returned to each institution in case of any problems.

Measurements
The Baseline characteristic information was following: sex, age, activities of daily living (ADL) before being hypothermic (independent, need some assistance, and need total assistance), residence (living alone at home, not living alone at home, nursing home, and homelessness), past medical history (

Key Group Definition
Acute care hospitals in this study were divided into the two groups: CCMC or non-CCMC.
The CCMC group included hospitals certified to provide intensive care including ECMO to all critically ill patients 24 h a day. The specialized centers were certified by the Japanese Ministry of Health, Labor and Welfare.
[ii] To be certified as a specialized center, a hospital needs to have ≥20 beds and an intensive care unit for critically ill patients. Nonspecialized centers in this study are open and staffed 24 h a day. There were 4 non-CCMCs and 8 CCMCs.

Outcomes
The primary outcome of this study was in-hospital death. The secondary outcomes were length of stay in the ICU and overall length of hospital stay.

Statistical analysis
Data were analysed using the Mann-Whitney U test for continuous variables and Fisher's exact test for comparing categorical variables between CCMC and non-CCMC. The association between care at CCMC and in-hospital death was analysed via univariable and multivariable logistic regression. We calculated the odds ratios (ORs) and adjusted odds ratios (AORs) and their 95% confidence interval (CI) as the effect variables. Based on previous studies, 3,9,10 we selected potential confounders that are likely to be associated with clinical outcomes and adjusted for the following: age category (18-64 years, 65-74 years, and ≥75 years), sex (male or female), past medical history (none, one, multiple, and unknown), ADL (independent, need some assistance, need total assistance, or unknown), systolic blood pressure category (cardiac arrest, unmeasurable, 40-90 mmHg, or >90 mmHg), exposure to cold (yes, no, or unknown), presence of associated internal diseases (yes or no), and active internal rewarming (yes or no). For subgroup analyses, the association between care at the specialized center and in-hospital death was investigated according to patients with severe hypothermia (<28°C) or systolic blood pressure of <90 mmHg via univariable and multivariable logistic regression analysis adjusting for the same confounders described above. All P-values were two-sided, and <0.05 was considered statistically significant. All statistical analyses were conducted the EZR software (version 1.36).

Results
A total of 572 patients were registered in our hypothermia study. After excluding 24 patients whose body temperature was >35.0°C, as well as 3 patients with unknown body temperature, and 8 patients who were below 18 years, 537 patients were enrolled. There were 413 patients (76.9%) in the CCMC and 124 patients (23.1%) in non-CCMC group ( Figure 1). Table 1 shows the characteristics of AH patients. Compared with the non-CCMC group, the CCMC group had a higher proportion of patients with independent ADL and lower proportion of patients with dementia. No significant differences were observed between the groups in terms of age, sex, mean outside temperature, and past history other than dementia.  Table 2 shows the in-hospital data. There was no difference between the 2 groups in terms of vital signs on hospital admission. Regarding biological data, the CCMC group had lower HCO 3 and glucose and higher lactate level. the CCMC group also had higher proportion of cold exposure, alcohol intoxication, and catecholamine use. Regarding the rewarming procedure, warm intravenous fluid, forced warm air, and active internal rewarming including ECMO were more frequent in the specialized center group.  (7) Self-harm 6 (5) 28 (7) Other 15 (12)   In the sub-group analyses, among patients with systolic blood pressure of <90 mmHg, the CCMC group experienced a lower likelihood of in-hospital death than did the nonspecialized center group (AOR 0.36, 95% CI 0.23-0.56). However, no such association was observed among patients with severe hypothermia (AOR 1.08, 95% CI 0.63-1.85) ( Table 4). Values are expressed as numbers (percentages) unless indicated otherwise.
*Adjusted for age category, sex, number of past history, systolic blood pressure category, activities of daily living category, cold exposure, active internal rewarming, internal disease etiology CI; confidence interval, CCMC; critical care medical center, OR; odds ratio. sBP; systolic blood pressure.

Discussion
Our multi-center study found that AH patients receiving care at the CCMC had lower likelihood of mortality compared to those receiving care at non-specialized centers.
Moreover, although there was no significant difference in mortality rate among patients with severe hypothermia between the two groups, among patients with blood pressure of <90 mmHg, the CCMC group had lower mortality rate. To the best of our knowledge, this is the first study investigating the impact of receiving care at a specialized center for AH patients, and our findings provide important information to inform better strategies for this life-threating illness.
The present study showed that AH patients receiving care at the CCMC had lower likelihood of mortality compared to those receiving care at non-CCMCs. Previous studies have highlighted several benefits in treatments delivered at specialized center for patients with critical diseases such as AMI, stroke, and severe trauma. [5][6][7] Regarding AH, the severe hypothermia center has been established to improve outcomes of AH patients in Poland.
[i] However, there has been no study to assess the impact of a specialized center on AH outcomes. One of the important functions about specialized center for AH is to perform ECMO. In this study, the proportion of CCMCs performing ECMO was only 5.3% which was higher compared to the non-CCMCs. Another important function is that the specialized center in Poland is expected to improve patient outcomes through education, coordination, and use of contemporary equipment. 12 The consolidation of AH patients is expected to result in higher hospital patient volume. The higher hospital patient volume could increase staff knowledge, standardize response, as well as improve the performance of ECMO at the time of circulatory failure. These effects could lead to an improvement in patients' prognosis. The consolidation of AH patients into the specialized center may be key to improving prognosis.
In the sub-group analysis, there was no significant difference in mortality rate between severe hypothermia group and non-severe hypothermia group as analyzed by In the field of ACS, stroke, and severe trauma, improvement of prognosis has been reported by patient consolidation. [5][6][7] Based on the results of our study, it is reasonable to promote the consolidation of AH patients, but the specialized center for AH seems not to be cost-effective due to the small number of cases in Japan due to the not so cold climate.
Furthermore, this study did not assess the effect of bypass emergency medical system transport on prognosis, and further research is needed to investigate as to whether the transport all AH patients with circulatory failure to the specialized center is effective or not.

Limitation
In this study, some inherent limitations should be noted. First, this is an observational study, and although we adjusted for as many confounders as possible, there may still be residual confounding factors. Second, the reasons for the visit or how the AH patients visited or were transported to a hospital was unknown, and selection bias might exist.
However, basic information or status on hospital arrival of the included patients between the 2 groups seemed balanced. Finally, we included patients with ICD 10 code, and we could have lost the populations of AH patients without ICD 10 code.

Conclusions
Our multicenter study indicated that Care at CCMC was associated with improved outcomes in patients with AH. Optimizing the transport of AH to the specialized center is likely to be beneficial.