Moderate hypothermia may be detrimental after traumatic brain injury in fentanyl-anesthetized rats

OBJECTIVES: To determine whether transient, moderate hypothermia is beneficial after traumatic brain injury in fentanyl-anesthetized rats. DESIGN: Prospective, randomized study. SETTING: University-based animal research facility. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: All rats were intubated, mechanically ventilated, and anesthetized with fentanyl (10 microg/kg intravenous bolus and then 50 microg.kg(-1).hr(-1) infusion). Controlled cortical impact was performed to the left parietal cortex, followed immediately by 1 hr of either normothermia (brain temperature 37 +/- 0.5 degrees C) or hypothermia (brain temperature 32 +/- 0.5 degrees C). Hypothermic rats were rewarmed gradually over 1 hr. Fentanyl anesthesia and mechanical ventilation were continued in both groups until the end of rewarming (2 hrs after traumatic brain injury). MEASUREMENTS AND MAIN RESULTS: Histologic assessment performed 72 hrs after traumatic brain injury was the primary outcome variable. Secondary outcome variables were physiologic variables monitored during the first 2 hrs after traumatic brain injury and plasma catecholamine and serum fentanyl concentrations measured at the end of both hypothermia and rewarming (1 and 2 hrs after traumatic brain injury). Contusion volume was larger in hypothermic vs. normothermic rats (44.3 +/- 4.2 vs. 28.6 +/- 4.0 mm, p <.05), but hippocampal neuronal survival did not differ between groups. Physiologic variables did not differ between groups. Plasma dopamine and norepinephrine concentrations were increased at the end of hypothermia in hypothermic (vs. normothermic) rats (p <.05), indicating that hypothermia augmented the systemic stress response. Similarly, serum fentanyl concentrations were higher in hypothermic (vs. normothermic) rats at the end of both hypothermia and rewarming (p <.05), demonstrating that hypothermia reduced the clearance and/or metabolism of fentanyl. CONCLUSIONS: Moderate hypothermia was detrimental after experimental traumatic brain injury in fentanyl-anesthetized rats. Since treatment with hypothermia has provided reliable benefit in experimental traumatic brain injury with inhalational anesthetics, these results indicate that the choice of anesthesia/analgesia after traumatic brain injury may dramatically influence response to other therapeutic interventions, such as hypothermia. Given that narcotics commonly are administered to patients after severe traumatic brain injury, this study may have clinical implications.     

Mild protective and resuscitative hypothermia for asphyxial cardiac arrest in rats

It has been shown in dogs that mild hypothermia (34°C) during or immediately after ventricular fibrillation cardiac arrest can improve cerebral outcome. The effect of mild hypothermia on outcome after 8 minutes of asphyxiation (5 minutes' cardiac arrest) was studied for the first time in rats. Restoration of spontaneous circulation was with external cardiopulmonary resuscitation and observation to 72 hours. Three groups of 10 rats each were studied. At 72 hours postarrest, compared with the normothermic control group 1, final overall performance categories (OPC) and neurological deficit scores (NDS) were numerically better in the resuscitative (post-arrest) hypothermia group 2 and significantly better in the protective (pre-intra-arrest) hypothermia group 3 (P < .05). Total brain histopathological damage scores (HDS) were 17 ± 5 in group 1, 14 ± 6 in group 2 (NS), and 6 ± 2 in group 3 (P < .001 versus group 1). HDS correlated with OPC (r = .6, P < .05) and NDS (r = .7, P < .05). Mild hypothermia improved cerebral outcome after asphyxial cardiac arrest in rats, more when induced before than after arrest. The model's insult is within the therapeutic window, which makes it also suitable for screening other cerebral resuscitation potentials.     

