Hypothermic Targeted Temperature Management Research Articles

Temperature Management in Patients After Cardiac Arrest


 Two systematic reviews (1 with a network meta-analysis and 1 with a meta-analysis), 1 randomized controlled trial, and 7 non-randomized studies were identified about the comparative clinical effectiveness of normothermia versus hypothermia in adult patients after cardiac arrest.
 Normothermia was found to be similar to hypothermia for several clinical- and patient-related outcomes, such as survival, hospital mortality, and quality of life. There was limited evidence to suggest that either type of targeted temperature management was more efficacious, with findings suggesting that normothermia may be associated with greater protocol adherence and decreased prescription medication use coming from low-quality non-randomized studies.
 Four evidence-based guidelines were identified regarding targeted temperature management (normothermia or hypothermia) in adult patients after cardiac arrest. All guidelines strongly recommend targeted temperature management for eligible patients, particularly for patients resuscitated following out-of-hospital cardiac arrest. Identified guidelines from the Canadian Cardiovascular Society and American Academy of Neurology present strong recommendations for hypothermic targeted temperature management.

Rapid Treatment with Intramuscular Magnesium Sulfate During Cardiopulmonary Resuscitation Does Not Provide Neuroprotection Following Cardiac Arrest.

Brain injury is the most common cause of death for patients resuscitated from cardiac arrest. Magnesium is an attractive neuroprotective compound which protects neurons from ischemic injury by reducing neuronal calcium overload via NMDA receptor modulation and preventing calcium-induced mitochondrial permeability transition. Intramuscular (IM) delivery of MgSO4 during CPR has the potential to target these mechanisms within an early therapeutic window. We hypothesize that IM MgSO4 administrated during CPR could achieve therapeutic serum magnesium levels within 15min after ROSC and improve neurologic outcomes in a rat model of asphyxial cardiac arrest. Male Long Evans rats were subjected to 8-min asphyxial cardiac arrest and block randomized to receive placebo, 107mg/kg, 215mg/kg, or 430mg/kg MgSO4 IM at the onset of CPR. Serum magnesium concentrations increased rapidly with IM delivery during CPR, achieving twofold to fourfold increase by 15min after ROSC in all magnesium dose groups. Rats subjected to cardiac arrest or sham surgery were block randomized to treatment groups for assessment of neurological outcomes. We found that IM MgSO4 during CPR had no effect on ROSC rate (p > 0.05). IM MgSO4 treatment had no statistically significant effect on 10-day survival with good neurologic function or hippocampal CA1 pyramidal neuron survival compared to placebo treatment. In conclusion, a single dose IM MgSO4 during CPR achieves up to fourfold baseline serum magnesium levels within 15min after ROSC; however, this treatment strategy did not improve survival, recovery of neurologic function, or neuron survival. Future studies with repeated dosing or in combination with hypothermic targeted temperature management may be indicated.

Differential Effectiveness of Hypothermic Targeted Temperature Management According to the Severity of Post-Cardiac Arrest Syndrome.

International guidelines recommend targeted temperature management (TTM) to improve the neurological outcomes in adult patients with post-cardiac arrest syndrome (PCAS). However, it still remains unclear if the lower temperature setting (hypothermic TTM) or higher temperature setting (normothermic TTM) is superior for TTM. According to the most recent large randomized controlled trial (RCT), hypothermic TTM was not found to be associated with superior neurological outcomes than normothermic TTM in PCAS patients. Even though this represents high-quality evidence obtained from a well-designed large RCT, we believe that we still need to continue investigating the potential benefits of hypothermic TTM. In fact, several studies have indicated that the beneficial effect of hypothermic TTM differs according to the severity of PCAS, suggesting that there may be a subgroup of PCAS patients that is especially likely to benefit from hypothermic TTM. Herein, we summarize the results of major RCTs conducted to evaluate the beneficial effects of hypothermic TTM, review the recent literature suggesting the possibility that the therapeutic effect of hypothermic TTM differs according to the severity of PCAS, and discuss the potential of individualized TTM.

