The role of hypothermia in the management of severe brain injury: a meta-analysis

CONTEXT: Hypothermia is utilized in the management of severe traumatic brain injury despite the lack of unequivocal evidence supporting its use. Because of its widespread use, the effects of hypothermia are a concern. OBJECTIVE: To determine the effectiveness of hypothermia in the management of severe brain injury. DATA SOURCES: Two investigators working independently abstracted data in a blinded fashion from studies identified using multiple literature databases, including MEDLINE, Ovid, PubMed, the Cochrane Database of Systematic Reviews, EMBASE, and the abstract center for the American Association of Neurological Surgery and the Congress of Neurological Surgery, as well as the bibliographies of these articles. Additionally, experts in the field of hypothermia and neurotrauma provided additional references. STUDY SELECTION: Seven studies met predetermined inclusion criteria: (1) the study was a randomized clinical trial comparing the efficacy of hypothermia vs normothermia in patients with posttraumatic head injury, (2) only subjects aged 10 years or older were included in the study, and (3) relative risks (odds ratios [ORs], cumulative incidence, or incidence density measures) and 95% confidence intervals (CIs) or weighted mean differences and 95% CIs could be calculated from the data presented in the article. These criteria were applied in a blinded fashion by 2 independent investigators. DATA EXTRACTION: No single outcome variable was evaluated in all studies. The following outcome variables were assessed: intracranial pressure, Glasgow Outcome Scale score, pneumonia, cardiac arrhythmia, prothrombin time, and partial thromboplastin time. Either ORs or weighted mean differences (when the data provided did not permit calculation of an OR) comparing the effects of hypothermia vs normothermia were calculated from the data provided. DATA SYNTHESIS: The weighted mean difference (hypothermia - normothermia) for intracranial pressure was -2.98 mm Hg (95% CI, -7.58 to 1.61; P =.2). The OR (hypothermia vs normothermia) for Glasgow Outcome Scale score was 0.61 (95% CI, 0.26-1.46; P =.3). The OR for pneumonia was 2.05 (95% CI, 0.79-5.32; P =.14). The OR for cardiac arrhythmia was 1.27 (95% CI, 0.38-4.25; P =.7). The weighted mean difference for prothrombin time was 0.02 seconds (95% CI, -0.07 to 0.10; P =.7). The weighted mean difference for partial thromboplastin time was 2.22 seconds (95% CI, 1.73-2.71; P<.001). CONCLUSIONS: This meta-analysis of randomized controlled trials suggests that hypothermia is not beneficial in the management of severe head injury. However, because hypothermia continues to be used to treat these injuries, additional studies are justified and urgently needed.     

Moderate hypothermia in neonatal encephalopathy: safety outcomes

Hypoxic-ischemic injury may cause multisystem organ damage with significant aberrations in clotting, renal, and cardiac functions. Systemic hypothermia may aggravate these medical conditions, such as bradycardia and increased clotting times, and very little safety data in neonatal hypoxic-ischemic injury is available. This study reports a multicenter, randomized, controlled pilot trial of moderate systemic hypothermia (33 degrees C) vs normothermia (37 degrees C) for 48 hours in infants with neonatal encephalopathy instituted within 6 hours of birth or hypoxic-ischemic event. The best outcome measures of safety were determined, comparing rates of adverse events between normothermia and hypothermia groups. A total of 32 hypothermia and 33 normothermia neonates were enrolled in seven centers. Adverse events and serious adverse effects were collected by the study team during the hospital admission, monitored by an independent study monitor, and reported to Institutional Review Boards and the Data and Safety Monitoring Committee. The following adverse events were observed significantly more commonly in the hypothermia group: more frequent bradycardia and lower heart rates during the period of hypothermia, longer dependence on pressors, higher prothrombin times, and lower platelet counts with more patients requiring plasma and platelet transfusions. Seizures as an adverse event were more common in the hypothermia group. These observed side effects of 48 hours of moderate systemic hypothermia were of mild to moderate severity and manageable with minor interventions.     