Mild hypothermia prolongs the survival time during uncontrolled hemorrhagic shock in rats

OBJECTIVE: To test our hypothesis that during lethal uncontrolled hemorrhagic shock (UHS) in rats, mild hypothermia of either 36 or 34 degrees C would prolong the survival time in comparison with normotherma of 38 degrees C. METHODS: Twenty-four rats were lightly anesthetized with halothane and maintained spontaneous breathing. UHS was induced by blood withdrawal of 2.5 ml/100 g over 15 min, followed by 75% tail amputation. Immediately after the tail cut, the rats were randomly divided into three groups (eight rats for each); normothermic Group 1 (control, rectal temperature 38 degrees C), and mild hypothermic Groups 2 (36 degrees C) and 3 (34 degrees C). Hypothermia was induced and maintained by body surface cooling. The rats were then observed without fluid resuscitation until their death (apnea and no pulse) or for a period of 240 min maximum. RESULTS: The rectal temperature was cooled down to 36 and 34 degrees C in 5 and 10 min, respectively. The mean survival time, which was 76+/-26 min in the control group (38 degrees C), was nearly doubled by mild hypothermia, 178+/-65 min for Group 2 (36 degrees C) (P<0.01 vs. control) and 144+/-54 min for Group 3 (34 degrees C) (P<0.05 vs. control) (no significant difference between Group 2 and 3). Additional blood losses from tail stumps were not significantly different among the three groups. CONCLUSION: Mild hypothermia of either 36 or 34 degrees C prolongs the survival time during lethal UHS in rats.     

Small volume resuscitation with tempol is detrimental during uncontrolled hemorrhagic shock in rats

BACKGROUND: In a previous study, titration of a hypertonic saline (HTS) solution during severe uncontrolled hemorrhagic shock (UHS) failed to reduce mortality. In a separate study, a novel antioxidant, polynitroxylated albumin (PNA) plus tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), infused during shock increased long-term survival. We hypothesized that combining potent antioxidants with a hypertonic solution during UHS would preserve the logistical advantage of small volume resuscitation and improve survival. METHODS: An UHS outcome model in rats was used. UHS phase I (90 min) included blood withdrawal of 30 ml/kg over 15 min, followed by tail amputation for uncontrolled bleeding. At 20 min, rats were randomized to four groups (n=10 each) for hypotensive resuscitation from 20 to 90 min (mean arterial pressure [MAP] > or = 40 mmHg): HTS/starch group received 7.2% NaCl/10% hydroxyethyl starch; HTS/albumin group received 7.5% NaCl/20% albumin; HTS/PNA group received 7.5% NaCl/20% PNA; HTS/albumin+tempol group received 7.5% NaCl/20% albumin plus tempol. Resuscitation phase II (180 min) included hemostasis, return of shed blood and administration of fluids to restore MAP > or = 80 mmHg. Observation phase III was to 72 h. RESULTS: The total amount of fluid required to maintain hypotensive MAP during HS was low and did not differ between groups (range: 3.4+/-1.9 to 5.3+/-2.5 ml/kg). The rate of fluid administration required was higher in the HTS/albumin+tempol group compared to all other groups (p=0.006). Additional uncontrolled blood loss was highest in the HTS/PNA group (16.2+/-5.7 ml/kg [p=0.01] versus 10.4+/-7.9 ml/kg in the HTS/starch group, 7.7+/-5.2 ml/kg in the HTS/albumin group and 8.2+/-7.1 ml/kg in the HTS/albumin+tempol group). MAP after start of resuscitation in phase I was lower in the HTS/albumin+tempol group than the HTS/albumin or HTS/PNA groups (p<0.01). This group was also less tachycardic. Long-term survival was low in all groups (2 of 10 after HTS/starch and 1 of 10 after HTS/albumin, 3 of 10 after HTS/PNA, 1 of 10 after HTS/albumin+tempol). Median survival time was shortest in the HTS/albumin+tempol group (72 min [CI 34-190]) compared to all other groups (p=0.01). CONCLUSIONS: Despite its benefits in other model systems, free tempol is potentially hazardous when combined with hypertonic fluids. PNA abrogates these deleterious effects on acute mortality but may lead to increased blood loss in the setting of UHS.     

