Meta-Analysis of Therapeutic Hypothermia for Traumatic Brain Injury in Adult and Pediatric Patients*

Crompton, Ellie M. BSc; Lubomirova, Irina MBBS; Cotlarciuc, Ioana PhD; Han, Thang S. PhD; Sharma, Sapna D. MD; Sharma, Pankaj PhD

doi: 10.1097/CCM.0000000000002205
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Objective: Therapeutic hypothermia has been used to attenuate the effects of traumatic brain injuries. However, the required degree of hypothermia, length of its use, and its timing are uncertain. We undertook a comprehensive meta-analysis to quantify benefits of hypothermia therapy for traumatic brain injuries in adults and children by analyzing mortality rates, neurologic outcomes, and adverse effects.

Data Sources: Electronic databases PubMed, Google Scholar, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov and manual searches of studies were conducted for relevant publications up until February 2016.

Study Selection: Forty-one studies in adults (n = 3,109; age range, 18–81 yr) and eight studies in children (n = 454; age range, 3 mo to 18 yr) met eligibility criteria.

Data Extraction: Baseline patient characteristics, enrollment time, methodology of cooling, target temperature, duration of hypothermia, and rewarming protocols were extracted.

Data Synthesis: Risk ratios with 95% CIs were calculated. Compared with adults who were kept normothermic, those who underwent therapeutic hypothermia were associated with 18% reduction in mortality (risk ratio, 0.82; 95% CI, 0.70–0.96; p = 0.01) and a 35% improvement in neurologic outcome (risk ratio, 1.35; 95% CI, 1.18–1.54; p < 0.00001). The optimal management strategy for adult patients included cooling patients to a minimum of 33°C for 72 hours, followed by spontaneous, natural rewarming. In contrast, adverse outcomes were observed in children who underwent hypothermic treatment with a 66% increase in mortality (risk ratio, 1.66; 95% CI, 1.06–2.59; p = 0.03) and a marginal deterioration of neurologic outcome (risk ratio, 0.90; 95% CI, 0.80–1.01; p = 0.06).

Conclusions: Therapeutic hypothermia is likely a beneficial treatment following traumatic brain injuries in adults but cannot be recommended in children.

1Institute of Cardiovascular Research Royal Holloway University of London (ICR2UL), Egham, United Kingdom.

2Department of Medicine, Imperial College London, London, United Kingdom.

3Ashford and St Peter’s NHS Foundation Trust, Surrey, United Kingdom.

*See also p. 744.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Professor P. Sharma was a Department of Health U.K. Senior Fellow. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: pankaj.sharma@rhul.ac.uk

Article Outline

The World Health Organization predicts that by 2020, traumatic brain injury (TBI) will exceed many diseases as a major cause of death and disability (1), whereas the U.S. Centers for Disease Control and Prevention estimates that 1.7 million Americans sustain a TBI every year of which an estimated 52,000 die (2). European prevalence is approximately 235 per 100,000 people with an average mortality rate of 15 per 100,000 (3). Epidemiology data for the prevalence of TBI within Asian populations are lacking (1), but estimates from India suggest that annually approximately 1.6 million individuals will sustain a TBI (4), whereas TBI is the leading cause of traumatic injury in China with approximately 10% of patients succumbing to death (5).

It is estimated that 5.3 million people in the United States (6) and 7.7 million people in the European Union (7) are living with a TBI-related disability. These disabled survivors are often unable to return to employment or school, with one study finding 50% of severely injured patients and 20% of patients with mild injuries failing to return to work 1 year post TBI (8). Studies from the United States have estimated that $56.3 billion of expenditures occur annually as a result of TBI from lost earnings of the patients and their carers (1).

Therapeutic hypothermia (TH), a procedure in which the purposeful and controlled lowering of body temperature is performed, acts as a neuroprotectant to minimize neuronal loss or damage, with an aim to improve patient outcome (9). TH can be divided into different levels according to the temperature achieved; mild (33–36°C) and moderate (28–32°C) are commonly used, whereas deep (10–28°C), profound (5–10°C), and ultraprofound (0–5°C) exist but are rarely used (10). In the case of TBI, numerous animal experimental trials have produced positive results (11), but translating results to human studies with reliable guidelines has proved more challenging (12).

We aimed to conduct a comprehensive, systematic meta-analysis to robustly quantify the benefits of hypothermia therapy for TBI in adult and pediatric patients by analyzing mortality rates, neurologic outcomes, and adverse effects.

