Target temperature management and therapeutic hypothermia in sever neuroprotection for traumatic brain injury: Clinic value and effect on oxidative stress

Abstract

This study is to explore the application of target temperature management and therapeutic hypothermia in the treatment of neuroprotection patients with severe traumatic brain injury and its effect on oxidative stress. From February 2019 to April 2021, 120 patients with severe traumatic brain injury cured were selected in our hospital. The patients were randomly divided into control and experimental groups. The control group accepted mild hypothermia therapy. The experimental group took targeted temperature management and mild hypothermia therapy. This study compared the prognosis, National Institute of Health Stroke Scale (NIHSS) score, oxidative stress level, brain function index and the incidence of complications in different groups. The prognosis of the experimental group was better (P < .05). After treatment, the NIHSS score lessened. The NIHSS score of the experimental group was lower at 3 and 6 weeks after treatment (P < .05). Following treatment, the level of superoxide dismutase-1 in the experimental group was higher and the level of malondialdehyde was lower (P < .05). After treatment, the brain function indexes of patients lessened. The experimental group’s myelin basic protein, neuron specific enolase and glial fibrillary acidic protein indexes were lower (P < .05). The incidences of pendant pneumonia, atelectasis, venous thrombosis of extremities and ventricular arrhythmias in the experimental group were remarkably lower (P < .05). Targeted temperature management and mild hypothermia treatment can improve neurological function, maintain brain cell function, and reduce stress-reactions risk. The incidence of complications during hospitalization was reduced.

1. Introduction

Severe traumatic brain injury (STBI) mainly refers to the serious brain injury caused by external direct violence. The main evaluation criteria are Glasgow Coma Scale (GCS) ≤ 8, coma and lasting more than 6 hours after injury.^[1] Medical technology has been developed greatly in recent years, and the mortality and disability rates have lessened remarkably. However, due to the high incidence of craniocerebral injury and the complexity and variability of the condition, the number of deaths and disabilities is still high.^[2] According to epidemiological data, traumatic brain injury (TBI) ranks second among all causes of trauma, after extremity trauma. TBI ranks first among the leading causes of death and disability for people under 45 years of age.^[3] Young and middle-aged people are the core members of the family who create economic income and the backbone of social and economic development. On the contrary, it brings a heavy burden on the family economy and society. Furthermore, craniocerebral injury has become a major risk factor that threatens human health and social progress. According to GCS score and coma time, craniocerebral injury can be divided into mild (GCS score 13–15, coma < 20 minutes after craniocerebral injury), moderate (GCS score 9–12, coma time more than 20 minutes but < 6 hours after injury) and severe (GCS score ≤ 8, coma time lasting more than 6 hours).^[4] The incidence of severe injury accounts for about 20% of all craniocerebral injuries. STBI has brought great harm to the family and society because of its mortality rate of 30%, 60%, poor prognosis and huge cost.^[5] How to reduce the mortality of the disease and enhance the prognosis has become a hot and difficult issue in the medical field.

Since the 1980s, medical experts in various countries have begun to use mild hypothermia in the treatment of craniocerebral injury. From the clinical definition, hypothermia is currently divided into the following 4 degrees internationally: Mild hypothermia is 33°C to 35°C; Moderate hypothermia is 28°C to 32°C; Profound hypothermia is 17°C to 27°C; Ultraprofound hypothermia is below 16°C.^[6] The experts from various countries call mild and moderate hypothermia as mild hypothermia. Some animal control studies found that the curative effect of mild hypothermia at 30°C was better than that at 33°C. However, it is found that hypothermia below 32°C can easily lead to lower blood pressure and atrial fibrillation in practical application. Therefore, mild hypothermia of 32° to 35°C is generally selected to assist the treatment of patients with STBI in more developed countries.^[7] Targeted temperature management (TTM) is a physiotherapy that aims to reduce temperature, protect brain tissue and improve the prognosis of patients. Previous studies have concluded that the application of targeted temperature management in STBI has the following advantages: reducing brain oxygen consumption and energy consumption, making brain tissue dormant, inhibiting a variety of pathophysiological reactions, protecting blood-brain barrier, alleviating brain edema, reducing intracranial pressure, and avoiding secondary brain injury.^[8,9] In the past, there are many reports on the application of both alone in patients with STBI. But there are few reports on the combination of them in STBI.^[10] On the basis of this, this study focused on the effects and clinical value of targeted temperature management and mild hypothermia therapy on neuroprotection and oxidative stress in patients with STBI.

