Discussion
The present nationwide study showed that frail patients with AH had a significantly higher risk of mortality in comparison to non-frail patients with AH, even after adjustment for important confounders. Additionally, the frail patient group included a higher rate of patients with a worsened neurological outcome in comparison to the non-frail patient group. The rewarming rate in frail patients was delayed in comparison to non-frail patients.
Recently, frailty has been shown to be associated with mortality and adverse outcomes in patients with various conditions [
7], including patients with chronic obstructive pulmonary disease [
19], patients with inflammatory bowel disease [
20], patients with AIDS [
21], patients awaiting liver transplantation [
22], hip fracture patients [
23] and patients undergoing elective vascular surgery [
24], independent of chronological age. However, whether or not frailty is associated with mortality in patients with AH has not previously been investigated. The present nationwide study showed, for the first time, that frailty is an important prognostic factor in patients with AH.
Previous studies showed that prognostic factors in AH include the potassium level, pH value, lactate level, and age [
2,
3,
25‐
27]. Although these factors may be useful for predicting the prognosis and selecting an appropriate rewarming intervention, these factors cannot be controlled and do not help improve the prognosis of patients with AH. However, in contrast to the other factors, frailty is a factor that can be avoided with preventive intervention [
28] [
29]. The reduction of frailty might consequently lead to a decrease in the number of deaths caused by AH.
The rewarming rate in frail patients was slower than that in non-frail patients. Although the rates at which ECMO or a warmed blanket were used in the frail patient group were lower in comparison to the non-frail patient group, the results were also similar in the subgroup analysis that excluded cases in which ECMO or a warmed blanket were used. The reasons for the difference in the rewarming rate may be as follows. It is hypothesized that intrinsic heat production by the patient, such as shivering thermogenesis, does not occur sufficiently in frail patients with AH, resulting in delayed rewarming. In the present study, the finding that the CPK level was lower in the frail patient group may support this mechanism. A previous study showed that a decreased rewarming rate in patients with AH is associated with a high risk of underlying infection [
30] and mortality [
31]. In recent years, many studies have shown that the prognosis of septic patients with hypothermia is poor [
32‐
34]. For this reason, it has been pointed out that homeostatic dysfunction, such as immune dysfunction, is related to the poor prognosis of these patients [
35,
36]. Although there was no significant difference in the occurrence of infectious complications between the frail and non-frail patient groups in the present study, a similar mechanism may be responsible for the relationship between frailty and a poor prognosis in patients with AH. On the other hand, the results of this study could not clarify whether or not the rapid rewarming using invasive internal rewarming methods will reduce mortality and improve the prognosis of frail patients with AH. Thus, further studies are needed to address this problem.
In our previous study, we found that frail patients with AH showed prolonged hospitalization [
16]. However, in this study, there was no significant difference in the length of hospital stay between the frail and non-frail patient groups. The reasons are as follows: the previous study excluded patients who died within 30 days, whereas the present study included these patients. The rate of early mortality within 30 days was higher in the frail group than in the non-frail group. As a result, the length of hospital stay in the frail group was shorter than that in the non-frail group, although the difference was not statistically significant.
A previous study showed that, among ICU patients requiring mechanical ventilation, the presence of frailty increased the likelihood of short-term mortality, and that these findings might play a role in informed shared decision-making with patients and families prior to the provision of mechanical ventilation [
37]. In this study, the rate of tracheal intubation was lower among frail patients than among non-frail patients. This may be because these patients and their families did not wish to receive invasive treatment with intubation and ventilation.
Regarding complications, previous studies have reported that the incidence of complications is higher in frail patients [
7]. However, in this study, the incidence of complications in the frail and non-frail patient groups did not differ to a statistically significant extent. The complications defined in this study (arrhythmia, pneumonia, pancreatitis, electrolyte abnormality and coagulopathy) occurred infrequently, which may have contributed to the lack of a significant difference.
The present study was associated with some limitations. First, we used the CFS score, which was calculated based on ADL and the CCI to determine frailty, while the standard tools for the diagnosis of frailty are the frailty index [
38] or frailty phenotype [
39]. Therefore, it remains to be verified whether the diagnosis of frailty in this study was accurate. In this regard, a comparative study regarding the accuracy of the CFS score is currently in progress [
40]. Second, there were numerous missing data in relation to the rewarming rate. However, the volume of data including in this nationwide study was sufficient; thus, the results are considered robust. Third, we could not to determine the rewarming rate according to individual rewarming methods, because several rewarming methods were used in combination. Finally, this study was based on the findings of registry data on hypothermia, and it did not include any data that was related to frail research, such as ADL after a long-term follow-up. Therefore, further studies will be needed to investigate the long-term ADL of frail patients with AH.
