Lovett et al. (2017)

USA

Retrospective

N=71

Population:  Preintervention Group (N=47): Median Age=4.6yr; Gender: N/A; Mean time post injury=acute; Median GCS=6. Intervention 1 Group (N=9): Median Age=9yr; Gender: N/A; Mean time post injury=acute; Median GCS=3. Maintenance Group (N=6): Median Age=4.5yr; Gender: N/A; Mean time post injury=acute; Median GCS=3. Intervention 2 Group (N=9): Median Age=8yr; Gender: N/A; Mean time post injury=acute; Median GCS=3.

Intervention: Retrospective chart review of a hyperthermia reduction protocol on a pediatric TBI inpatient unit. The preintervention phase cohort was analyzed before the implementation. The intervention 1 group had a cooling blanket placed on the patient bed prior to arrival and turned on when their temperature rose above normothermia. The maintenance phase focused on sustaining the results of intervention 1 group. The intervention 2 group focused on total prevention by initiating the cooling blanket immediately upon patient arrival.

Outcomes: median duration of hyperthermia, acetaminophen administration, neurosurgical intervention, mortality, and lengths of stay.

1.        The median duration of hyperthermia in the preintervention group was 135 min, down to 45 min in the Intervention 1 group, rose to 88.5 min in the Maintenance group, and declined to 0 min in the intervention 2 group. This was a statistically significant reduction based on phase of the study (p=0.04)

2.        There was significantly less acetaminophen administered in the intervention and maintenance groups compared to the preintervention group (p=0.04).

3.      There were no significant group-differences in measures of neurosurgical intervention, mortality, and lengths of stay.

Hutchison et al. (2010)

A post-hoc analysis of Hutchison et al. (2008)

Intervention: A post-hoc analysis of aforementioned study to determine the relationship between cerebral perfusion pressure (CPP), hypotension, and outcomes following hypothermia treatment in children post-TBI.

Outcome Measure: Hypotension, Pediatric Cerebral Performance Category (PCPC), Unfavorable Outcomes, Cerebral Perfusion Pressure (CPP).

1.        CPP was significantly higher in the hypothermia group at 8hr and 12hr post-treatment than it was in the normothermia group (p<0.050).

2.        A lower CPP was noted in the hypothermia group 32-60hr post treatment compared to the normothermia group (p<0.050).

3.        Hypothermia patients experienced significantly more episodes of hypotension within 24hr post injury (p=0.030) and low CPP 25-72 hr post injury (p=0.020) compared to normothermia patients.

4.        One or more episodes of hypotension (low systolic pressure) or low CPP levels within 25-72 hr post-injury for the hypothermia group was significantly associated with unfavourable outcomes (p=0.040 and p=0.030 respectively).

Hutchison et al.

(2008)

Canada

RCT

PEDro=7

N=225

Population: TBI; Hypothermia Group (n=108): Mean Age=9.8yr; Gender: Male=70, Female=38; Mean Time Post Injury=6.3 hr; Median GCS=5. Normothermia Group (n=118): Mean Age=10.2yr; Gender: Male=71, Female=47; Median GCS=5.

Intervention: Patients were randomly assigned to either a hypothermia therapy group (where a mean temperature of 32.5^oC was maintained via surface cooling techniques for 24 hr) 8 hours after treatment, or a normothermia group (where a mean temperature of 37^oC was maintained). After 24 hr, hypothermia patients were warmed 0.5°C every 2 hr. Outcomes were assessed at 6mo follow-up.

Outcome Measure: Pediatric Cerebral Performance Category (PCPC), Mortality Rates, Intracranial Pressure (ICP) , Cerebral Perfusion Pressure (CPP) , Blood Pressure rates, Heart Rate.

1.        Thirty-two of 102 patients (31%) in the hypothermia group and 23 of 103 (22%) in the normothermia group had an unfavorable outcome at 6 mo. (p=0.140).

2.        A total of 23 deaths were recorded among the hypothermia group in contrast to the 14 deaths among the normothermia group, however the difference was not significant (p=0.060).

3.        Intracranial pressures were lower during the cooling period and higher during the rewarming period in the hypothermia group compared to the normothermia group at 16 hours (P=0.020), 24 hours (P=0.010), 48 hours (P=0.010), and 72 hours (P=0.030).

4.        At 24hr post-treatment, heart rate was significantly lower in the hypothermia group compared to the normothermia group (p<0.001)

5.        At 25-72hr post-treatment, CPP and mean blood pressure were significantly lower amongst hypothermia patients compared to normothermia patients (both p<0.001) whereas heart rate was no longer significantly different.

Adelson et al. (2013)

USA

RCT

PEDro=7

N=77

Population: TBI; Hypothermia Group (n=39): Median Age=9.7yr; Gender: Male=21, Female=18; Time Post Injury=<6 hr; Median GCS=6. Normothermia Group (n=38): Median Age=12.5yr; Gender: Male=27, Female=11; Time Post Injury=<6 hr; Median GCS=6.