Impact of controlled normothermia following hypothermic targeted temperature management for post-rewarming fever and outcomes in post-cardiac arrest patients: A propensity score-matched analysis from a multicentre registry

Aim of the studyWe investigated whether controlled normothermia (CN) after the rewarming phase of targeted temperature management (TTM) is associated with preventing post-rewarming fever and outcomes 6 months after out-of-hospital cardiac arrest (OHCA). MethodsThis was an analysis of a prospective registry comprising OHCA patients treated with TTM at 22 academic hospitals between October 2015 and December 2018. We calculated the incremental area under the curve (iAUC) for body temperature greater than or equal to 37.5 °C for each patient during the first 24 h after the end of rewarming. The relationships among CN and iAUC, 6-month survival and good neurological outcome were analysed. To minimize differences in the baseline characteristics of the patients, we used propensity score-matched analysis. ResultsIn total, 1144 patients were enrolled. After propensity score matching, 646 patients (comprising 323 pairs) were obtained. In the unmatched cohort, post-rewarming CN was significantly associated with a lower iAUC (0.34 [1.38] vs. 1.19 [2.27]; p < 0.001) but not 6-month survival (adjusted odds ratio (OR): 1.121; 95% confidence interval (CI): 0.836−1.504; p = 0.446) and good neurological outcome (adjusted OR: 1.030; 95% CI: 0.734−1.446; p = 0.863). The results were similar in the propensity score-matched cohort (0.38 [1.56] vs. 1.03 [2.21], p < 0.001, OR: 1.347, 95% CI: 0.989−1.835, p = 0.059 and OR: 1.280, 95% CI 0.925−1.772, p = 0.137, respectively). ConclusionPost-rewarming CN prevents high fever in the normothermia phase of TTM. However, our data suggest the lack of association between CN and the patient’s 6-month survival and good neurological outcome.

Targeted Temperature Management Suppresses Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Expression in a Pig Model of Cardiac Arrest.

BackgroundThe hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor subtype 2 (VEGFR-2) pathway has been implicated in ischemia/reperfusion injury. The aim of this study was to clarify whether whole-body hypothermic targeted temperature management (HTTM) inhibits the HIF-1α/VEGF/VEGFR-2 pathway in a swine model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR).MethodsTwenty-four domestic male Beijing Landrace pigs were used in this study. CA was electrically induced with ventricular fibrillation and left untreated for 8 min. Return of spontaneous circulation (ROSC) was achieved in 16 pigs, which were randomly assigned either to normothermia at 38 °C or to HTTM at 33 °C (each group: n = 8). HTTM was intravascularly induced immediately after ROSC. The core temperature was reduced to 33 °C and maintained for 12 h after ROSC. The serum levels of HIF-1α, VEGF, VEGFR-2, and neuron-specific enolase (NSE) were measured with enzyme immunoassay kits 0.5, 6, 12, and 24 h after ROSC. The expression of HIF-1α, VEGF, and VEGFR-2 in cerebral cortical tissue was measured by RT-PCR and Western blot analysis 24 h after ROSC. Neurological deficit scores and brain cortical tissue water content were evaluated 24 h after ROSC.ResultsThe serum levels of HIF-1α, VEGF, and VEGFR-2 were significantly increased under normothermia within 24 h after ROSC. However, these increases were significantly reduced by HTTM. HTTM also decreased cerebral cortical HIF-1α, VEGF, and VEGFR-2 mRNA and protein expression 24 h after ROSC (all p < 0.05). HTTM pigs had better neurological outcomes and less brain edema than normothermic pigs.ConclusionThe HIF-1α/VEGF/VEGFR-2 system is activated following CA and CPR. HTTM protects against cerebral injury after ROSC, which may be part of the mechanism by which it inhibits the expression of components of the HIF-1α/VEGF/VEGFR-2 signaling pathway.

