**2. Methods**

We queried the Medline database with the MeSH terms "Hypothermia, induced," "Fever", "Intracranial Hypertension", and "Traumatic Brain Injury" from 1993 till 2011. We utilized both PubMed and OVID to maximize database penetration. We searched the Cochrane Database of Systematic Reviews. We also hand searched bibliographies of relevant citations and reviews. Inclusion criteria were double-blind, placebo-controlled, randomized controlled trials (RCTs), observational studies or meta-analysesof therapeutic hypothermia for TBI patients in which ICPs are monitored.We limited the search to human literature; We did not limit language, but we extracted studies that involved only adult subjects excluding studies on the pediatric population. Information extracted included number of patients, ICP, length of cooling, length of re-warming, outcome, complications, methods used to control ICP and the quality of each study. We reviewed the literature pertaining to pathophysiology of Traumatic Brain Injury. We also reviewed the literature pertaining to major published guidelines in this area.

## **3. Intracranial hypertension in TBI**

In comatose TBI patients with an abnormal CT scan, the incidence of ICH was 53–63% [75]. Patients with a normal CT scan at admission, on the other hand, had a relatively low incidence of ICH (13%). However, within the normal CT group, if patients demonstrated at least two of three adverse features (age over 40 years, unilateral or bilateral motor posturing, or systolic BP < 90 mm Hg); their risk of ICH was similar to that of patients with abnormal CT scans [75]. ICP is a strong predictor of outcome from severe TBI [5,6, 9,76-78]. Because of this, ethically a randomized trial of ICP monitoring with and without treatment is unlikely to be carried out. Similarly, a trial for treating or not treating systemic hypotension is not likely. Both hypotension and raised ICP are the leading causes of death in severe TBI. Furthermore, several studies have shown that patients who do not have ICH or who respond to ICP-lowering therapies have a lower mortality than those whose ICH does not respond to therapy [4-11, 79-82]. As a result, Guidelines for the Management of Severe TBI recommend that treatment should be initiated with ICP thresholds above 20 mm Hg (level II) as well as target a cerebral perfusion pressure (CPP) within the range of 50-70 (level III) [12]. Prevention and/or treatment of ICH is commonly accomplished by employing a


Therapeutic Hypothermia in Traumatic Brain Injury 81

GOS = Glascow Outcome Score

80 Therapeutic Hypothermia in Brain Injury

**2. Methods** 

hypothermia [13-50]. In addition, several studies have shown that development of fever following TBI is closely linked to intracranial hypertension and worsened outcome [51-53].

Clinical trials of hypothermia and temperature management for severe traumatic brain injury are divided into trials in which hypothermia is used to treat elevated intracranial pressure and those in which hypothermia is intended as a neuroprotectant, irrespective of intracranial pressure. In this article, we will review the current clinical evidence behind therapeutic hypothermia for the treatment of intracranial hypertension (ICH) in severe TBI

We queried the Medline database with the MeSH terms "Hypothermia, induced," "Fever", "Intracranial Hypertension", and "Traumatic Brain Injury" from 1993 till 2011. We utilized both PubMed and OVID to maximize database penetration. We searched the Cochrane Database of Systematic Reviews. We also hand searched bibliographies of relevant citations and reviews. Inclusion criteria were double-blind, placebo-controlled, randomized controlled trials (RCTs), observational studies or meta-analysesof therapeutic hypothermia for TBI patients in which ICPs are monitored.We limited the search to human literature; We did not limit language, but we extracted studies that involved only adult subjects excluding studies on the pediatric population. Information extracted included number of patients, ICP, length of cooling, length of re-warming, outcome, complications, methods used to control ICP and the quality of each study. We reviewed the literature pertaining to pathophysiology of Traumatic Brain Injury. We also reviewed the literature

In comatose TBI patients with an abnormal CT scan, the incidence of ICH was 53–63% [75]. Patients with a normal CT scan at admission, on the other hand, had a relatively low incidence of ICH (13%). However, within the normal CT group, if patients demonstrated at least two of three adverse features (age over 40 years, unilateral or bilateral motor posturing, or systolic BP < 90 mm Hg); their risk of ICH was similar to that of patients with abnormal CT scans [75]. ICP is a strong predictor of outcome from severe TBI [5,6, 9,76-78]. Because of this, ethically a randomized trial of ICP monitoring with and without treatment is unlikely to be carried out. Similarly, a trial for treating or not treating systemic hypotension is not likely. Both hypotension and raised ICP are the leading causes of death in severe TBI. Furthermore, several studies have shown that patients who do not have ICH or who respond to ICP-lowering therapies have a lower mortality than those whose ICH does not respond to therapy [4-11, 79-82]. As a result, Guidelines for the Management of Severe TBI recommend that treatment should be initiated with ICP thresholds above 20 mm Hg (level II) as well as target a cerebral perfusion pressure (CPP) within the range of 50-70 (level III) [12]. Prevention and/or treatment of ICH is commonly accomplished by employing a

patients, as well as therapeutic hypothermia as a neuroprotectant in severe TBI.

pertaining to major published guidelines in this area.

**3. Intracranial hypertension in TBI** 

**Table 1.** Effects of Hypothermia on intracranial pressure and outcome in patients with severe Traumatic Brain Injury: Randomized Controlled Trials

progression of therapeutic approaches that are efficacious in controlling ICP and uniformly believed to be easily applied with minimal or rare negative side effects. These measures include elevation of the head of the bed , avoiding hypotension, hypoxia, and hypercapnea or prolonged hypocapnea, intravenous sedation and analgesia, episodic administration of hyperosmolar agents (mannitol, hypertonic saline), and CSF drainage [12]. Reviewing the evidence behind all these aforementioned therapies is beyond the scope of this review, but the evidence of efficacy for all of these treatments is variable at best. They are recommended not so much because there is clear-cut proof of morbidity or mortality benefit but because they are deemed treatments without significant downside.

Therapeutic Hypothermia in Traumatic Brain Injury 83

GOS = Glascow Outcome Score

**Table 2.** Effects of Hypothermia on intracranial pressure and outcome in patients with severe

Traumatic Brain Injury: Nonrandomized Observational Trials
