A novel indicator for temperature control in heat stroke treatment

Temperature control plays a pivotal role in patients with heat stroke (HS), but little work has been done sufficiently on the use of temperature control to reflect disease progression. Here, we defined and analyzed the concrete role of controlling time for core temperature to physiological level (CTTP), in order to explore a potential index to guide the treatment of HS.


| INTRODUCTION
Heat stroke (HS), an emergent medical condition, represents the pathologic state that results from increases in internal body temperature (>40.8C) and concurrent neurocognitive impairments. 1 The incidence of HS is closely related to temperature and humidity, with the epidemiologic data varying from 17.6 to 250 cases per 100 000 population in different areas. 2 Seriously, the morbidity rate of HS rises each year with global warming. 3And up to 1.2 billion people worldwide will be at risk of a HS each year by the year 2100 if global warming continues at this rate. 4Statistical data have shown that the incidences of HS and HS-induced deaths in China are increasing each year.[7][8] Reducing core temperature is considered the key strategy of HS treatment. 9Studies show that the fatality rate is closely related to hyperpyrexia and its duration, and patients exposure to higher temperatures for more extended periods may progress to multiple organ failure. 102][13] Mortality rates can be reduced by more than 20% when cooling is completed within 60 min. 14Furthermore, Yoon found that targeted temperature management (<36 C) will help treat severe heat stroke. 15Nevertheless, it has been reported that deaths purportedly because of over-cooling. 16viously, in the treatment of HS, the target and duration of temperature control are very controversial.To touch a scientific temperature control strategy, establishing a temperature control evaluation index is the key step.
Based on the facts, we propose the concept of controlling time for core temperature to the physiological level (CTTP) and define it as the time interval from the onset of HS to the stabilization of core body temperature below 37.7 C.Then, we performed a retrospective study to include all HS patients admitted to our hospital over the past 12 years.The purpose of this study was to evaluate the association between CTTP and the survival prognosis of HS patients and develop CTTP as a promising indicator to guide the treatment of HS.

| Cases selection
Present study was conducted in the Department of Critical Care Medicine, the General Hospital of Western Theater Command (The Institutional Review Board of The General Hospital of Western Theater Command, approval no: 2020ky025).The Helsinki Declaration was strictly obeyed in the study to project patients' privacy.The patients were all anonymous in data collection, analysis and report.We confirmed that all analyses followed the relevant guidelines and regulations.We collected the records of HS patients treated in The General old; patients died pre-hospital or in the emergency department.In total, there were 179 HS cases enrolled for this study (Figure 1).

| Basic information
Patient information was collected, including gender, age, smoking history, drinking history, underlying diseases (blood lipid abnormality, hypertension, diabetes, cerebral stroke), and others.

| Clinical index
Clinical data were collected, including onset temperature (the core body temperature measured for the first time after onset), cardiac injury, liver injury, renal injury, rhabdomyolysis, pancreas injury, blood coagulation disorder, gastrointestinal hemorrhage, shock, infection, and other complications.All organ injuries were diagnosed strictly according to the Expert Consensus On the Diagnosis and Treatment of HS in China. 8

| CTTP score
Considering the physical characteristics of Chinese people and the consensus of Chinese experts, CTTP scores were calculated in hours from the onset recorded in current history to the final stabilization of core body temperature (rectal temperature) below 37.7 C (Figure 2).

| Cooling and temperature monitoring
The core body temperature is measured by inserting the flexible rectal thermistor 15 cm from the anal sphincter. 17The cooling is performed by full body immersion in cold water.The core body temperature was measured every 10 minutes, and once dropping below 38.5 C, stop cooling.Temperature monitoring frequency depends on temperature fluctuation, and the monitoring interval can be appropriately extended when the temperature is stable.