Abstract 123: Intra-arrest Delivery of Intra-muscular Magnesium Sulfate in a Rat Model of Cardiac Arrest

Introduction: Brain injury is the most common cause of death for patients resuscitated from cardiac arrest. Magnesium is an attractive neuroprotective therapy that has the potential to reduce neuronal calcium overload via NMDA receptor modulation and prevent mitochondrial permeability transition. Intramuscular (IM) delivery of MgSO4 during CPR has the potential to target these mechanisms within their presumed therapeutic window. Hypothesis: IM MgSO4 administrated during CPR will achieve therapeutic serum magnesium levels, which is ≥ 2 times of baseline, within 15 minutes after ROSC and improve neurologic outcomes. Methods: Male Long Evans rats were subjected to 8-minute asphyxial cardiac arrest. For the dose-finding study (n = 4/group), rats were block randomized to receive placebo, 107 mg/kg, 215 mg/kg, or 430 mg/kg MgSO4 IM at the onset of CPR. Serial blood samples were collected at baseline, 15 min, 30 minutes, 1 hour and 2 hours after return of spontaneous circulation (ROSC) and analyzed for serum magnesium concentration. For the long-term outcome study (n = 9/group), rats subjected to cardiac arrest were blindly block randomized to the same treatment groups with the addition of a sham-operated group. Post-cardiac arrest care included maintenance of normothermia (36.7 °C - 37.3 °C) for 72 hours. Serial blood samples were collected at baseline, 15 min and 1 hour after ROSC and neurologic function score (NFS) was performed daily for 10 days. Good neurologic function was predefined as NFS ≥ 450. Results: IM MgSO4 during CPR had no effect on ROSC rate (p &gt; 0.05). The serum magnesium concentrations at 15 min after ROSC of 107 mg/kg group, 215 mg/kg group and 430 mg/kg group were 3.9 ± 0.9, 6.2 ± 1.8, and 7.6 ± 1.8 mg/dl, which were 2.0 fold, 3.1 fold and 4.2 fold of baseline respectively. IM MgSO4 had no statistically significant effect on 10-day survival or 10-day survival with good neurologic function. Conclusion: Single dose IM MgSO4 during CPR achieves up to 4-fold baseline magnesium levels within 15 min after ROSC in a rat model of asphyxia cardiac arrest. This treatment strategy did not improve survival or recovery of neurologic function. Future studies with repeated dosing or in combination with hypothermic targeted temperature management may be indicated.

High HbA1c is associated with decreased 6-month survival and poor outcomes after out-of-hospital cardiac arrest: a retrospective cohort study

BackgroundTo evaluate the associations between glycated hemoglobin (HbA1c) at admission and 6-month mortality and outcomes after out-of-hospital cardiac arrest (OHCA) treated by hypothermic targeted temperature management (TTM).MethodsThis single-center retrospective cohort study included adult OHCA survivors who underwent hypothermic TTM from December 2011 to December 2019. High HbA1c at admission was defined as a level higher than 6%. Poor neurological outcomes were defined as cerebral performance category scores of 3–5. The primary outcome was 6-month mortality. The secondary outcome was the 6-month neurological outcome. Descriptive statistics, log-rank tests, and multivariable regression modeling were used for data analysis.ResultsOf the 302 patients included in the final analysis, 102 patients (33.8%) had HbA1c levels higher than 6%. The high HbA1c group had significantly worse 6-month survival (12.7% vs. 37.5%, p < 0.001) and 6-month outcomes (89.2% vs. 73.0%, p = 0.001) than the non-high HbA1c group. Kaplan-Meier analysis and the log-rank test showed that the survival time was significantly shorter in the patients with HbA1c > 6% than in those with HbA1c ≤6%. In the multivariable logistic regression analysis, HbA1c > 6% was independently associated with 6-month mortality (OR 5.85, 95% CI 2.26–15.12, p < 0.001) and poor outcomes (OR 4.18, 95% CI 1.41–12.40, p < 0.001).ConclusionsThis study showed that HbA1c higher than 6% at admission was associated with increased 6-month mortality and poor outcomes in OHCA survivors treated with hypothermic TTM. Poor long-term glycemic management may have prognostic significance after cardiac arrest.