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MATERIALS AND METHODS

Study Identification

Electronic databases PubMed, Google Scholar, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched for relevant published studies between 1940 and February 2016. Search (MeSH) terms were “hypothermia,” “therapeutic hypothermia,” “cooling,” “induced hypothermia,” “brain injury,” “traumatic brain injury,” “head injury,” and “head trauma” with the Boolean operators “AND” and “OR.” All languages were included, and relevant articles were translated where necessary. Manual searching of the bibliographies of electronically identified studies was conducted.

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Study Selection Criteria

Eligibility for TBI (including only blunt trauma) was based on the following inclusion criteria: 1) induced hypothermia rather than patients who were hypothermic at admission and 2) Glasgow Outcome Scale (GOS) and/or mortality data allowing a number of patients with favorable and unfavorable outcomes to be extracted. The control participants were not subject to temperature management except for fever control. Where duplicate studies were found to include the same patient cohorts in multiple trials, data from the most recent trial were used. Extracerebral trauma was excluded. The preferred reporting items for systematic reviews and meta-analyses statement was used for reporting of this meta-analysis (13).

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Data Extraction

Baseline characteristics of patients including age, sex, initial Glasgow Coma Scale (GCS) score, ethnicity, outcome data for GOS, mortality, and frequency of pneumonia and cardiac arrhythmias were extracted. TBI was defined as mild (GCS score, 13–15), moderate (GCS score, 9–12), and severe (GCS score, 3–8). The duration of follow-up assessments to obtain outcome measures was documented. GOS data were dichotomized into favorable (score, 4–5) and unfavorable (score, 1–3) neurologic outcomes. Mean GOS scores with SDs were extracted for use in a continuous outcome analysis, quantifying the effectiveness of TH. Details of hypothermia induction and maintenance were extracted including patient enrollment time, methodology of cooling, target temperature, duration of hypothermia, and rewarming protocols. Intracranial pressure (ICP) and cerebral perfusion pressure goals and interventions to achieve these goals were also extracted.

Outcomes were divided into two categories: 1) safety of TH through recording of frequency events such as mortality, pneumonia, and arrhythmias and 2) effectiveness of TH as a neuroprotectant to improve neurologic outcome based on GOS. Analyses were conducted to examine the effects on the safety and effectiveness of TH of several variables, such as varying target temperatures, durations of maintained hypothermia, method of induced hypothermia, and the rate at which patients were rewarmed. The influence of age and type of trial (randomized controlled trials [RCTs] vs observational studies) on the safety and effectiveness of TH were assessed. Target temperatures from some original studies were given as ranges: “mild” if the lowest temperature in the range was greater than or equal to 33°C or “moderate” if the lowest temperature in the range was less than 33°C.

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Statistical Analysis

Pooled risk ratios (RRs) were calculated with 95% CIs by the random effect model for analyses using dichotomous outcomes. The mean difference was calculated with 95% CI for continuous data outcomes. Funnel plots were constructed to assess publication bias. Statistical analysis was performed using Review (RevMan) version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

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Patient Involvement

Patients were not directly involved in this study as it is a meta-analysis.

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RESULTS

Study Characteristics

Of 1,523 records identified, 49 studies (28 RCTs; 21 observational studies) met eligibility criteria (Fig. 1) (14–62). In total, 3,848 patients (73.4% men) were included (TH group: 1,922; normothermic control group: 1,926). The majority (41 studies) used adult patients, with 43 studies using patients with a GCS score less than or equal to 7 (Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/CCM/C276).

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Adult Studies

Effect of TH on Favorable Neurologic Outcome. A significant 35% increase in favorable outcomes was seen in adults when patients were treated with TH (35 studies; 1,561 TH; 1,548 controls; RR, 1.35; 95% CI, 1.18–1.54; p < 0.00001)(Fig. 2). In addition, this beneficial effect in adults was maintained in long-term (up to 24 mo) (31, 34, 37, 41, 42) follow-up (208 TH; 192 controls; RR, 1.64; 95% CI, 1.33–1.55; p < 0.00001).

To ascertain a quantitative result for the level of neurologic improvement seen in adults, a mean difference analysis was conducted to compare differences in mean GOS scores. GOS scores are significantly improved by 0.58 points for adults (24 studies; 985 TH; 955 controls; mean difference, 0.58; 95% CI, 0.30–0.87; p < 0.0001).

Effect of TH on Mortality. A significant reduction in mortality rates was seen with adult patients treated with TH (39 studies; 1,710 TH; 1,716 controls) with 18% decrease in deaths (RR, 0.82; 95% CI, 0.70–0.96; p = 0.01) (Fig. 3). Heterogeneity was observed within adult studies (I2, 49%; χ2, 72.53; p = 0.0004), which was eliminated by excluding three studies (15, 29, 49), following which outcome results remained significant (RR, 0.77; 95% CI, 0.67–0.88; p = 0.0001). There was no suggestion of publication bias with symmetrical funnel plots.