2. Methods

2.1. General information

A total of 120 patients with STBI, who were treated in our hospital from February 2019 to April 2021, were selected in the present study. The patients were randomly divided into control and experimental groups. The control group accepted mild hypothermia therapy. The experimental group accepted targeted temperature management and mild hypothermia therapy. In the control group, the age ranged from 37 to 67 years old with an average of 45.91 ± 3.53 years, including 34 males and 26 females. The GCS score was 3 to 7 with an average of (5.13 ± 1.31). Types of injury included 8 cases of intracranial hematoma, 45 cases of brain contusion and laceration and 7 cases of other injuries. The time from injury to admission was 1 to 3.1 hour with an average of 2.12 ± 0.22 hours. In the experimental group, the age ranged from 35 to 70 years old with an average age of 42.75 ± 3.53 years. The experimental group included 31 males and 29 females with a GCS score of 3 to 7 and an average of 5.53 ± 1.42 points. The type of injury included 10 cases of intracranial hematoma, 43 cases of brain contusion and laceration and 7 cases of others. The time from injury to admission was 1 to 3.5 hours with an average of 2.53 ± 0.21 hours. There exhibited no statistical significance in the general data. This study was permitted by the medical ethics association of our hospital and all patients signed informed consent.

Inclusion criteria: All patients were admitted to hospital within 12 hours after injury; The diagnosis was confirmed by head computerized tomography or magnetic resonance imaging scan and there was no serious combined injury of other organs; No cerebral hemorrhage, cerebral infarction and traumatic brain injury, no major diseases of cardiopulmonary system, liver and kidney system and hematopoietic system were found in the past; There was no history of infection before injury; According to the GCS coma scoring method: 3 ≤ GCS < 8.

Exclusion criteria: Severe combined injury or organ injury, which was life-threatening; GCS limb motor score = 6, or unable to assess consciousness with severe alcoholism; Complicated with severe systemic diseases, such as severe heart disease, hepatorenal insufficiency; Systolic blood pressure < 90 mm Hg or blood oxygen saturation < 93% after resuscitation; Platelet count < 50000/mm³; and Pregnant or lactating women.

2.2. Treatment methods

The control group received mild hypothermia treatment. Nourishment of cerebral nerves, acid suppression and rehydration and reduction of intracranial pressure and antiinfection were given. All patients received mild hypothermia treatment within 12 hours after injury or surgery. The body uses cooling blanket and head ice cap to cool down, and the hibernation mixture uses chlorpromazine 100mg + promethazine 100mg + atraconine 200mg + normal saline 500mL intravenous drip to control the temperature at 32°C to 35°C (the whole-body temperature). Whether to add other physical cooling measures such as placing ice bags in armpits according to the cooling effect. After hypothermia treatment, the patient’s response to stinging pain became remarkably slower, pupils dilated and gradually narrowed, response to light became slower, respiratory rate lessened, deep reflexes were weakened or disappeared, and mild hypothermia was maintained for 5 days. During the treatment of mild hypothermia, the patient’s vital signs, heart rhythm, electrolytes, coagulation function and bleeding should be observed. If chills occur, diazepam, chlorpromazine or magnesium sulfate can be given for intravenous drip.

The experimental group received targeted temperature management and mild hypothermia therapy, mild hypothermia therapy was the same as the control group. The targeted temperature management was that ice blanket and mild hypothermia therapy apparatus were used to cool the whole body, micro pump into hibernation mixture, pump speed 6 mL/hour. The whole-body temperature of the patients was controlled at 32°C to 35°C for 5 days. After 5 days, the patient underwent natural rewarming method. The hibernating mixture, ice blanket and mild hypothermia therapeutic apparatus were stopped in turn. The natural rewarming time was 24 hours.