Intervention: Patients were randomly assigned to either the hypothermia group or the normothermia group. The hypothermia group was cooled with iced intravenous saline to 34-45°C then surface cooled to 32-33°C. This was maintained for a 48hr period at which time all were rewarmed. Those in the normothermia group were maintained at 36.5-37.5°C. A 3mo follow-up was conducted.

Outcome Measure: Mortality rate, Glasgow Outcome Scale (GOS), Glasgow Outcome Scale-Extended Pediatrics (GOS-E Peds).

1.        No significant difference was reported between the two groups (p=0.150) in mortality rates at 3mo.

2.        Six patients in the hypothermia group died and two patients in the normothermia group died over the course of the study (p=0.150).

3.        No significant differences were found between the two groups in GOS and GOS-E Peds scores (p=0.900, p=0.730 respectively) at 3mo follow-up.

Bayir et al.

(2009)

USA

RCT

PEDro=6

N=28

Population: TBI; Hypothermia Group (n=13): Mean Age=6.8yr; Gender: Male=9, Female=4; Time Post Injury=<24 hr; Mean GCS=6.3. Normothermia Group (n=15): Mean Age=5.1y r; Gender: Male=8, Female=7; Time Post Injury=<24 hr; Mean GCS=6.

Intervention: Patients were randomized into one of two conditions: hypothermia or normothermia. Both groups received temperature monitoring via a rectal probe with the hypothermia group maintained at a temperature of 32-33^oC and normothermia patients maintained at 36.5-37.5^oC for 48 hr. Data was collected over 3 d of treatment.

Outcome Measure: Cerebrospinal fluid (CSF) Protein Sulfhydryls (Prot-SH), CSF Glutathione concentrations, CSF F2-isoprostane levels, CSF Anti-oxidant Reserve (AOR) levels.

1.        The effect of temperature was not significant on CSF prot-SH (p=0.104) or CSF F2-isoprostane levels (p=0.104).

2.        An inverse relationship between temperature and AOR was reported (p=0.022) with the hypothermia group demonstrating significantly greater AOR levels.

3.        Glutathione concentration in CSF and temperature were inversely related (p=0.002).

Adelson et al.

(2005)

USA

RCT

PEDro=6

N=74

Population: TBI; Phase 1 (HYPO 1): Gender: Male=27, Female=21. Hypothermia Group (n=23): Mean Age=6.92yr; Mean Time Post Injury=4.62 hr; Mean GCS=5.74. Normothermia Group (n=25): Mean Age=6.86yr; Time Post Injury=<6 hr; Mean GCS=5.64. Phase 2 (HYPO 2): Gender: Male=17, Female=9. Hypothermia Group (n=13): Mean Age=7.17 yr; Mean Time Post Injury=15.03 hr; Mean GCS=6.42. Normothermia Group (n=13): Mean Age=5.6 yr; Time Post Injury=6-24 hr; Mean GCS=6.23.

Intervention: Patients were randomized into one of two conditions, hypothermia or normothermia. HYPO 1 – Both the hypothermia group (32-33^oC) and normothermia group (36.5-37.5^oC) maintained via a surface temperature control unit with a rectal probe. Information about complications was collected daily for the first 5 d.

HYPO 2 – Patients who did not meet inclusion criteria but followed the same study protocol as HYPO 1. Assessments were conducted at 3 and 6 mo follow-ups.

Outcome Measure: Mortality rates, complication rates, Glasgow Outcome Scale (GOS), Intracranial Pressure (ICP) , Cerebral Perfusion Pressure (CPP) .

1.        In HYPO 1, the hypothermia group demonstrated lower mortality rates than the normothermia group but the difference was not statistically significant. In HYPO 2, both groups reported three deaths.

2.        Within the first 24 hr of treatment, hypothermia patients had significantly lower ICP than normothermia patients (p=0.024). However, this difference was no longer significant after 24 hr.

3.        Although there were no significant differences between groups on GOS scores, patients with good GOS outcomes had significantly lower ICP levels (p=0.036) and lower CPP levels (p=0.010).

Biswas et al. (2002)

USA

RCT

PEDro=7

N=21

Population: TBI; Hypothermia Group (n=10): Mean Age=5.9yr; Mean Time Post Injury=4.1 hr; Mean GCS=4.7. Normothermia Group (n=11): Mean Age=6.5yr; Mean Time Post Injury=4.5 hr; Mean GCS=5.7.

Intervention: After randomization to receive either hypothermia or normothermia treatment, all patients were administered sedatives, analgesics and neuromuscular blocking agents during the first 48 hr of hospital admission. In the hypothermia group, rectal temperature was lowered and maintained at 32°-34°C for a period of 48 hr. Follow-ups were conducted at 3, 6 and 12 mo.