Early prognostication of neurological outcome by heart rate variability in adult patients with out-of-hospital sudden cardiac arrest

BackgroundMost deaths of comatose survivors of out-of-hospital sudden cardiac arrest result from withdrawal of life-sustaining treatment (WLST) decisions based on poor neurological prognostication and the family’s intention. Thus, accurate prognostication is crucial to avoid premature WLST decisions. However, targeted temperature management (TTM) with sedation or neuromuscular blockade against shivering significantly affects early prognostication. In this study, we investigated whether heart rate variability (HRV) analysis could prognosticate poor neurological outcome in comatose patients undergoing hypothermic TTM.MethodsBetween January 2015 and December 2017, adult patients with out-of-hospital sudden cardiac arrest, successfully resuscitated in the emergency department and admitted to the intensive care unit of the Niigata University in Japan, were prospectively included. All patients had an initial Glasgow Coma Scale motor score of 1 and received hypothermic TTM (at 34 °C). Twenty HRV-related variables (deceleration capacity; 4 time-, 3 geometric-, and 7 frequency-domain; and 5 complexity variables) were computed based on RR intervals between 0:00 and 8:00 am within 24 h after return of spontaneous circulation (ROSC). Based on Glasgow Outcome Scale (GOS) at 2 weeks after ROSC, patients were divided into good outcome (GOS 1–2) and poor outcome (GOS 3–5) groups.ResultsSeventy-six patients were recruited and allocated to the good (n = 22) or poor (n = 54) outcome groups. Of the 20 HRV-related variables, ln very-low frequency (ln VLF) power, detrended fluctuation analysis (DFA) (α1), and multiscale entropy (MSE) index significantly differed between the groups (p = 0.001), with a statistically significant odds ratio (OR) by univariate logistic regression analysis (p = 0.001). Multivariate logistic regression analysis of the 3 variables identified ln VLF power and DFA (α1) as significant predictors for poor outcome (OR = 0.436, p = 0.006 and OR = 0.709, p = 0.024, respectively). The area under the receiver operating characteristic curve for ln VLF power and DFA (α1) in predicting poor outcome was 0.84 and 0.82, respectively. In addition, the minimum value of ln VLF power or DFA (α1) for the good outcome group predicted poor outcome with sensitivity = 61% and specificity = 100%.ConclusionsThe present data indicate that HRV analysis could be useful for prognostication for comatose patients during hypothermic TTM.

Abstract 222: Role of Pathologic Calpain Activity in Post-Cardiac Arrest Hypothermic Targeted Temperature Management