2.3. Observation index

2.3.1. Prognosis.

The patients were followed up by telephone at 6 months after discharge. The therapeutic effect was evaluated by Glasgow Outcome Scale,^[11] including grade I (death), grade II (vegetative state), grade III (severe disability requiring care), grade IV (mild disability, independent life) and grade V (good recovery, normal life and work). Among them, grade I and grade II were judged as poor curative effect. Grade III was judged as moderate, and grade IV and V were judged as good. The moderate curative effect and good curative effect were regarded as good prognosis. The proportion of patients with good prognosis in the group was calculated and compared with each other.

2.3.2. National Institute of Health Stroke Scale (NIHSS) scoring.

Neurological function evaluation: the NIHSS scale was used to evaluate the language ability, dysarthria, upper limb movement, and lower limb movement and so on.^[12]

2.3.3. Laboratory index.

Detection of laboratory indexes: 5mL venous blood was taken before and after treatment and centrifuged (3000 r/minute) 10 minutes. The serum was isolated and stored in the refrigerator at -80°C to be tested. The functional indexes of brain cells such as serum myelin basic protein (MBP), neuron specific enolase (NSE) and glial fibrillary acidic protein (GFAP) were detested by enzyme-linked immunosorbent assay. The kit was harvested from Shanghai Hengyuan biochemical Reagent Co., Ltd. Oxidative stress index included superoxide dismutase-1 and malondialdehyde, determined by colorimetry. The kit was harvested from Shanghai Saimo Biotechnology Development Co., Ltd.

2.3.4. Incidence of complications.

The incidence of complications during hospitalization was counted.

2.4. Statistical analysis

The data were processed by SPSS 21.0 statistical software. First, the measurement data are examined by Shapiro–Wilk normality test. The data were presented by the mean ± standard deviation, when the normal variance is uniform, 2 independent sample t-tests were used. If the normal variance was not uniform, t test was selected. The counting data were expressed by frequency, rate or percentage (%). The results were analyzed by χ² test, continuous correction test or Fisher exact probability test. P < .05 demonstrated that the difference exhibits statistically remarkable.

3. Results

3.1. Comparison of prognosis

The experimental group had a good prognosis in 36 cases, disability in 20 cases, vegetative survival in 1 case and death in 3 cases. In the control group, the prognosis was good in 18 cases, disability in 25 cases, vegetative survival in 7 cases and death in 10 cases (Fig. 1). It was observed that the prognosis of the experimental group was better, when compared to the control group (P < .05).

Figure 1.

Comparison of prognosis of 2 groups of patients.

3.2. Comparison of the NIHSS score

The NIHSS score in the experimental group and control group was not significantly different before treatment (P > .05). Compared with before treatment, there was significant difference after treatment (all P < .05). Furthermore, the NIHSS score was significantly lower in the experimental group than in the control group at 3 and 6 weeks after treatment (all P < .05) (Table 1).

Table 1.

NIHSS scores between the 2 groups.

Group	N	Before treatment	Treatment for 3 w	Treatment for 6 w	F	P value
The control group	60	28.29 ± 3.42	27.19 ± 2.11	26.93 ± 2.42	4.263	< .01
The experimental group	60	28.59 ± 3.11	25.14 ± 2.31	22.85 ± 3.31	57.88	< .01
t		0.502	5.075	7.707
P value		> .05	< .01	< .01

Data are presented as mean ± standard deviation.

NIHSS = National Institute of Health Stroke Scale.

3.3. Comparison of oxidative stress level

The serum level of oxidative stress in the experimental group and control group was not significantly different before treatment (P > .05). After treatment, the serum superoxide dismutase-1 level was significantly higher in the experimental group than in the control group, but the serum malondialdehyde level was significantly lower in the experimental group than in the control group (all P < .01) (Table 2).

Table 2.

Oxidative stress levels between the 2 groups.

Group	N	SOD-1 (μg/L)		MDA (μmol/L)
		Before treatment	After treatment	Before treatment	After treatment
The control group	60	260.29 ± 30.42	253.55 ± 32.21	4.98 ± 0.42	3.79 ± 0.92
The experimental group	60	260.93 ± 30.18	321.82 ± 23.53	4.91 ± 0.45	3.01 ± 0.34
t		0.115	13.257	0.88	6.16
P value		> .05	< .01	> .05	< .01

Data are presented as mean ± standard deviation.