Effect of Methodological Assessment. Analyses were conducted to assess any difference in outcome between RCTs and observational studies. Adult patients in both RCTs (RR, 1.27; 95% CI, 1.06–1.54; p = 0.01) and observational studies (RR, 1.46; 95% CI, 1.26–1.68; p < 0.00001) showed significantly improved neurologic outcome when treated with TH. Similarly, overall mortality rates were reduced when patients were treated with TH with a significant effect from observational studies (RR, 0.75; 95% CI, 0.57–0.99; p = 0.04) and a strong trend from RCT data (RR, 0.84; 95% CI, 0.70–1.02; p = 0.07). By excluding one study (15), heterogeneity was eliminated, and significant decreases in mortality rates in the RCT subgroup were obtained (RR, 0.79; 95% CI, 0.67–0.94; p = 0.008).

Effect of Hypothermia Management. Analyses were carried out to determine the best management strategy for hypothermia treatment. The aspects of the management strategy considered included: whether hypothermia was induced only in the head region or systemically; depth and duration of hypothermia; speed of rewarming; and whether any adjunct interventions were used to control ICP.

The optimal management strategy to improve both morbidity and mortality was determined to be selective brain cooling to 33°C, maintaining this for 72 hours, followed by a period of spontaneous rewarming at the natural rate (Tables 1 and 2). The use of adjunctive therapy in addition to hypothermia, for example, barbiturates, to reduce ICP limited the effectiveness of hypothermia (Tables 1 and 2). Those analyses with only a few included studies may exaggerate the effect size, and therefore, this must be treated with a degree of caution.

Complication Rates. Secondary complications to TH included pneumonia (17 studies; 527 TH; 432 controls) and cardiac arrhythmias (nine studies; 210 TH; 188 controls).

Patients undergoing hypothermia treatment were 28% more likely to suffer pneumonia compared with normothermic controls (RR, 1.28; 95% CI, 1.01–1.62; p = 0.04), but there was no significant increase in cardiac arrhythmias (RR, 1.23; 95% CI, 0.72–2.10; p = 0.46).

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Pediatric Studies

There was a significant 66% increase in the mortality rate in pediatric studies (eight studies; 244 TH; 248 controls; RR, 1.06; 95% CI, 1.06–2.59; p = 0.03) (Fig. 3). A 10% decrease in favorable neurologic outcomes was seen in pediatric patients (six studies; 225 TH; 229 controls; RR, 0.90; 95% CI, 0.80–1.01; p = 0.06) (Fig. 2). GOS scores decreased by 0.17 points in children (three studies; 67 TH; 64 controls; MD, −0.17; 95% CI, −0.64 to 0.31; p = 0.50).

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DISCUSSION

TH is associated with significantly improved neurologic outcome and reduced mortality rates in adult patients but is detrimental in children. This effect was most significantly seen in observational studies, and the beneficial trend was also supported by RCTs although its use in patients with a GCS score above 13 is doubtful. The use of hypothermia as a therapy was not without risk. Hypothermic adults were more likely to get pneumonia although cardiac arrhythmias were not more significantly seen.

The finding that treating adult patients with hypothermia significantly affects both neurologic outcome and mortality rates in positive manners supports the conclusions drawn from one previous meta-analysis (63) but conflicts two more recent meta-analyses on the subject that showed that the effects were nonsignificant (64, 65). Previous meta-analyses of studies focusing on pediatric patients found similar conclusions about the detrimental effects of TH for TBI patients with significant increases of 73% and 84% in the risk of mortality of children, which correlate with the risk of 87% found in this study (66, 67).

TH attenuates some of the secondary injury mechanisms that are initiated by a TBI. Studies on animals have shown that metabolism and cerebral blood flow are decreased by 5–7% for each degree Celsius that the body temperature is decreased, therefore reducing oxygen consumption and carbon dioxide production (68, 69). Reducing oxygen consumption decreases the need for anaerobic metabolism, which results in a decrease of membrane permeability. This reduction in the influx of ions will reduce the cascade initiated by Ca2+ and Na+. It has also been shown that mild posttraumatic hypothermia reduced the levels of excitatory neurotransmitters (70, 71), proinflammatory cytokines (72, 73), and lactate accumulation (74) in experimental studies. In addition to its ability to attenuate the events that lead to cellular apoptosis and necrosis, TH has also been shown to prevent apoptosis by reducing the levels of caspase 3 and cytochrome C (mediators of apoptosis) (75).

