Protective Effect of Moderate Hypothermia on Severe Traumatic Brain Injury in Children

Abstract

This study investigated the safety and neuroprotective effect of moderate hypothermia in children with severe traumatic brain injury (TBI). Twenty-two children suffering from TBI were randomly divided into groups treated with moderate hypothermia (intracranial temperature of 34.5 ± 0.2°C, maintained for 72 h, n = 12) or normothermia (intracranial temperature of 38.0 ± 0.5, n = 10). The cerebrospinal fluid levels of neuron-specific enolase (NSE), S-100, brain-specific creatine kinase (CK-BB), and intracranial pressure (ICP) levels were used to assess the protective effects. The variations in pH and electrolyte balance were also examined. The results indicated that the peak ICP level in the normothermia group (26.30 ± 1.08 mm Hg) was reached 48 h after TBI. The ICP level in the moderate hypothermia group was lower than in the control group at every time point examined (p < 0.01). Furthermore, at 24, 48, and 72 h, the NSE, S-100, and CK-BB levels in the moderate hypothermia group were also lower than that of the normothermia group (p < 0.01). In the moderate hypothermia group, the pH and electrolyte balance at the end of the monitoring period were normal, but the heart rates were lower (p < 0.05). There were a total of three deaths (13.6%) in this study: one in the moderate hypothermia group (8.3%) and two in the normothermia group (20%). In conclusion, moderate hypothermia provided neuronal protection for children with severe TBI, and maintaining the intracranial temperature at 34.5°C for 72 h was safe in this clinical setting.

Introduction

C hildhood traumatic brain injury (TBI) is a world-wide public health concern, which can lead to permanent disability and death in children. The protection of brain function is a research topic of great interest, and numerous studies have shown that moderate hypothermia provides some protection against TBI in the adult (Clifton et al., 1993; Marion et al., 1993, 1997; Shiozaki et al., 1993), particularly through selective hypothermia of the brain (Liu et al., 2006; Qiu et al., 2006). Previous work also indicates that hypothermia is safe and possesses clear therapeutic potential in children after hypoxia-induced ischemic encephalopathic brain injuries (Compagnoni et al., 2002; Gunn et al., 1998a,b; Simbruner et al., 1999). However, there are few reports examining whether moderate hypothermia can provide the same therapeutic benefits in children after TBI (Adelson et al., 2005; Biswas et al., 2002; Hutchison et al., 2008). The primary goal of this study was to investigate the safety and neuroprotection of moderate hypothermia in children with severe TBI.

Methods

Patients

Twenty-two children with severe TBI were admitted for treatment at the Department of Pediatric Surgery in the Children's Hospital of Fudan University (between January 2006 and August 2007). Children of both genders (6–108 months old) with a Glasgow Coma Scale (GCS) score of 8 or less were included. All patients underwent a computed tomographic scan within 8 h of the brain injury; children with other serious accompanying injuries were not included. Furthermore, children with a previous history of neurological conditions and/or chronic disease states were also excluded from this study. The causes of the TBIs included the following: traffic accidents, n = 12; tumbles and/or falls, n = 7; game-related accidents, n = 3. The patients were divided randomly into a moderate hypothermia group (HYPO group; n = 12) and a normothermia group (NORM group; n = 10) on the basis of arrival date (odd number = HYPO; even number = NORM).

The age range in the HYPO group was ∼8–96 months, and the average GCS score was 6.4 ± 1.8. In addition, the average time taken before the initiation of treatment was 7.2 ± 1.4 h after the injury.

The age range in the NORM group was ∼6–108 months, and the average GCS score was 6.5 ± 1.7. The average time taken before the initiation of treatment was 6.8 ± 1.2 h after the injury (all of the above data exhibited no statistically significant difference).

All of the patients had an intracranial pressure (ICP) monitor with similar therapeutic regimens. Fourteen patients underwent identical operative procedures for clearance of intracranial hematomas and bone flap removal (eight in the HYPO group and six in the NORM group).