Acknowledgements
Aidu Chuo Hospital.
Aizawa Hospital.
Akita Red Cross Hospital.
Aomori Prefectural Central Hospital.
Asahikawa City Hospital.
Asahikawa Medical University Hospital.
Asahikawa Red Cross Hospital.
Center Hospital of the National Center for Global Health and Medicine.
Chiba Emergency Medical Center.
Chikamori Hospital.
Daiyukai General Hospital.
Dokkyo Medical University Nikko Medical Center.
Dokkyo Medical University Saitama Medical Center.
Eastern Chiba Medical Center.
Ehime Prefectural Niihama Hospital.
Esashi Hospital.
Fujieda Municipal General Hospital.
Fujisawa City Hospital.
Fukui Prefectural Hospital.
Fukuoka University Hospital.
Fukushima Medical University Hospital.
Funabashi Municipal Medical Center.
Gifu Prefectural General Medical Center.
Gifu University Hospital.
Hachinohe City Hospital.
Hamamatsu Medical Center.
Hidaka Tokushukai Hospital.
Hiroshima Prefectural Hospital.
Hokkaido Medical Center.
Hyogo Emergency Medical Center.
Hyogo Prefectural Nishinomiya Hospital.
Ina Central Hospital.
Ise Red Cross Hospital.
Ishikawa Prefectural Central Hospital.
Ishinomaki Red Cross Hospital.
Iwata City Hospital.
Iwate Prefectural Central Hospital.
JA Onomichi General Hospital.
Japanese Red Cross Society Kyoto Daiichi Hospital.
Jichi Medical University Saitama Center.
Jikei University Daisan Hospital.
Juntendo University Nerima Hospital.
Juntendo University Urayasu Hospital.
Kagawa University Hospital.
Kansai Medical University Hospital.
Kasugai Municipal Hospital.
Kawaguchi Municipal Medical Center.
Kawasaki Municipal Hospital.
Kimitsu Chuo Hospital.
Kishiwada Tokushukai Hospital.
Kitakyushu General Hospital.
Kumamoto Red Cross Hospital.
Kushiro City General Hospital.
Kyorin University Hospital.
Kyoto University Hospital.
Maebashi Red Cross Hospital.
Mie Prefectural General Medical Center.
Mie University Hospital.
Miyazaki Prefectural Nobeoka Hospital.
Nagano Red Cross Hospital.
Nagasaki University Hospital.
Nagoya Ekisaikai Hospital.
Nagoya University Hospital.
Narita Red Cross Hospital.
Nasu Red Cross Hospital.
National Defense Medical College Hospital.
National Hospital Organization Mito Medical Center.
National Hospital Organization Nagoya Medical Center.
National Hospital Organization Osaka National Hospital.
National Hospital Organization Yokohama Medical Center.
Nayoro City General Hospital.
Nihon University Hospital.
Nihon University Itabashi Hospital.
Nihonkai General Hospital.
Niigata University Medical & Dental Hospital.
Nippon Medical School Hospital.
Nippon Medical School Tamanagayama Hospital.
Oita University Hospital.
Okinawa Prefectural Nanbu Medical Center & Children’s Medical Center.
Okitama Public General Hospital.
Ome Municipal Central Hospital.
Omihachiman Community Medical Center.
Osaka City General Hospital.
Ota Memorial Hospital.
Rinku General Medical Center.
Saiseikai Shiga Hospital.
Saiseikai Utsunomiya Hospital.
Sapporo City General Hospital.
Sapporo Medical University Hospital.
Seirei Hamamatsu General Hospital.
Seirei Mikatahara General Hospital.
Shinshu University Hospital.
Shizuoka Red Cross Hospital.
Shonan Kamakura General Hospital.
St.Mary’s Hospital.
Steel Memorial Hirohata Hospital.
Sunagawa City Medical Center.
Takasaki General Medical Center.
Teikyo University Hospital.
Teine Keijinkai Hospital.
Tenshi Hospital.
Toho University Omori Medical Center.
Tohoku University Hospital.
Tokai University Hospital.
Tokushima Prefectural Miyoshi Hospital.
Tokuyama Central Hospital.
Tokyo Metropolitan Tama Medical Center.
Tosei General Hospital.
Toyama University Hospital.
Tsuyama Chuo Hospital.
Uji Tokushukai Medical Center.
University of Tokyo Hospital.
University of Yamanashi Hospital.
Wakayama Red Cross Medical Center.
Yamagata Prefectural Central Hospital.
Yamagata University Hospital.
Yamaguchi University Hospital.
Yamanashi Prefectural Central Hospital.
Yokkaichi Municipal Hospital.
Yokohama Minami Kyosai Hospital.