TH used for the purposes of neuroprotection has been established in areas of medicine other than for TBI, most notably for neonatal hypoxic encephalopathy (76, 77). TH is being explored in further areas of medicine such as cardiac arrest, stroke, and neurosurgery (78–80), but consensus as to whether the treatment is beneficial has not yet been reached.

Cooling patients to mild (above 33°C) or moderate (below 33°) degrees of hypothermia produced very similar improvements in neurologic outcome. However, the mortality rate was reduced by 18% more with mild hypothermia compared with moderate hypothermia, suggesting that reducing body temperature by ≈4° is required to elicit the beneficial effects of this treatment, which would correspond to a 20–28% decrease in cerebral metabolism and oxygen consumption. Hypothermia induced through selective head cooling using cooling caps and irrigation of the head with cold solution produced better patient outcomes compared with systemic cooling, but the number of studies in this group was small (28, 34).

Elevated ICP has been found to correlate with worsened outcome in TBI patients (81), possibly because of decreases in cerebral perfusion pressure and cerebral blood flow, potentially leading to hypoxic-ischemic injury (82). Hypothermia has long been known to reduce ICP; therefore, maintaining the treatment for a duration of 72 hours encompasses the start of the 3- to 10-day period in which intracranial hypertension secondary to the TBI may present, allowing early attenuation of the elevated ICP, preventing further brain damage. Our findings show that hypothermia for 72 hours seems to be the optimal duration, yielding the largest increase in favorable neurologic outcome. TH reduces ICP, as do barbiturates. Studies have shown that the additional use of barbiturates with TH did not improve neurologic outcome or decrease mortality, compared with highly significant improvements by hypothermia alone. These results suggest that barbiturate therapy may limit the effectiveness of TH (44, 45).

The 72 hours of cooling should be followed by a period of natural rewarming where patients are allowed to spontaneously return to normal body temperature. The rewarming phase of hypothermia treatments has previously been associated with fatal rebounds in ICP, when lower ICP levels induced by cooling suddenly increase when cooling is removed because of temperature being increased too quickly (83). Allowing patients to rewarm passively at the natural rate may help avoid rapid changes in temperature but not be too slow to prolong hypothermia for much longer than the optimum (83).

Because of their different physiology and metabolism to adults, children may have a very different response to injury (55), which may explain their unfavorable results. Following TBI, children have 70% of normal energy expenditure levels (84) compared with a hypermetabolic response in adults (85–87). Hypothermia acts to reduce metabolic response (88); therefore, as children exhibit ≈50% lower energy levels, there may be less of a target for hypothermia to act upon, so outcomes cannot be improved. Another possible factor in this explanation comes from the fact that all eight pediatric trials used barbiturates to control elevated ICP. Administration of barbiturates decreased metabolism to 14% below predicted levels compared with patients without barbiturate therapy who exhibited 26% above predicted levels (89). This mechanism would maintain low energy expenditure levels and reduce the target for hypothermia to act upon.

A number of limitations to our work need to be discussed. Variations in inclusion criteria to enroll patients could have affected our results and may account for some of the observed heterogeneity. However, much of this heterogeneity was eliminated by iterative analysis without affecting the significance of the results. One common inclusion criterion was that the TBI was a blunt injury; therefore, it would be unwise to extrapolate these results for the use of TH in the treatment of penetrating trauma. More than half of the studies did not report any data for complications, making it difficult to determine the full extent to which these arise. Thirty-seven studies reported that the temperature was not actively maintained in the normal range within the normothermic control group. Therefore, in these studies, the effect size may have been altered because of the deleterious effect of fever in the normothermic group rather than the beneficial effects of cooling patients in the hypothermia group. GOS scoring to determine neurologic outcome is cautioned as it uses short, unspecific descriptions. Finally, as with all meta-analyses, there is a possibility of publication bias. However, we have attempted to undertake a comprehensive search, and funnel plots were symmetrical, but of course, publication bias cannot be entirely excluded.

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CONCLUSIONS

TH is a likely beneficial treatment following TBI in adults, improving both neurologic outcomes and decreasing mortality rates. Our work suggests that the optimal management strategy to improve both morbidity and mortality was determined to be selective brain cooling to 33°. We then suggest maintaining this temperature for 72 hours, followed by a period of spontaneous rewarming at the natural rate, although the dataset for this advice is smaller. Barbiturates may be used to control ICP, but this may limit the effectiveness of the hypothermia therapy. TH is not recommended for use in children with TBI. RCTs with these targets in mind may help to provide more definitive clinical protocols.

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adult; hypothermia; morbidity; mortality; pediatric; traumatic brain injury

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