Objective: Optimization of post-cardiac arrest hypothermic-targeted temperature management (HTTM) is limited by an inadequate understanding of the fundamental mechanisms of action. This study tested the hypothesis that post-cardiac arrest HTTM reduces delayed secondary neuronal cytosolic Ca 2+ overload that causes pathologic calpain activity and neuronal death after cardiac arrest (CA) Methods: Male Long Evens rats were subjected to 8-minute asphyxial CA (ACA) followed by CPR. Rats that achieved return of spontaneous circulation (ROSC) were block randomized to normothermic- targeted temperature management (NTTM; n=13), hypothermic-TTM at 36 o C (HTTM-36;n=13) or 33 o C (HTTM-33;n=10). HTTM was initiated 1h after ROSC and maintained for 24h. Neurologic function score was assessed daily. Rats were euthanized at 48h post-ROSC. Regional brain homogenates were generated in a subset of animals for Western blot analysis of calpain-cleaved alpha-spectrin as a measure of pathologic calpain activity (n=6/group). Sham rats were used as uninjured controls (n=9) Results: Survival at 48h post-ROSC was 69%, 69%, and 90% in the NTTM, HTTM-36 and HTTM-33 groups respectively (p&gt;0.05: chi-squared). Survival with good neurologic function (GNF: defined as NFS &gt; 450 out of 500) was 0%, 15%, and 60% in the NTTM, HTTM-36 and HTTM-33 groups respectively (p&lt;0.05 for HTTM-33 vs. HTTM-36 and NTTM: chi-squared). Compared to NTTM, pathologic calpain activity in the hippocampus, cortex, caudoputamen, and cerebellum was decreased by 23±20%, 38±56%, 40±55%, 62±20% in the HTTM-36 groups and 33±13%, 55±72%, 66±89%, 69±17% in the HTTM-33 group respectively (p &lt;0.05 for HTTM-33 and HTTM-36 cerebellum, p&gt; 0.05 for all other regions: ANOVA, Tukey’s post-hoc) Conclusion: In this rat model of asphyxial cardiac arrest, HTTM with a target temperature of 33°C improved 48-hour survival with GNF compared to HTTM with a target temperature of 36°C and NTTM. Post-cardiac arrest regional brain calpain activity was significantly reduced with HTTM at 33°C and 36°C compared to NTTM in the cerebellum, but not other brain regions. Further work is needed to explore the potential causal link between the reduction of pathologic calpain activity and the neuroprotective effect of post-cardiac arrest HTTM

Real-time quantitative monitoring of cerebral blood flow by laser speckle contrast imaging after cardiac arrest with targeted temperature management

Brain injury is the main cause of mortality and morbidity after cardiac arrest (CA). Changes in cerebral blood flow (CBF) after reperfusion are associated with brain injury and recovery. To characterize the relative CBF (rCBF) after CA, 14 rats underwent 7 min asphyxia-CA and were randomly treated with 6 h post-resuscitation normothermic (36.5–37.5℃) or hypothermic- (32–34℃) targeted temperature management (TTM) (N = 7). rCBF was monitored by a laser speckle contrast imaging (LSCI) technique. Brain recovery was evaluated by neurologic deficit score (NDS) and quantitative EEG – information quantity (qEEG-IQ). There were regional differences in rCBF among veins of distinct cerebral areas and heterogeneous responses among the three components of the vascular system. Hypothermia immediately following return of spontaneous circulation led to a longer hyperemia duration (19.7 ± 1.8 vs. 12.7 ± 0.8 min, p < 0.01), a lower rCBF (0.73 ± 0.01 vs. 0.79 ± 0.01; p < 0.001) at the hypoperfusion phase, a better NDS (median [25th–75th], 74 [61–77] vs. 49 [40–77], p < 0.01), and a higher qEEG-IQ (0.94 ± 0.02 vs. 0.77 ± 0.02, p < 0.001) compared with normothermic TTM. High resolution LSCI technique demonstrated hypothermic TTM extends hyperemia duration, delays onset of hypoperfusion phase and lowered rCBF, which is associated with early restoration of electrophysiological recovery and improved functional outcome after CA.

Valproic Acid Combined With Postcardiac Arrest Hypothermic-Targeted Temperature Management Prevents Delayed Seizures and Improves Survival in a Rat Cardiac Arrest Model