| Statistical approach
Data are presented as median and interquartile range [IQR] for nonnormal distribution continuous variables and as counts and percentages for categorical variables.Normality tests were conducted using the Shapiro-Wilk test.Inpatient death was stratified by the tertile of CTTP.Proportions according to tertiles were compared using a Chisquare test.A p-value for trend was measured for inpatient death across tertiles of CTTP using linear regression.Multiple logistic regression models were used to evaluate the associations between CTTP and inpatient death of HS patients.Both non-adjusted and multivariate-adjusted models (variables adjusted for age, gender, and HS type) were applied.All of the analyses were performed with T A B L E 1 Baseline characteristics according to tertiles of CTTP.To verify the stability of the relationship between CTTP and inpatient death, we constructed three models respectively.The specific values of the effect size and 95% confidence interval are shown in Table 4. Model 2 was adjusted for age and gender; model 3 was adjusted for age, gender, history of diabetes, and HS type.In all three models, the effect size and 95% confidence interval were of the same size.
As organ damage was considered as the primary cause of inpatient death in HS patients, we analyzed the relationship between CTTP and organ damage.As shown in

| DISCUSSION
In the current study, our results show a graded increase in the risk of inpatient death as CTTP tertile increased above 18 h in patients with HS, suggesting that CTTP is an important factor in determining inpatient death of HS patients.Moreover, the organ damage was significantly aggravated as CTTP increased above 18 h, indicating that organ damage may be the underlying mechanism by which prolonged CTTP increases the risk of inpatient death.
A hot environment was considered to be the key factor in the pathogenesis of HS. 10 As the body temperature increases, cutaneous vasodilation increases blood flow and initiates thermal sweating, which causes a relative reduction in intravascular volume, dehydration, and salt depletion followed by the reduction of visceral perfusion and organ failure. 10 caused by thermal energy.The difference is that EHS is caused by excessive heat production, while CHS is caused by underdeveloped or damaged heat dissipation function.Nevertheless, the treatment principle of both is the same, which is to cool down and protect organ function as soon as possible. 8However, as the core part of the cooling strategy, the specifically defined end-point temperature for safe cessation of cooling is still absent so far. 18The common practice dictates a target temperature below 39 C (preferably 38.5-38.0C) to lessen the risk of clinical deterioration. 19Recently, Yoon et al. proposed that temperature control should be continued after the rapid cooling of the core body temperature to <38.6 C. 18 They believed that targeted temperature management (<36 C) will help treat severe heatstroke by reducing the chance of development of complications in multiple organs, especially in the central nervous system. 15However, the above-mentioned studies are small sample studies in different regions, and the cooling targets are highly controversial.Some patients will have body temperature rebound after the core temperature drops to the target body temperature, requiring a restart of cooling measures, 8 which is consistent with our clinical observation.Not only that, we have also observed that patients with body temperature rebound seem to have a worse prognosis, but the current attention to this population is woefully inadequate.In this research, we proved that the risk of inpatient death increased 5.31-fold when CTTP exceeds 6 h and 18.75-fold when CTTP exceeds 18 h.Our study suggests that rapid early cooling is of great importance, but it is closely related to the patient's prognosis to prevent and reduce the rebound of body temperature and stabilize the core body temperature below 37.7 C (shorten CTTP) as soon as possible.The reason why the previous temperature control target value was higher than the upper limit of the Lowering the core temperature as soon as possible to prevent further damage to cells and tissues by thermal energy can protect organ function and improve patient prognosis, which has been confirmed by multiple previous studies. 8The underlying reason by which CTTP affected inpatient death of HS may be organ damage.Our results showed that the risk of respiratory failure, shock, rhabdomyolysis, and renal damage was significantly higher when CTTP exceeds 18 h.Primary brain injury and secondary multiple organ dysfunction are the major causes of death and disability in HS patients. 18,20The respiratory system is often damaged in HS, it was reported that more than 60% of patients treated by mechanical ventilation, and more than 10% developed acute respiratory distress syndrome. 8,21Acute respiratory distress syndrome is an important cause of death in severe patients. 22Besides, thermal load can also cause a hyperdynamic left ventricle. 23For the majority of HS patients who experience distributive/hypovolemic shock, it is related to low systemic vascular resistance and high cardiac index. 24However, a minority of patients develop cardiogenic shock, with a reduced cardiac index and increased systemic vascular resistance, particularly those with pre-existing cardiovascular disease. 24,25ose with cardiogenic shock have an increased mortality rate. 26Rhabdomyolysis is another common complication of HS, especially EHS. 18pid skeletal muscle breakdown results in the subsequent release of intracellular muscle components into the systemic circulation, thus leading to multiple organ injury and failure. 279][30] Consistent with rhabdomyolysis, the incidence of acute renal damage was found to be higher in EHS patients. 31,32In addition to rhabdomyolysis, HS-related renal damage can be caused by direct heat stress, hypovolemia, disseminated intravascular coagulation, inflammatory reactions, and so on. 33Each damaged organ will affect In summary, longer CTTP means a higher risk of inpatient death, and shortening CTTP may mean lowering the end-point temperature.