Outcome Measure: Glasgow Outcome Scale (GOS), Pediatric Cerebral Performance Category (PCPC), Pediatric Overall Performance Category (POPC), Intracranial Pressure (ICP), Cerebral Perfusion Pressure (CPP), White Blood Cell Count.

1.        There were no significant differences in GOS, PCPC or POPC scores between both groups.

2.        There were no significant differences between treatment groups regarding changes in ICP over time (p=0.730) and overall ICP level (p=0.770).

3.        In both groups CPP declined slowly before increasing after 60 hr but the rate of increase was not significant.

4.        All patients demonstrated a significant decrease in white blood cell count (p<0.001) during the study but there was no statistical significance between groups.

Beca et al. (2015)

Australia

RCT

PEDro=7

N_I=55, N_F=50

Population: TBI; Hypothermia Group (n=24): Mean Age=11.0 yr; Gender: Male=11, Female=13; Mean Time Post Injury=5.3 hr; Mean GCS=5.5. Normothermia Group (n=26): Mean Age=9.5 yr; Gender: Male=16, Female=10; Mean Time Post Injury=5.0 hr; Mean GCS=4.5.

Intervention: Individuals in the normothermia group maintained a body temperature between 36^o and 37^oC. The hypothermia group was maintained at a body temperature between 32 and 33^oC followed by rewarming. Both groups were monitored for 72 hr. Outcomes were analyzed at 12 mo follow-up.

Outcome Measure: Development of Comorbidities, Death, Hospital/intensive Care Unit (ICU) Length of Stay (LOS).

1.        There was no significant difference between groups for unfavourable outcomes (p=0.700), death (p=0.340), ICU LOS (p=0.870), or hospital LOS (p=0.70).

2.        There was no significant difference between groups in the need for mechanical ventilation (p=0.770).

3.        There was no significant difference between groups for any type of infection (p>0.250), bleeding (p>0.480), arrhythmia (p=0.480) or acute respiratory distress syndrome (p=0.230).

Li et al. (2009)

China

RCT

PEDro=6

N=22

Population: TBI; Hypothermia Group (n=12): Age Range=0.7-8.0yr; Mean Time Post Injury=7.2 hr; Mean GCS=6.4. Normothermia Group (n=10): Age Range=0.5-9.0; Mean Time Post Injury=6.8 hr; Mean GCS=6.5.

Intervention: Patients were randomized to either a localized hypothermia treatment using a cooling cap on the patient’s head and maintained at an intracranial temperature of 34.5°C or a normothermia group maintained at 38°C for 72 hours. Data was collected at 8, 24, 48 and 72 hr intervals.

Outcome Measure: Intracranial Pressure (ICP), Neuron-specific Enolase (NSE) Levels, S-100 levels, Brain-specific Creatine Kinase (CK-BB) levels, Blood Pressure.

1.        The hypothermia group demonstrated lower ICP values which were statistically significant at 8, 24, 48 and 72 hr (all p<0.050).

2.        S-100 levels were significantly lower in the hypothermia group compared to the normothermia group at 8, 24 and 48 hr post-treatment (all p<0.010).

3.        At 24, 48 and 72 hr post-treatment, patients in the hypothermia group had significantly lower NSE and CK-BB levels (all p<0.050 and p<0.0001 respectively) compared to the normothermia group.

4.        There was no significant difference between groups with regards to blood pressure.

Rosario et al. (2018)

USA

Secondary RCT Analysis

N=77

Population:  TBI Group (N=77): Median Age=11yr (IQR, 3 – 15); Gender: Male=62%, Female=38%; Mean time post injury=acute; Median GCS=6 (IQR, 5-7).

Intervention: Children from a severe TBI unit were enrolled in a therapeutic hypothermia clinical trial. Study authors investigated characteristics associated with unfavorable outcomes on the GOS-E and mortality at 3-months post-TBI. Bivariate and stepwise regression analyses were used.

Outcomes: Mortality, Glasgow Outcome Scale – Extended (GOS-E).

1.        No demographic, clinical, or CT characteristics in the bivariate analysis were associated with mortality. In the stepwise regression analysis, abbreviated injury severity spine (3.48 [1.14-10.58]) and midline shift on CT (8.35 [1.05-66.59]) were significantly associated with mortality.

2.        Characteristics in the bivariate analysis associated unfavorable GOS-E scores were: two fixed pupils (14.17 [3.38-59.37]), abdominal abbreviated injury (2.03 [1.19-3.39]), and subarachnoid hemorrhage (3.36 [1.30-8.70]). In the stepwise regression analysis, both 1 and 2 fixed pupils, hypoxia (5.22 [1.02-26.67]), and subarachnoid hemorrhage were associated with unfavorable GOS-E scores.