Mild hypothermia during hemorrhagic shock in rats improves survival without significant effects on inflammatory responses

OBJECTIVE: To explore the hypothesis that the survival benefit of mild, therapeutic hypothermia during hemorrhagic shock is associated with inhibition of lipid peroxidation and the acute inflammatory response. DESIGN: Prospective and randomized. SETTING: Animal research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats underwent pressure-controlled (mean arterial pressure 40 mm Hg) hemorrhagic shock for 90 mins. They were randomized to normothermia (38.0 +/- 0.5 degrees C) or mild hypothermia (33-34 degrees C from hemorrhagic shock 20 mins to resuscitation time 12 hrs). Rats were killed at resuscitation time 3 or 24 hrs. MEASUREMENTS AND MAIN RESULTS: All seven rats in the hypothermia group and seven of 15 rats in the normothermia group survived to 24 hrs (p <.05). Hypothermic rats had lower serum potassium and higher blood glucose concentrations at 90 mins of hemorrhagic shock (p <.05). At resuscitation time 24 hrs, the hypothermia group had less liver injury (based on serum concentrations of ornithine carbamolytransferase and liver histology) and higher blood glucose than the normothermia group (p <.05). There were no differences in serum free 8-isoprostane (a marker of lipid peroxidation by free radicals) between the two groups at either baseline or resuscitation time 1 hr. Serum concentrations of interleukin- 1 beta, interleukin-6, and tumor necrosis factor-alpha peaked at resuscitation time 1 hr. Tumor necrosis factor-alpha concentrations were higher (p <.05) at resuscitation time 1 hr in the hypothermia group compared with the normothermic group. Serum cytokine concentrations were not different between survivors and nonsurvivors in the normothermia group. Serum cytokine concentrations returned to baseline values in both groups by 24 hrs. There were no differences in the number of neutrophils in the lungs or the small intestine between the groups. More neutrophils were found in the lungs at resuscitation time 3 hrs than at resuscitation time 24 hrs in both groups (p <.01). CONCLUSIONS: These data suggest that lipid peroxidation and systemic inflammatory responses to hemorrhagic shock are minimally influenced by mild hypothermia, although liver injury is mitigated and survival improved. Other mechanisms of benefit from mild hypothermia need to be explored.     

Mild hypothermia after near drowning in twin toddlers

Introduction  

We report a case of twin toddlers who both suffered near drowning but with different post-trauma treatment and course, and different neurological outcomes.     

亚低温与脑缺血大鼠骨髓间充质干细胞的迁移

背景:关于亚低温运用到神经损伤修复领域的研究已有一些报道,但亚低温对神经干细胞在脑内移植迁移的影响还不太清楚.目的:观察亚低温对移植入脑缺血大鼠侧脑室的骨髓间质干细胞迁移的影响.方法:采用Longa法永久性闭塞SD大鼠大脑中动脉制作局灶性脑缺血损伤模型,亚低温组于移植前应用亚低温处理大鼠急性脑缺血损伤,对照组于移植前应用常温处理大鼠急性脑缺血损伤;造模术后24 h,在脑立体定向下,经侧脑室注射移植用5-BrdU标记的骨髓间充质干细胞.经过5,14,21,28 d,7周后用免疫组织化学方法检测各组大鼠脑组织BrdU阳性细胞数.结果与结论:移植第14天多数标记的骨髓基质细胞细胞已经迁移至梗死灶周围,移植后各时间点亚低温组梗死灶周边皮质的BrdU阳性细胞数明显多于对照组(P < 0.05).提示移植前宿主亚低温处理可以促进骨髓间充质细胞的定向迁移,对局灶性脑缺血有神经保护作用.     

Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms

Aim

Mild therapeutic hypothermia (32-34 °C) improves neurological recovery and reduces the risk of death in comatose survivors of cardiac arrest when the initial rhythm is ventricular fibrillation or pulseless ventricular tachycardia. The aim of the presented study was to investigate the effect of mild therapeutic hypothermia (32-34 °C for 24 h) on neurological outcome and mortality in patients who had been successfully resuscitated from non-ventricular fibrillation cardiac arrest.