We emphasize that the treatment of HS should not only focus on early and rapid cooling but also stabilize the core temperature as soon as possible (shorten CTTP) to prevent further damage caused by temperature rebound.If CTTP exceeds 18 h, more experience may need to be invested in focusing on organ damage, especially respiratory failure, shock, rhabdomyolysis, and renal damage.
Our study is a retrospective study and the lack of prospective control of CTTP limited our ability to verify the prognostic effect of CTTP on HS.In addition, the included subjects are all from southwest China, so our conclusions cannot be generalized to other groups.
Hospital of Western Theater Command, The Chengdu Fifth People's Hospital, and The People's Hospital of Santai County for the period between 2010 and 2021.All patients were admitted through the emergency department and underwent standard cooling and body temperature monitoring after admission.Inclusion criteria: the diagnosis standard defined in Expert Consensus on Standardized Diagnosis and Treatment for Heat Stroke 8 ; aged over 18 years old.Exclusion criteria: cases misdiagnosed as HS; patients with incomplete information; patients aged under 18 years normal core temperature was related to the lack of precise temperature control equipment and dynamic real-time temperature monitoring equipment, which may lead to serious consequences caused by hypothermia.But at present, the automatic ice blanket machine that can dynamically monitor the core temperature in real time and accurately control the temperature according to the preset temperature range has been widely used in clinical practice.It follows that it is necessary to carry out prospective clinical research to verify whether further lowering of the cooling target (such as setting it at 37.7 C) can reduce the number of patients who need to restart the cooling measures, shorten the recovery time of organ function and improve the prognosis of patients.We emphasize not only the need to focus on cooling down as soon as possible, but also to stabilize the core temperature as soon as possible (shorten CTTP) to prevent further damage caused by body temperature rebound.Perhaps just like the treatment of hypertension, early research mainly emphasized lowering blood pressure, while later research found that preventing repeated fluctuations in blood pressure is equally important.
others and may eventually lead to secondary multiple organ dysfunction and inpatient death.Deservedly, patients in the highest CTTP tertile (>18 h) in our study had more damaged organs and longer inpatient days.The early manifestations of brain injury caused by HS are mainly disturbance of consciousness, while the long-term manifestations are mainly cognitive impairment, both of which lack specific test indexes and imaging indexes.8In addition, computed tomography (CT), (magnetic resonance imaging), electroencephalogram, and other examinations are mainly used to differentiate and diagnose patients suspected of heatstroke from diseases that can cause consciousness disorders such as intracranial infections, stroke, and epilepsy.This study is a retrospective study, and it is impossible to evaluate the patients' consciousness disorder and cognitive function, so further prospective study is needed.Beyond that, vital signs such as heart rate, blood pressure, and oxygen saturation in patients with HS are greatly affected by treatment factors such as cooling measures, volume resuscitation therapy, ventilator-assisted breathing, sedative and analgesic drugs, and vasoactive drugs.Therefore, the patient's vital signs fluctuate greatly during hospitalization and cannot accurately reflect changes in the condition.Therefore, vital signs data were not included in data collection and statistical analysis, which may be a limitation of this study.

Table 1 .
Those in the highest tertile of CTTP were significantly more likely to have a history of diabetes.While, there were no significant differences in age, gender, HS type, onset temperature, the status of smoking and drinking, and the histories of hypertension and hyperlipemia.Clinical characteristics according to tertiles of CTTP., ( p for trend 0.0003) and renal damage: 70.49versus 33.93, respectively, ( p for trend 0.0002).What's more, compared with those in the lowest and median CTTP tertiles, subjects in the highest tertile had the higher rates of inpatient death: 37.70% versus 16.39% versus 3.57% ( p for trend <0.0001).

Table 5
The model 2 were adjusted for age and gender; the model 3 were adjusted for age, gender, HS type and the history of diabetes.Abbreviation: CTTP, controlling time for core temperature to physiological level.The relationship between CTTP and organ damage.
HS is divided into EHS and classical heat stroke (CHS), both of which are fundamentally caused by organ damageT A B L E 4The relationship between CTTP and inpatient death in different models.T A B L E 5Note: All adjusted for age and gender.Abbreviation: CTTP, controlling time for core temperature to physiological level.