# Abstract

 

## Background: Induced hypothermia for treatment of traumatic brain injury is controversial. Since many pathways involved in the pathophysiology of secondary brain injury are temperature dependent, regional brain hypothermia is thought capable to mitigate those processes. The objectives of this study are to assess the therapeutic effects and complications of regional brain cooling in severe head injury with Glasgow coma scale (GCS) 6-7. 

## Materials and Methods: A prospective randomized controlled pilot study involving patients with severe traumatic brain injury with GCS 6 and 7 who required decompressive craniectomy. Patients were randomized into two groups: Cooling and no cooling. For the cooling group, analysis was made by dividing the group into mild and deep cooling. Brain was cooled by irrigating the brain continuously with cold Hartmann solution for 24-48 h. Main outcome assessments were a dichotomized Glasgow outcome score (GOS) at 6 months posttrauma. 

## Results: A total of 32 patients were recruited. The cooling-treated patients did better than no cooling. There were 63.2% of patients in cooling group attained good GOS at 6 months compared to only 15.4% in noncooling group (*P* = 0.007). Interestingly, the analysis at 6 months post-trauma disclosed mild-cooling-treated patients did better than no cooling (70% vs. 15.4% attained good GOS, *P* = 0.013) and apparently, the deep-cooling-treated patients failed to be better than either no cooling (*P* = 0.074) or mild cooling group (*P* = 0.650). 

## Conclusion: Data from this pilot study imply direct regional brain hypothermia appears safe, feasible and maybe beneficial in treating severely head-injured patients. # Results 

## Demographic and clinical characteristics A total of 32 patients were recruited into the 2 years study period from 1^st^ January 2010 to 1^st^ January 2012, aged between 14 and 74 years old. Of these, five patients aged more than 60 years old (19.2%). There were 27 (84.4%) males and 5 (15.6%) females. Patients were randomized into 2 groups; cooling group consisted of 19 patients (59.4%) and no cooling group consisted of 13 patients (40.6%). Finally, further stratification of cooling group based on the temperature of infused solution created 3 analyzable groups; mild cooling consisted of 10 patients (31.3%), deep cooling of 9 patients (28.1%) and no cooling of 13 patients (40.6%). The mean ages of the recruited patients were 28.9, 26.7 and 45.5 years old for the mild cooling, deep cooling and no cooling groups, respectively. Fifteen patients were admitted with GCS of 6 (46.9%) and 17 patients with GCS of 7 (53.1%). Among these, 28 patients (87.5%) underwent unilateral decompresive craniectomy, while four patients had bifrontal decompressive craniectomy (12.5%). [Table 1](#) illustrates those parameters where all groups were comparable with non-statistical difference shown for gender, GCS, ISS, Marshall score and clotting profiles. Age was the only basic parameters that differed among the three studied groups (*P* = 0.02). Even though the highest mean age was found in the control group, the 95% CIs (95% CI) for all three groups were still within the age of \<60 years old. ::::table-wrap