Methods

In this retrospective cohort study we included cardiac arrest survivors of 18 years of age or older suffering a witnessed out-of-hospital cardiac arrest with asystole or pulseless electric activity as the first documented rhythm. Data were collected from 1992 to 2009. Main outcome measures were neurological outcome within six month and mortality after six months.

Results

Three hundred and seventy-four patients were analysed. Hypothermia was induced in 135 patients. Patients who were treated with mild therapeutic hypothermia were more likely to have good neurological outcomes in comparison to patients who were not treated with hypothermia with an odds ratio of 1.84 (95% confidence interval: 1.08-3.13). In addition, the rate of mortality was significantly lower in the hypothermia group (odds ratio: 0.56; 95% confidence interval: 0.34-0.93).

Conclusion

Treatment with mild therapeutic hypothermia at a temperature of 32-34 °C for 24 h is associated with improved neurological outcome and a reduced risk of death following out-of-hospital cardiac arrest with non-shockable rhythms.     

亚低温辅助治疗重型颅脑外伤患者82例

目的探讨亚低温在治疗重型颅脑外伤中的应用价值。方法对连续收治的160例重型颅脑外伤患者,随机分为亚低温治疗组（n=82）和常温组（n=78）,观察两组的治疗效果。结果随访6个月,亚低温组20例轻度残疾、正常生活,24例中残,16例重残,9例植物生存,13例死亡;对照组10例轻度残疾、正常生活,18例中残,16例重残,14例植物生存,20例死亡;两组比较有统计学差异（P〈0．05）,亚低温组的治疗效果优于常温组。结论亚低温有显著的脑保护作用,能降低重型颅脑外伤患者的死残率,改善预后。     

Mild hypothermia in improving multiple organ dysfunction after cardiac arrest

BACKGROUND:

Resuscitation after cardiac arrest (CA) with a whole-body ischemia–reperfusion injury causes brain injury and multiple organ dysfunction (MODS). This study aimed to determine whether mild systemic hypothermia could decrease multiple organ dysfunctions after resuscitation from cardiac arrest.

METHODS:

The patients who had been resuscitated after cardiac arrest were reviewed. During the resuscitation they had been assigned to undergo therapeutic hypothermia (target temperature, 32°C to 34°C, measured in the rectum) over a period of 24 to 36 hours or to receive standard treatment with normothermia. Markers of different organ injury were evaluated for the first 72 hours after recovery of spontaneous circulation (ROSC).

RESULTS:

At 72 hours after ROSC, 23 patients in the hypothermia group for whom data were available had favorable neurologic, myocardial, hepatic and pulmonic outcomes as compared with 26 patients in the normothermia group. The values of renal function were not significantly different between the two groups. However, blood coagulation function was badly injured in the hypothermia group.

CONCLUSION:

In the patients who have been successfully resuscitated after cardiac arrest, therapeutic mild hypothermia can alleviate dysfunction after resuscitation from cardiac arrest.KEY WORDS: Cardiac arrest, Ischemia reperfusion injury, Mild hypothermia, Multiple organ dysfunction     

Mild induced hypothermia and survival after out-of-hospital cardiac arrest

Background

Mild induced hypothermia (MIH) was introduced for post cardiac arrest care in Sweden in 2003, based on two clinical trials. This retrospective study evaluated its association with 30-day survival after out-of-hospital cardiac arrest (OHCA) in a Swedish community from 2003 to 2015.

Mild or moderate hypothermia, but not increased oxygen breathing, increases long-term survival after uncontrolled hemorrhagic shock in rats