MDA = malondialdehyde, SOD-1 = superoxide dismutase-1.

3.4. Comparison of brain function indexes

The brain function indexes (MBP, NSE, and GFAP) in the experimental group and control group was not significantly different before treatment (P > .05). After treatment, the brain function indexes were significantly lower in the experimental group than that in the control group (all P < .01) (Table 3).

Table 3.

The brain function indexes between the 2 groups.

Group	N	MBP (ng/mL)		NSE (ng/mL)		GFAP (pg/mL)
		Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
The control group	60	65.19 ± 3.31	34.19 ± 4.23	9.49 ± 0.53	3.48 ± 0.33	21.83 ± 3.54	11.82 ± 1.33
The experimental group	60	65.49 ± 3.43	22.95 ± 2.11	9.48 ± 0.51	1.94 ± 0.34	21.49 ± 3.42	7.39 ± 0.53
t		0.487	18.418	0.105	25.176	0.535	23.967
P value		> .05	< .01	> .05	< .01	> .05	< .01

Data are presented as mean ± standard deviation.

GFAP = glial fibrillary acidic protein, MBP = myelin basic protein, NSE = neuron specific enolase.

3.5. Comparison of the incidence of complications

The incidences of gravitactic pneumonia, atelectasis, venous thrombosis of extremities and ventricular arrhythmias in the experimental group were remarkably lower than those in the control group (P < .05) (Fig. 2).

Figure 2.

Incidence of complications in 2 groups.

4. Discussion

TBI is a neurosurgical disease often encountered in clinic. The number of patients with TBI such as traffic accident injury, violent blow injury and fall injury is also gradually increasing. The fatality rate and disability rate have remained high. Mild or severe TBI will bring heavy burden to patients and their families in mental, emotional and cognitive aspects, which makes families and society suffer huge losses. So far, the prevention, diagnosis and rehabilitation of TBI have been the focal spot and difficulty in the field of neurosurgery all over the world. According to the global burden of disease study, the mixed standardized mortality ratio of TBI survivors is 2.18.^[13] A summary analysis of 16 case-control studies showed that the combined odds ratio of advanced dementia after simple TBI with disturbance of consciousness was 1.58. The patients who have developed TBI after the age of 55 will have a 43% augmented risk of developing Parkinson disease over the next 5 to 7 years.^[14] posttraumatic epilepsy is also recognized as a complication of TBI. Epilepsy rates after mild traumatic brain injury increase 1.5 times and those after severe traumatic brain injury increase 17 times. The 30-year cumulative risk of posttraumatic epilepsy in mild TBI is 2.1%, and that of severe TBI is 16.7%. In the past 150 years, the case mortality rate of severe TBI has been reduced by more than 50%. However, in the last 30 years, the decline in mortality of severe TBI patients seems to have stagnated.^[15,16] Therefore, clinicians need to further improve and improve diagnosis and treatment measures to reduce the mortality of TBI patients and enhance the prognosis of TBI survivors.