Hypothermia implementation

As opposed to systemic hypothermia (a reduction in core body temperature), we adopted a localized hypothermic method to selectively reduce the temperature of the head region. This was accomplished by placing a cooling cap on the patients' head (Blanketrol II; Cincinnati Sub-Zero Products, Inc., Cincinnati, OH). The intracranial temperature in this group of patients was 34.5 ± 0.2°C over 72 h as determined by computer-linked indwelling catheter.

The normal temperature group did not undergo the moderate hypothermia treatment, and the intracranial temperatures were 37.5–38.5°C (mean, 38.0 ± 0.5°C).

Examination indices

Heart rate, arterial hemoglobin saturation (SaO₂), and blood pressure were monitored and recorded for all patients.

Plasma pH levels and electrolyte concentrations were assessed at the time of treatment and 8, 24, 48, and 72 h afterwards.

Patients also had an ICP monitor placed intraoperatively during surgical procedures or in the intensive care unit (ICU) if there was no surgical intervention. Devices (CAMINO MPM-1 ICP monitor and CAMINO 110 transducer; CAMINO Laboratories, San Diego, CA) recorded the ICP values (mm Hg) at the time of treatment and 8, 12, 24, 48, and 72 h afterwards. Cerebrospinal fluid (CSF) was collected via intracerebroventricular catheter for all patients at the time of treatment and 8, 24, 48, and 72 h afterwards. These CSF samples were stored at −70°C. One week later, the NSE, S-100, and CK-BB concentrations in the CSF were measured.

Statistical analysis

Continuous data are expressed as the mean ± standard deviation. The patient indices, ICP, and CSF biochemical analyses data were compared by t-tests. Mortality was compared using Fisher's exact test. Data were analyzed using SAS 9.0 (SAS Institute Inc., Cary, NC), and a p value of <0.05 was considered statistically significant.

Results

Safety of hypothermia treatment

There were a total of three deaths (13.6%), which included one in the HYPO group (8.3%) and two in the control group (20%). The reason for these mortalities appeared to be from uncontrollable ICP elevations due to severe contusions. These patients were maximally treated both surgically (intracranial hematomas and bone flap removal) and pharmacologically (mannitol and barbital) prior to death. There was no significant difference in mortality between the HYPO and NORM groups (p = 0.5714). The long-term clinical outcome for the remaining 19 patients was only available for five of the patients who were transferred to a neuropediatric department. The others were lost to follow-up examination.

All of the patients in the HYPO group were mechanically ventilated, and the average ventilation time was 86.3 ± 23.6 h. There were eight patients in the NORM group who received routine machine assistance to ventilate, and the average ventilation time was 64.8 ± 48.7 h. Again, there was no difference between the HYPO and NORM groups.

In the HYPO group, the patients' heart rate was reduced at the 24, 48, and 72 h time points. Thus, compared with the NORM group, these differences were statistically significant (all p < 0.05; Table 1). In addition, the patients' mean blood pressure decreased in the HYPO group, but there was no statistical difference between the two groups. Furthermore, the pH and BE levels in the HYPO group were significantly different from the NORM group at 8, 24, 48, and 72 h (all p < 0.05; Table 1), with the exception of the pH values at 72 h. The electrolyte level for Na⁺ was significantly different at 0 and 8 h (both p < 0.05), and K⁺ was significantly different at 8 and 24 h (both p < 0.05; Table 1).

Table 1.