High-dose valproic acid in combination with hypothermic-targeted temperature management has been reported to synergistically improve neurologic outcomes after cardiac arrest. This study investigated the potential synergistic mechanisms. Prospective, randomized, experimental study. University research institution. Male Long Evans rats. Rats resuscitated from asphyxial cardiac arrest were randomized to one of the three groups: normothermic-targeted temperature management (37°C ± 1°C), hypothermic-targeted temperature management (33° ± 1° × 24 hr + placebo infusion), hypothermic-targeted temperature management plus high-dose valproic acid (300 mg/kg IV × 1 initiated 5 min post return of spontaneous circulation and infused over 20 min) (hypothermic-targeted temperature management + valproic acid). Seventy-two-hour survival was significantly greater with hypothermic-targeted temperature management + valproic acid, compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p < 0.05). Survival with good neurologic function, neurodegeneration, expression of HSP70, phosphorylation of Akt and Erk1/2 were not significantly different between hypothermic-targeted temperature management and hypothermic-targeted temperature management + valproic acid. The prevalence of seizures during the first 72-hour postcardiac arrest was significantly lower with hypothermic-targeted temperature management + valproic acid compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p = 0.01). High-dose valproic acid combined with hypothermic-targeted temperature management prevents postcardiac arrest seizures and improves survival. It remains to be determined if the mechanism of seizure prevention is through the antiepileptic effect of valproic acid or direct neuroprotection. Overall, the combination of high-dose valproic acid and hypothermic-targeted temperature management remains a promising strategy to improve cardiac arrest outcomes.

Establishment of an ideal time window model in hypothermic-targeted temperature management after traumatic brain injury in rats

Although hypothermic-targeted temperature management (HTTM) holds great potential for the treatment of traumatic brain injury (TBI), translation of the efficacy of hypothermia from animal models to TBI patientshas no entire consistency. This study aimed to find an ideal time window model in experimental rats which was more in accordance with clinical practice through the delayed HTTM intervention. Sprague-Dawley rats were subjected to unilateral cortical contusion injury and received therapeutic hypothermia at 15mins, 2 h, 4 h respectively after TBI. The neurological function was evaluated with the modified neurological severity score and Morris water maze test. The brain edema and morphological changes were measured with the water content and H&E staining. Brain sections were immunostained with antibodies against DCX (a neuroblast marker) and GFAP (an astrocyte marker). The apoptosis levels in the ipsilateral hippocampi and cortex were examined with antibodies against the apoptotic proteins Bcl-2, Bax, and cleaved caspase-3 by the immunofluorescence and western blotting. The results indicated that each hypothermia therapy group could improve neurobehavioral and cognitive function, alleviate brain edema and reduce inflammation. Furthermore, we observed that therapeutic hypothermia increased DCX expression, decreased GFAP expression, upregulated Bcl-2 expression and downregulated Bax and cleaved Caspase-3 expression. The above results suggested that HTTM at 2h or even at 4h post-injury revealed beneficial brain protection similarly, despite the best effect at 15min post-injury. These findings may provide relatively ideal time window models, further making the following experimental results more credible and persuasive.

Combined intra- and post-cardiac arrest hypothermic-targeted temperature management in a rat model of asphyxial cardiac arrest improves survival and neurologic outcome compared to either strategy alone

AimPost-cardiac arrest hypothermic-targeted temperature management (HTTM) improves outcomes in preclinical cardiac arrest studies. However, inadequate understanding of the mechanisms and therapeutic windows remains a barrier to optimization. We tested the hypothesis that combined intra- and post-cardiac arrest HTTM provides a synergistic outcome benefit compared to either strategy alone. MethodsRats subjected to 8-min asphyxial cardiac arrest were block randomized to 4 treatment groups (n=12/group): NTTM) normothermic-targeted temperature management; 1-24 HTTM) HTTM initiated 1h post-ROSC and maintained for 24h; Intra-1 HTTM) HTTM initiated at CPR onset and maintained for 1h; and Intra-24 HTTM) HTTM initiated at CPR onset and maintained for 24h. HTTM was induced by nasopharyngeal cooling and maintained using an automated temperature regulation system. Target temperature range was 36.5–37.5°C for NTTM and 32.0–34.0°C for HTTM. Post-arrest neurologic function score (NFS) was measured daily, and rats surviving 72h were euthanized for histological analysis of neurodegeneration. ResultsTarget brain temperature was achieved 7.8±3.3min after initiating intra-arrest cooling. The survival rate was 42%, 50%, 50%, and 92% in the NTTM, 1-24 HTTM, Intra-1 HTTM, and Intra-24 HTTM groups, respectively (p<0.05, Intra-24 group vs. all other groups). The rate of survival with good neurologic function (NFS≥450) was 33% in the Intra-24 HTTM group vs. 0% in all other groups (mid p<0.05). Hippocampal CA1 sector neurodegeneration was significantly reduced in the Intra-24 HTTM group compared to all other groups (p<0.05). ConclusionCombined intra- and post-cardiac arrest HTTM has greater outcome benefits than either strategy alone.