Hypothermia in acute stroke--slow versus fast rewarming an experimental study in rats

The rewarming phase after therapeutic hypothermia in cerebral ischemia appears crucial as rapid rewarming may lead to rebound phenomena and enhance deleterious ischemic effects. We hypothesized that slow and controlled rewarming after moderate hypothermia is superior to fast rewarming in rats subjected to 90 min temporary middle cerebral artery occlusion (tMCAO). Two experiments were designed: (i) 34 rats were randomly assigned to either normothermic treatment, to hypothermia (33 degrees C) with rapid rewarming within 20 min, or to hypothermia with slow rewarming within 2 h after 4 h of hypothermia starting 2 h after tMCAO. Infarct size, neuroscore, myeloperoxidase and aquaporin 4 (AQP4) positive cells were assessed on day 5 after tMCAO. (ii) In 15 rats, striatal cerebral microdialysis was performed from 1.5 h before until 8 h after tMCAO. Total infarct volume was largest in the normothermic group (89.9+/-16.8 mm(3)) followed by the fast rewarming group (69.2+/-12.6 mm(3)), and a significantly smaller infarct volume in the slow rewarming group (41.1+/-6.6 mm(3), p<0.05). Neurological functions improved in both hypothermia groups at day 5 after tMCAO (Neuroscore median 2.5 in normothermia vs. 1.5 in both hypothermia groups) though without any difference between slowly and fast rewarmed animals. Periinfarct expression of AQP4 was less prominent in slowly rewarmed animals as was the count of MPO-positive cells in subcortical regions. Glutamate release was significantly higher at 4 distinct time points in the control group. Slow rewarming after a period of hypothermia is superior to fast rewarming. It may blunt deleterious rebound effects such as overexpression of AQP4, sustain anti-inflammatory mechanisms and thereby preserve the neuroprotection delivered by hypothermia.     

Assessment of prognostic factors in severe traumatic brain injury patients treated by mild therapeutic cerebral hypothermia therapy

Abstract

This study analyzed the predictable factors of outcome such as neuro-parameters and systemic complications to elucidate the indications for therapeutic hypothermia. In our institute, 35 patients with severe head injury (Glasgow Coma Scale 3-7) were treated with mild hypothermia therapy (33° - 35°C). Twenty-two of these 35 patients underwent complete neuromonitoring and outcome assessments by Glasgow Outcome Scale (GOS) at three months after injury. GOS of hypothermia group was significantly better than another patient group which was treated without mild hypothermia therapy. The hypothermia group was divided into two groups: good outcome (GOOD) (good recovery or moderate disability; n = 9, 40.9%) and poor outcome (POOR) (severe disability, vegetative state, or death; n = 13, 59.1%). The mean age (mean 30.2 years, range 9-46) was significantly lower in GOOD than in POOR (mean 45.2 years, range 17-62). Patients aged over 50 years had poor outcome. CPP was significantly higher in GOOD during hypothermia. All patients with thrombocytopenia had poor outcome. Hypothermia therapy can improve outcome in patients with traumatic brain injury who are younger than 50 years old, without severe brain damage, and if improvement of cerebral perfusion is expected. Systemic complications must be prevented as far as possible by combination with other therapies.     

Moderate hypothermia in neonatal encephalopathy: efficacy outcomes

Therapeutic hypothermia holds promise as a rescue neuroprotective strategy for hypoxic-ischemic injury, but the incidence of severe neurologic sequelae with hypothermia is unknown in encephalopathic neonates who present shortly after birth. This study reports a multicenter, randomized, controlled, pilot trial of moderate systemic hypothermia (33 degrees C) vs normothermia (37 degrees C) for 48 hours in neonates initiated within 6 hours of birth or hypoxic-ischemic event. The trial tested the ability to initiate systemic hypothermia in outlying hospitals and participating tertiary care centers, and determined the incidence of adverse neurologic outcomes of death and developmental scores at 12 months by Bayley II or Vineland tests between normothermic and hypothermic groups. Thirty-two hypothermic and 33 normothermic neonates were enrolled. The entry criteria selected a severely affected group of neonates, with 77% Sarnat stage III. Ten hypothermia (10/32, 31%) and 14 normothermia (14/33, 42%) patients expired. Controlling for treatment group, outborn infants were significantly more likely to die than hypoxic-ischemic infants born in participating tertiary care centers (odds ratio 10.7, 95% confidence interval 1.3-90). Severely abnormal motor scores (Psychomotor Development Index < 70) were recorded in 64% of normothermia patients and in 24% of hypothermia patients. The combined outcome of death or severe motor scores yielded fewer bad outcomes in the hypothermia group (52%) than the normothermia group (84%) (P = 0.019). Although these results need to be validated in a large clinical trial, this pilot trial provides important data for clinical trial design of hypothermia treatment in neonatal hypoxic-ischemic injury.     

A systematic review of clinical outcomes, perioperative data and selective adverse events related to mild hypothermia in intracranial aneurysm surgery

Background

In the last two decades, mild intraoperative hypothermia has become widely accepted as a protective therapy in neurosurgery. However, its effect in intracranial aneurysm surgery remains unclear.

Objective

The purpose of this study was to assess the perioperative effects and selected adverse events associated with intraoperative mild hypothermia in aneurysm surgery and to compare those with events in normothermic surgery.