Summary of Patient Indices, Intracranial Pressure, and Cerebrospinal Fluid Biochemical Markers

	HYPO (n = 12)	NORM (n = 10)	p values		HYPO (n = 12)	NORM (n = 10)	p values
Heart rate (beats/min)				Na⁺(mmol/L)
0 h	154.08 ± 12.09	150.00 ± 13.31	0.4599	0 h	145.00 ± 8.68	135.30 ± 7.20	0.0107*
8 h	158.42 ± 23.94	159.90 ± 19.03	0.8757	8 h	139.33 ± 4.92	144.10 ± 4.07	0.0240*
24 h	109.92 ± 19.48	153.70 ± 23.88	0.0001*	24 h	142.25 ± 8.14	138.50 ± 4.74	0.2139
48 h	100.00 ± 13.93	148.70 ± 7.33	<0.0001*	48 h	140.50 ± 5.27	144.60 ± 8.38	0.1772
72 h	110.25 ± 13.90	145.20 ± 10.20	<0.0001*	72 h	138.25 ± 5.69	142.40 ± 6.38	0.1225
Systolic BP (mm Hg)				K⁺(mmol/L)
0 h	62.75 ± 6.84	58.80 ± 5.55	0.1582	0 h	4.17 ± 0.38	4.11 ± 0.88	0.8531
8 h	57.33 ± 5.96	62.20 ± 11.18	0.2066	8 h	4.33 ± 0.39	3.88 ± 0.48	0.0271*
24 h	48.92 ± 10.98	59.70 ± 5.48	0.0084*	24 h	4.09 ± 0.37	4.52 ± 0.36	0.0120*
48 h	51.17 ± 7.65	58.80 ± 10.56	0.0635	48 h	4.40 ± 0.55	4.06 ± 0.71	0.2199
72 h	48.25 ± 9.36	55.80 ± 5.55	0.0368*	72 h	4.25 ± 0.77	4.26 ± 0.40	0.9708
Diastolic BP (mm Hg)				ICP (mm Hg)
0 h	36.17 ± 8.04	38.50 ± 7.85	0.5013	0 h	18.34 ± 1.89	19.59 ± 1.55	0.1104
8 h	38.67 ± 7.90	40.40 ± 9.92	0.6530	8 h	14.72 ± 1.07	20.32 ± 1.08	<0.0001*
24 h	36.00 ± 9.30	37.40 ± 10.07	0.7384	24 h	12.45 ± 1.03	25.62 ± 1.55	<0.0001*
48 h	36.17 ± 6.25	42.20 ± 10.35	0.1069	48 h	10.08 ± 1.77	26.30 ± 1.08	<0.0001*
72 h	38.00 ± 7.90	37.10 ± 6.37	0.7748	72 h	8.39 ± 1.07	13.33 ± 1.17	<0.0001*
Mean BP (mm Hg)				NSE (μg/L)
0 h	49.46 ± 6.46	48.65 ± 5.57	0.7594	8 h	3.34 ± 0.67	3.22 ± 0.29	0.5751
8 h	48.00 ± 6.23	51.30 ± 8.07	0.2919	24 h	3.57 ± 0.56	6.44 ± 1.56	0.0002*
24 h	42.46 ± 8.46	48.55 ± 5.92	0.0698	48 h	4.58 ± 1.24	8.36 ± 0.98	<0.0001*
48 h	43.67 ± 6.68	50.50 ± 9.84	0.0673	72 h	3.24 ± 0.66	4.23 ± 0.34	0.0004*
72 h	43.13 ± 8.22	46.45 ± 4.75	0.2720	S-100 (μg/L)
pH				8 h	0.46 ± 0.33	0.98 ± 0.25	0.0006*
0 h	7.29 ± 0.10	7.28 ± 0.06	0.8705	24 h	0.58 ± 0.26	1.54 ± 0.87	0.0068*
8 h	7.23 ± 0.05	7.36 ± 0.08	0.0001*	48 h	0.64 ± 0.23	1.98 ± 0.65	<0.0001*
24 h	7.28 ± 0.08	7.42 ± 0.05	0.0001*	72 h	0.65 ± 0.25	0.84 ± 0.27	0.1045
48 h	7.30 ± 0.03	7.37 ± 0.08	0.0220*	CK-BB (IU/L)
72 h	7.40 ± 0.05	7.34 ± 0.05	0.0163*	8 h	33.42 ± 8.45	36.10 ± 5.32	0.3951
BE (mmol/L)				24 h	27.92 ± 4.32	58.50 ± 10.70	<0.0001*
0 h	−5.68 ± 0.39	−6.07 ± 1.13	0.3232	48 h	27.42 ± 12.03	88.10 ± 13.61	<0.0001*
8 h	−6.01 ± 0.81	−2.38 ± 0.66	<0.0001*	72 h	25.58 ± 9.67	48.30 ± 9.55	<0.0001*
24 h	−5.39 ± 0.77	−1.20 ± 0.52	<0.0001*
48 h	−4.78 ± 0.54	0.81 ± 0.52	<0.0001*
72 h	−2.11 ± 0.85	0.69 ± 0.77	<0.0001*