Abstract 17230: Early Continuous EEG Biomarkers Predicts Neurologic Outcome in Post-cardiac Arrest Rats

Introduction: Hypothermic targeted temperature management (TTM) has greatly improved post-cardiac arrest patient outcomes, but also makes prognostication more difficult. In this study, we tested the hypothesis that early continuous EEG biomarkers are associated with neurologic outcome in post-cardiac arrest rats treated with normothermic and hypothermic TTM. Methods: Male rats were instrumented for continuous telemetric EEG (cEEG) recording and then subjected to 8-minute asphyxia cardiac arrest. Eight rats that achieved ROSC underwent either normothermic or hypothermic TTM (37 ± 0.5 °C or 33 ± 0.5 °C) for 24 hours and cEEG monitoring up to 72 hours. Quantitative EEG analysis determined the power density of delta (0.1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz) and sigma (13-18 Hz) frequency bands in all 10 second windows. The mean spectral power and Spearman correlation with time for the first 12 hours after return of spontaneous circulation (ROSC) were calculated and correlated with best neurologic function score (NFS) and survival with good NFS (NFS ≥ 450 out of 500). Results: Over all rats tested, the mean delta band power in the first 12 hours after ROSC was inversely correlated with best neurologic function score and associated with poor outcome (Table and Figure). There was no statistical difference in other frequency bands. Similar findings were present when stratifying into normothermic and hypothermic treatment groups. Conclusions: This study suggests that, the early power density of delta frequency bands from cEEG is a potential predictor of neurologic outcome in a mixed population of rats treated with normothermic and hypothermic TTM.

P.6.e.004 Prevalence, characteristics, and associated mental disorders of nicotine dependence in South Korea

Although hypothermic-targeted temperature management (HTTM) holds great potential for the treatment of traumatic brain injury (TBI), translation of the efficacy of hypothermia from animal models to TBI patients has no entire consistency. This study aimed to find an ideal time window model in experimental rats which was more in accordance with clinical practice through the delayed HTTM intervention. Sprague-Dawley rats were subjected to unilateral cortical contusion injury and received therapeutic hypothermia at 15 mins, 2 h, 4 h respectively after TBI. The neurological function was evaluated with the modified neurological severity score and Morris water maze test. The brain edema and morphological changes were measured with the water content and H&E staining. Brain sections were immunostained with antibodies against DCX (a neuroblast marker) and GFAP (an astrocyte marker). The apoptosis levels in the ipsilateral hippocampi and cortex were examined with antibodies against the apoptotic proteins Bcl-2, Bax, and cleaved caspase-3 by the immunofluorescence and western blotting. The results indicated that each hypothermia therapy group could improve neurobehavioral and cognitive function, alleviate brain edema and reduce inflammation. Furthermore, we observed that therapeutic hypothermia increased DCX expression, decreased GFAP expression, upregulated Bcl-2 expression and downregulated Bax and cleaved Caspase-3 expression. The above results suggested that HTTM at 2 h or even at 4 h post-injury revealed beneficial brain protection similarly, despite the best effect at 15 min post-injury. These findings may provide relatively ideal time window models, further making the following experimental results more credible and persuasive.