Methods

Three literature databases, namely the Cochrane Library, PubMed and EMBASE, were searched for randomised controlled trials (RCTs) of aneurysm surgery that compared intraoperative mild hypothermia and normothermia from January 1965 to August 2010. Three RCTs were identified. We extracted the following information: author names and publication year; clinical outcome (number of deaths and Glasgow outcome scales); perioperative data (number of moderate or severe intraoperative brain swelling occurrences, hypertensive episodes, ruptured or leaking aneurysms, volume of blood loss during surgery, duration of temporary clipping, and number of patients who received protective drugs, who required rewarming and who were intubated); number of adverse events (cerebral infarctions, brain swelling, myocardial ischaemia or infarction, congestive heart failure, meningitis or ventriculitis and pneumonia). Except for author names and publication year, the data were pooled to perform a mean effect size estimate. The effects of intraoperative mild hypothermia were then analysed.

Results

The number of patients requiring rewarming in the mild hypothermia group was significantly greater than in the normothermia group (odds ratio, 33.89; 95% confidence intervals, 3.61–318.36). There were no other statistically significant differences.

Conclusion

Based on available RCTs, especially involving surgery of low-grade aneurysms, intraoperative mild hypothermia showed no advantages compared with normothermia.     

Effects of hypothermia and rewarming on evoked potentials during transient focal cerebral ischemia in cats

Abstract

We examined the effects of mild to moderate hypothermia and the influence of rewarming on electrophysiological function using somatosensory evoked potentials (SEPs) in transient focal ischemia in the brain. Nineteen cats underwent 60 min of left middle cerebral artery occlusion under normothermic (36 ° -37 ° C, n = 6) or hypothermic (30 ° -31 ° C, n = 13) conditions followed by 300 min of reperfusion with slow (120 min, n = 6) or rapid (30 min, n = 7) rewarming. Whole-body hypothermia was induced during ischemia and the first 180 min of reperfusion. SEPs and regional cerebral blood flow were measured before and during ischemia and during reperfusion. The specific gravity of gray and white matter was examined as the indicator of edema. During rewarming, SEP amplitudes recovered gradually. After rewarming, SEPs in the normothermic and rapid rewarming groups remained depressed (20%-40% of pre-occlusion values); however, recovery of SEPs was significantly enhanced in the slow rewarming group (p < 0.05). Hypothermia followed by slow rewarming reduced edema in gray and white matter. Rapid rewarming did not reduce edema in the white matter. The recovery of SEPs correlated with the extent of brain edema in transient focal ischemia. Rapid rewarming reduced the protective effect of hypothermia. [Neurol Res 2002; 24: 621-626]     

Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury

Therapeutic hypothermia is a promising treatment for patients with severe traumatic brain injury (TBI). We present here the results of a study in which noninvasive selective brain cooling (SBC) was achieved using a head cap and neckband. Ninety patients with severe TBI were divided into a normothermia control group (n=45) and a SBC group (n=45), whose brain temperature was maintained at 33-35 degrees C for 3 days using a combination of head and neck cooling. At 24, 48 and 72h after injury, the mean intracranial pressure (ICP) values of the patients who underwent SBC were lower than those of the normothermia controls (19.14+/-2.33, 19.72+/-1.73 and 17.29+/-2.07 mmHg, versus 23.41+/-2.51, 20.97+/-1.86, and 20.13+/-1.87 mmHg, respectively, P<0.01). There was a significant difference in the neurological recovery of the two groups at the 6-month follow-up after TBI. Good neurological outcome (Glasgow Outcome Scale score of 4 to 5) rates 6 months after injury were 68.9% for the SBC group, and 46.7% for the control group (P<0.05). There were no complications resulting in severe sequelae. In conclusion, the noninvasive SBC described here is a safe method of administering therapeutic hypothermia, which can reduce ICP and improve prognosis without severe complications in patients with severe TBI.     

重型颅脑损伤患者亚低温治疗的临床研究

目的 通过比较重型颅脑损伤患者亚低温治疗组与常温治疗组的预后来证实亚低温治疗的脑保护作用. 方法 选取重型颅脑损伤患者76例(GCS≤8分),分为亚低温治疗组(36例)和常温治疗组(40例).常温治疗组患者应用脱水降颅压、营养神经、止血、抑制胃酸分泌、营养支持等常规治疗.亚低温治疗组患者除常规治疗外,合并应用冰毯实行亚低温治疗(患者躺在冰毯垫上,通过体表散热使中心体温和脑温降至所需温度,通常为32～34℃,并根据病情需要维持3～14 d).结果亚低温治疗组患者预后优于常温组,差异有统计学意义(P<0.05). 结论 亚低温治疗对重型颅脑损伤患者具有脑保护作用,能提高临床疗效,值得推广应用.