Statistical significance, p < 0.05.

Data are presented as mean ± standard deviation and were analyzed by t-test.

HYPO, hypothermic group; NORM, normothermic group; BP, blood pressure; BE, buffer excess; ICP, intracranial pressure; NSE, neuron-specific enolase; CK-BB, brain-specific creatine kinase.

Intracranial pressure

Children treated with hypothermia tended to have a lower ICP compared with children treated with NORM (Table 1). At the beginning of the treatment period, the ICP in both groups was elevated. Although, the ICP reached a peak value of 26.30 ± 1.08 mm Hg in the NORM group at 48 h; in the HYPO group, the average ICP values gradually decreased (Table 1). These data were statistically different at the time points of 8, 24, 48, and 72 h (all p < 0.05; Table 1).

Cerebrospinal fluid biochemical markers

At 24, 48, and 72 h after treatment, the NSE levels were lower in the HYPO group compared with that of the NORM group (all p < 0.05; Table 1). In addition, the HYPO group exhibited significantly lower levels of S-100 at the time points of 8, 24, and 48 h (all p < 0.01; Table 1), and lower CK-BB values at 24, 48, and 72 h (all p < 0.0001; Table 1).

Discussion

TBI is composed of a primary insult and accompanying secondary injury according to the clinical course of the illness. The secondary injuries typically manifest 6–8 h after the TBI and persist up to several weeks. This post-injury period is characterized by the degeneration and apoptosis of neurons. Unfortunately, the current management protocols for improving the outcome in children after severe TBI do little to address these secondary neuropathologies. Nevertheless, there are multiple studies reporting the utility and potential improvements in outcome for patients receiving hypothermic treatment for TBI, but most of these studies are limited to adult patients. In children, there have been an extremely limited number of clinical studies examining hypothermic treatment after severe TBI (Adelson et al., 2005; Biswas et al., 2002; Gruszkiewics et al., 1973; Hendrick et al., 1963; Hutchison et al., 2008). Ironically, children suffer more severe edema and experience a higher ICP after TBI than adults (Biswas et al., 2002). In addition, children often present with complications such as permanent paralysis, traumatic epilepsy, and other adverse effects (Adelson et al., 2003).

In this study, monitoring results demonstrated that there were elevated ICP values during the initial stages after TBI; this underscores the importance of the subsequent treatment for neuropathologies secondary to TBI. A selective reduction in cranial temperature was used to provide a moderate hypothermic treatment for TBI, whereby intracranial temperatures were maintained at 34.5 ± 0.2°C for 72 h. The results showed that the ICP values were reduced in the HYPO group at all time points tested as compared with the NORM group (p < 0.01). Thus, we concluded that the hypothermia treatment lowered the ICP after TBI and reduced brain edema. Also, mortality in the HYPO group (8.3%) was lower than that in the NORM group (20%), although this difference was not statistically significant due to the small numbers. Unfortunately, due to logistical problems, no additional functional and survival data could be ascertained for the majority of the remaining patients, and the study lacked a long-term follow up of clinical information. However, recent results have indicated that, up to 12 months after hypothermia treatment for TBI in children, there were few significant differences in neurological outcome (Hutchison et al., 2008). Nevertheless, the results of moderate hypothermia therapy seem to be promising.