OBJECTIVE: To test the hypotheses that, for uncontrolled hemorrhagic shock (UHS) in rats, mild hypothermia, compared with normothermia, would increase long-term survival as well as moderate hypothermia, oxygen breathing would increase survival further, and hypothermia and oxygen would mitigate visceral ischemia (dysoxia) during UHS. DESIGN: Prospective, randomized study. SETTING: Animal research laboratory. SUBJECTS: A total of 54 male Sprague-Dawley rats. INTERVENTIONS: Under light anesthesia and spontaneous breathing, rats underwent UHS phase I of 75 mins, with initial withdrawal of 3 mL/100 g of blood over 15 mins, followed by UHS via tail amputation and limited fluid resuscitation to maintain mean arterial pressure at > or =40 mm Hg; resuscitation phase II of 60 mins (from 75 mins to 135 mins) with hemostasis and aggressive fluid resuscitation to normalize hemodynamics; and observation phase III to 72 hrs. Rats were randomly divided into nine groups (n = 6 each) with three rectal temperature levels (38 degrees C [normothermia] vs. 34 degrees C [mild hypothermia] vs. 30 degrees C [moderate hypothermia]) by surface cooling; each with 3 FIO2 levels (0.25 vs. 0.5 vs. 1.0). MEASUREMENTS AND MAIN RESULTS: Hypothermia increased blood pressure compared with normothermia. Increased FIO2 had no effect on blood pressure. Additional blood loss from the tail cut was small, with no differences among groups. Hypothermia and FIO2 of 0.5 decreased visceral hypoxia, as measured by the difference between visceral (liver and jejunum) surface Pco2 and PaCO2 during UHS. Compared with normothermia, mild hypothermia increased the survival time and rate as well as moderate hypothermia (p < .01 by life table), without a significant difference between mild and moderate hypothermia. Increased FIO2 had no effect on survival time or rate. CONCLUSIONS: After severe UHS and resuscitation in rats, mild hypothermia during UHS, compared with normothermia, increases blood pressure, survival time and 72-hr survival rate as well as moderate hypothermia. Mild hypothermia is clinically more feasible and safer than moderate hypothermia. Increased FIO2 seems to have no significant effect on outcome.     

Mild hypothermia during prolonged cardiopulmonary cerebral resuscitation increases conscious survival in dogs

OBJECTIVE: Therapeutic hypothermia during cardiac arrest and after restoration of spontaneous circulation enables intact survival after prolonged cardiopulmonary cerebral resuscitation (CPCR). The effect of cooling during CPCR is not known. We hypothesized that mild to moderate hypothermia during CPCR would increase the rate of neurologically intact survival after prolonged cardiac arrest in dogs. DESIGN: Randomized, controlled study using a clinically relevant cardiac arrest outcome model in dogs. SETTING: University research laboratory. SUBJECTS: Twenty-seven custom-bred hunting dogs (19-29 kg; three were excluded from outcome evaluation). INTERVENTIONS: Dogs were subjected to cardiac arrest no-flow of 3 mins, followed by 7 mins of basic life support and 10 mins of simulated unsuccessful advanced life support attempts. Another 20 mins of advanced life support continued with four treatments: In control group 1 (n = 7), CPCR was with normothermia; in group 2 (n = 6, 1 of 7 excluded), with moderate hypothermia via venovenous extracorporeal shunt cooling to tympanic temperature 27 degrees C; in group 3 (n = 6, 2 of 8 excluded), the same as group 2 but with mild hypothermia, that is, tympanic temperature 34 degrees C; and in group 4 (n = 5), with normothermic venovenous shunt. After 40 mins of ventricular fibrillation, reperfusion was with cardiopulmonary bypass for 4 hrs, including defibrillation to achieve spontaneous circulation. All dogs were maintained at mild hypothermia (tympanic temperature 34 degrees C) to 12 hrs. Intensive care was to 96 hrs. MEASUREMENTS AND MAIN RESULTS: Overall performance categories and neurologic deficit scores were assessed from 24 to 96 hrs. Regional and total brain histologic damage scores and extracerebral organ damage were assessed at 96 hrs.In normothermic groups 1 and 4, all 12 dogs achieved spontaneous circulation but remained comatose and (except one) died within 58 hrs with multiple organ failure. In hypothermia groups 2 and 3, all 12 dogs survived to 96 hrs without gross extracerebral organ damage (p < .0001). In group 2, all but one dog achieved overall performance category 1 (normal); four of six dogs had no neurologic deficit and normal brain histology. In group 3, all dogs achieved good functional outcome with normal or near-normal brain histology. Myocardial damage scores were worse in the normothermic groups compared with both hypothermic groups (p < .01). CONCLUSION: Mild or moderate hypothermia during prolonged CPCR in dogs preserves viability of extracerebral organs and improves outcome.     