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Basic parameters comparison among the 3 studied groups
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## Effect of regional brain cooling on Glasgow outcome score There was a strong significant difference at 6 months post-trauma outcomes with *P* = 0.007 between the two studied groups: Cooling versus no cooling \[[Table 2](#)\]. There were 63.2% of patients (12 patients) in cooling group attained good GOS at 6 months compared with only 15.4% in non-cooling group (2 patients). There was no significant difference between the two groups when outcomes analysis was made at time of discharge. Further analysis at 6 months post-trauma was made after stratifying the cooling group into 2: Mild and deep cooling. [Table 3](#) disclosed presence of significant difference among the three analyzed groups at 6 months post-trauma (*P* = 0.023). When comparison was only made between 2 groups (no cooling vs mild cooling; no cooling vs deep cooling and mild cooling vs deep cooling), it seems that the mild-cooling-treated patients fared better than no cooling (70% of mild cooling attained good GOS compared with only 15.4% attained good GOS in no cooling group, *P* = 0.013); and apparently, the deep-cooling-treated patients failed to be better than either no cooling (*P* = 0.074) or mild cooling group (*P* = 0.650). ::::table-wrap
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Effect of regional brain cooling on GOS at discharge and at 6 months
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Effect of regional brain cooling on GOS at 6 months after stratifying
the cooling group into mild and deep cooling
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## Effect of regional brain cooling on trends of intracranial pressure, cerebral perfusion pressure, brain oxygenation, brain and body temperature and brain-body temperature gradient All recruited patients did have ICP monitored but there were one patient in deep cooling, two patients in mild cooling and three patients in no cooling groups did not have neuromonitoring for focal brain oxygenation (PtiO~2~) and temperature due to unavailability at certain time of the study period (26 patients did have those two specific neuromonitorings). Cooling the severely injured brain which had underwent decompressive craniectomy did not reduce the ICP further, but instead shown marked improvements in CPP and Licox PtiO~2~ after 12 h of cooling. [Figure 2](#) discloses mean IC*P* values and patterns for the three studied groups. All ICP readings stayed below 25 mmHg, and marked fluctuations were noted in cooling groups. Figures [3](#) and [4](#) reveal mean values and trends for CPP and Licox PtiO~2~, respectively. Mild cooling group had ascending trends of CPP with mean values above 60 mmHg but \<75 mmHg together with PtiO~2~ mean values of above 40 mmHg after 12 h of cooling therapy. Interestingly, the deep cooling group did have similar ascending trends for CPP and PtiO~2~ but their mean values after 12 h of cooling therapy were above 75 mmHg and \<30 mmHg, respectively. [Figure 5](#) gives additional information on brain-body (axillary) temperature gradient and types of cooling therapy. Patients in mild cooling group appeared to have a larger difference in brain-body (axillary) temperature gradient. [Figure 6](#) shows, even during brain cooling therapy for severely injured brain, the brain temperature is still higher than body (axillary) temperature. <figure> <p><img src="" /></p> <figcaption>Trends of mean intracranial pressures for three different groups within 48 h of monitoring and therapy</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Trends of mean cerebral perfusion pressures for three different groups within 48 h of monitoring and therapy</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Trends of mean focal brain oxygenation for three different groups within 48 h of monitoring and therapy</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Trends of mean difference between brain and body temperature (brain – body temperature) for three different groups within 48 h of monitoring and therapy</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Brain temperature is higher (0.1-2°C higher) than body (axillary) temperature. The figures depicted in such way that the scales were aligned and therefore, the figures were comparable</figcaption> </figure> 

## Effect of regional brain cooling on immunological biomarkers Due to inadequate volume of blood taken for immunological analysis for either before or after cooling therapy, immunological data of three patients in mild cooling and one patient in deep cooling were excluded from the analysis. Trend analysis of seven patients in mild cooling and eight patients in deep cooling showed obvious decrements in values for both, T cell markers and pro-inflammatory cytokines after cooling therapy. Intriguingly, markers for pro-inflammatory cytokines (IL-1, IL-6 and TNF) did show more marked decrement than markers for T-cell \[[Table 4](#)\]. Despite of marked decrement in most studied immunological biomarkers after cooling therapy, the Wilcoxon Signed Ranked test for two related samples disclosed insignificant difference between pre- and post-cooling for all immunological parameters. This presumably related to our small sample size, which incapable to detect significant differences in those studied immunological parameters. ::::table-wrap
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Effects of regional brain cooling (both mild and deep cooling groups
combined together) on immunological parameters
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## Correlation between studied parameters with Glasgow outcome score at 6 months post-trauma Correlation analysis using Spearman rank correlation coefficient discloses age (*r* = 0.46) and Licox brain oxygenation (*r* = 0.40) as the only two studied parameters that reasonably correlated with outco\]me score at 6 months post-trauma. [Table 5](#) illustrates the results. ::::table-wrap
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Correlation analysis between studied parameters with outcome score at 6
months
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## Incidence of complications Of the 32 patients, 50% (*n* = 16) had developed complications as shown in [Table 6](#). The complications included wound infection in 21.9% (*n* = 7), CSF infection in 9.4% (*n* = 3), pneumonia in 6.25% (*n* = 2), hydrocephalus in 3.12% (*n* = 1) and brain infarct in 9.4% (*n* = 3). The number of patients who developed complications was higher in no cooling, and deep cooling groups compared with mild cooling group. Kruskal Wallis non-parametric statistical test comparing the three groups for complication disclosed insignificant difference with *P* = 0.405. In conclusion, no significant difference is found in the incidence of complication among the three groups. ::::table-wrap
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Association between treatment groups and incidence of complication
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Extracted trial result:
Outcome: Improvement in Glasgow outcome score at 6 months post-trauma (continuous)
Intervention: Deep-cooling
Comparator: Mild-cooling
Intervention group size: 9
Comparator group size: 10
Comparator mean: 70