The neuroprotective effect of moderate hypothermia has been known for many years. However, its underlying mechanism of action is still not clear (Haaland et al., 1997; Thoreson et al., 1996; Williams et al., 1997). Nevertheless, there are several serum and CSF markers commonly used to assess primary brain injury and secondary insults. NSE is a metabolic enzyme and is a well recognized neuronal marker, and normal body fluids contain very little of it. S-100 is a Ca²⁺ binding protein mainly found in astrocytes and has been demonstrated to be indicative of outcome in patients with TBI (Hayakata et al., 2004; Korfias et al., 2007). CK-BB mainly exists in the glia and, along with NSE, has been a long recognized marker of brain damage (Skogseid et al., 1992). TBI causes neuronal degeneration and the eventual compromise of the blood-brain barrier (BBB). Subsequently, these proteins (NSE, S-100, and CK-BB) leak into the CSF, and it has been shown that the CSF levels of these three proteins accurately reflect the degree of brain injury. Therefore, the central levels of these neuropathological markers can be used as prognostic indicators of patient outcome. In our study, NSE, S-100, and CK-BB levels in the HYPO group were clearly lower than those in the NORM group. This demonstrated that moderate hypothermia provided brain protection for children with TBI.

In adult studies using 32°C as the low temperature limit (Clifton et al., 1993; Marion et al., 1993; Shiozaki et al., 1993), there was no difference in the rate of complications or toxicities. hypothermia also has been used after a number of neurological insults in children (Battin et al., 2001; Gunn et al., 1998a,b; 2000; Simbruner et al., 1999), thereby indicating that this management protocol may be useful for younger patients. Previous clinical studies examining hypoxia encephalopathic injury have demonstrated that young children and infants tolerate hypothermia treatment well, and the hypothermia protocol was associated with improved outcomes in neonates treated acutely after an insult. Amess et al. (1998) reported that the heart, lung, spleen, kidney, and intestines of the newborn pig after the hypothermia did not show excrescent pathological changes. Furthermore, Zhou et al. (2001) administered hypothermia treatment in 11 newborns suffering hypoxic-ischemic brain damage and did not find any damage to cardiac, kidney, or coagulation functions. In this study, the pH and electrolyte levels were statistically different between the two test groups. Specifically, the pathological acidosis observed in the NORM group was abrogated in the HYPO group, which was consistent with similar studies in patients after head injury (Jia et al., 2005). Thus, we concluded that 72 h of hypothermia treatment for children with TBI was safe and clinically effective. However, as expected from the thermal sensitivity of cardiovascular tone (Heistad et al., 1973), we did notice that the patient's heart rate and blood pressure descended during the hypothermia period, and medical maintenance was occasionally required. In addition, the patient's body temperature was not stable during the entire monitoring period. Hence, the safety of hypothermia for children with TBI appears to be adequate but needs further research.

Hutchison et al. (2008) recently reported that hypothermia therapy did not improve neurological outcome (as noted earlier) and appeared to increase mortality. We did not directly assess the neurological outcome of patients in the present study, but did find that markers of neuronal function damage were decreased. The seemingly disparate findings between our and Hutchison and colleagues study may be a reflection of the differing lengths of hypothermia and the temperature applied (72 h at 34.5 ± 0.2°C in our study versus 24 h at 32.5°C in Hutchison's study).

In conclusion, hypothermia initiated after severe TBI was a safe therapeutic intervention in children with no additional complications as compared to NORM controls. Our preliminary findings indicate that hypothermia can reduce ICP during the cooling phase in brains of children after TBI. Hypothermia also exhibits potential protective effects, as manifested by the changes in CSF NSE, S-100, and CK-BB levels. However, this study is only the first step for establishing a clinical management protocol for TBI in children. In addition, the patient sample size was small, and there was no long-term observation. Broader and longer clinic studies are needed to define the protective effect of hypothermia.

Footnotes

Acknowledgments

This research was supported by a grant from Doctor Wenhao Zhou and Professor Xianming Xiao.

Author Disclosure Statement

There are no conflicting financial interests.

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