In the middle and late 20th century, foreign neurologists used ice cubes and cryogenic beds and infusion of medicine to make patients hibernate and reduce their temperature to 32°C to 35°C to slow down the development of the disease and strive for treatment time.^[17] It has been recorded those dozens of hospitals in the world have used this kind of treatment like hypothermic hibernation for more than 100 patients with STBI.^[18,19] Most of the doctors involved in the study hold that lowering the temperature of patients can promote the recovery of severe TBI. Mild hypothermia therapy inhibits the accumulation of lactic acid in brain cells by reducing oxygen consumption in brain cells. Most scholars believe that the rapid increase of lactic acid in extracellular fluid after traumatic brain injury is a vital reason for the destruction and loss of function of mitochondria caused by accidental stress, which further causes pyruvate to lose its ability to form tricarboxylic acid cycle and convert into lactic acid.^[20,21] Foreign scholars treated 56 patients with STBI with mild hypothermia, keeping the temperature of the convex cortex of the brain tissue at 28°C to 30°C and the measured rectal temperature at 33°C to 34°C. Through the treatment, it was found that mild hypothermia was helpful to the early treatment of STBI patients and could reduce the symptoms of STBI patients.^[22] The experimental study of Chinese scholars shows that 30°C to 34°C hypothermia can remarkably protect the brain tissue of TBI animals in the experiment.^[23] The mortality rate of TBI animals without hypothermia treatment was 37.5%. The mortality rate of animals treated with 30°C hypothermia intervention was 9.1%. The intervention treatment of cooling immediately within 10 minutes after injury (30°C–33°C) could remarkably reduce the grade of limb dyskinesia in TBI animals. Among the treatments at different temperatures, the treatment group of maintaining 30°C hypothermia had the best effect.^[24] TTM belongs to physiotherapy, which aims to lower the temperature, protect brain tissue and improve the prognosis of patients. TTM can effectively reduce the damage of brain tissue cells caused by toxic substances produced by human body, remarkably reduce the synthesis and release of glutamate after TBI.^[25–28] At the same time, TTM can also effectively reduce the diffuse axonal injury of brain tissue. Diffuse axonal injury is the main pathophysiological basis of persistent coma and death after TBI. It is the interruption of the reticular connection structure between the cortex and subcortex, so that the conduction signal of the brainstem reticular ascending activation system is interrupted in the nucleus of the thalamus, resulting in the coma and coma of patients cannot wake up for a long time.^[29,30] TTM can reduce the damage of intracranial blood vessels and blood-brain barrier caused by inflammatory substances. The rapid production of inflammatory factors promotes the aggregation of inflammatory cells, which strengthens the adhesion function of monocytes and neutrophils. Furthermore, it leads to the injury of intracranial vascular inner wall and blood-brain barrier, which makes the TBI more serious.^[31–33]

Our analysis has shown that targeted temperature management and mild hypothermia therapy can decrease craniocerebral excitability, reduce tissue oxygen consumption, relieve brain edema and inhibit stress response to some extent. It can also reduce the degree of neurological impairment, improve brain trauma, protect neurons and reduce brain tissue damage.^[34,35] The combination of the 2 can complement each other and can further alleviate the patient’s condition.

MBP, NSE and GFAP are important markers of brain cell function damage.^[36] MBP is a strongly basic protein, which exists in myelin sheath and white matter. MBP is mainly secreted by hematopoietic cells and oligodendrocytes and its secretory ability decreases with age, so it is rarely expressed in adult brain.^[37] NSE is a specific protein secreted in nerve cells and is an important marker of nerve cell injury. GFAP is a filamentous protein that makes up the cytoskeleton of astrocytes and attaches importance to maintaining the morphology and function of astrocytes.^[38,39] After the occurrence of STBI, the blood-brain barrier will be seriously damaged, myelin, neurons, astrocytes disintegrate, MBP, NSE, GFAP are released into the blood circulation. The data show that the increase of serum MBP, NSE and GFAP levels is an important reflection of brain cell function damage. The level is positively correlated with the degree of brain cell function damage.^[40,41] The current data has also shown that the combined treatment scheme has an inhibitory effect on the oxidative stress response. The improvement effect of neurological deficits in the experimental group is better. And the overall curative effect is better.

There are several limitations of this study. First, this is an observational study with and arbitrary group formation method, further randomized controlled studies are needed to validate our findings. Second, the sample size was small, with only 120 participating patients; studies with a large sample size are necessary to confirm our results. Third, this study is based on single-center study, Chinese patients enrolled only, which may all affect the generalization of the outcomes. Future studies will have to resolve these issues for better outcomes.

To sum up, targeted temperature management and mild hypothermia treatment can improve neurological function, maintain brain cell function, and reduce the risk of stress reactions. The incidence of complications during hospitalization was reduced.

Author contributions

Conceptualization: Cheng Huang.

Data curation: Cheng Huang.

Formal analysis: Cheng Huang.

Funding acquisition: Cheng Huang.

Investigation: Cheng Huang.

Methodology: Yechao Wang.

Project administration: Yechao Wang.

Resources: Yechao Wang.

Software: Yechao Wang.

Supervision: Yechao Wang.

Validation: Renfu Tian.

Visualization: Renfu Tian.

Writing – original draft: Xi Yang.

Writing – review & editing: Xi Yang.