Mild brain hypothermia for influenza encephalitis/encephalopathy and its significance

During the Winter or Influenza season in Japan, there has been an increase in the number of patients presenting with Central Nervous System complaints or symptoms. One of the causes is reported be Influenza encephalitis/encephalopathy. Some of these patients undergo a course of Reye's Syndrome, Acute Necrotizing Encephalopathy (ANE), or Hemorrhagic Shock and Encephalopathy(HSE), of which the pathologic features are still unknown. It is likely that the major underlying feature is cerebral edema, caused by impairments in the blood-brain barrier, which is mediated by inflammatory cytokines. Mild brain hypothermia may be an effective treatment in preventing cerebral edema by preventing the cytokine activation and elevations in brain temperature. A combination of mild brain hypothermia and high-dose corticosteroid therapy is thought to be effective in the treatment of influenza encephalitis/encephalopathy.     

Mild hypothermia during advanced life support: a preliminary study in out-of-hospital cardiac arrest

Introduction  

Induction of mild hypothermia after cardiac arrest may confer neuroprotection. We assessed the feasibility, safety and effectiveness of therapeutic infusion of 2 l of normal saline at 4°C before return of spontaneous circulation during cardiopulmonary resuscitation after out of hospital cardiac arrest.     

Mild hypothermia can enhance pial arteriolar vasodilation induced by isoflurane and sevoflurane in cats

OBJECTIVE: Volatile anesthetics have been shown to dilate cerebral vessels. Recent evidence suggests that mild hypothermia can alter vascular reactivity of the cerebral vessels. However, the effect of mild hypothermia on volatile anesthetic-induced vasodilation of cerebral vessels is unknown. In the present study, we investigated the effect of mild hypothermia on pial arteriolar vasodilation induced by isoflurane and sevoflurane in cats. DESIGN: Prospective, randomized, experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Forty cats were used for the study of systemic administration of volatile anesthetics, and 22 cats were used for the study of topical administration of volatile anesthetics. INTERVENTIONS: This study was approved by the Animal Experiment Committee of Nara Medical University. Animals were anesthetized with pentobarbital to maintain suppressive electroencephalographic patterns, which were introduced to measure direct effects of anesthetic agents after removing metabolic effects. The cranial window technique, combined with microscopic video recording, was used for the measurement of small (50-100 microm) and large (100-200 microm) pial arteriolar diameter in an experiment. Animals were randomly assigned to either a normothermic (37 degrees C) or a hypothermic group (33 degrees C). Desired temperatures were maintained by using a water blanket. In the first phase of the study, the effect of hypothermia on pial arteriolar vasodilation induced by systemic administration of isoflurane or sevoflurane was assessed. Each cat received isoflurane or sevoflurane at 0.5, 1.0, 1.5, and 2.0 minimum alveolar anesthetic concentrations, and the diameter of pial arterioles was measured. In the second group of animals, the direct effect of isoflurane and sevoflurane on pial vessels was evaluated. The artificial cerebrospinal fluid bubbled with isoflurane or sevoflurane (minimum alveolar anesthetic concentrations of 1 or 3) was topically administered in the cranial window. MEASUREMENTS AND MAIN RESULTS: Systemic and topical administration of isoflurane and sevoflurane produced significant dilation of both small and large pial arterioles in a dose-dependent manner during normothermia. In the hypothermic group, vasodilation of small pial arterioles by systemic administration of isoflurane and sevoflurane at a high concentration was significantly larger than in the normothermic group (p <.05). Vasodilation of both small and large pial arterioles by topical administration of isoflurane and sevoflurane was significantly greater in the hypothermic group than in the normothermic group (p <.05). CONCLUSIONS: These results suggest that pial arteriolar vasodilation induced by isoflurane and sevoflurane can be enhanced by mild hypothermia in cats anesthetized with pentobarbital.