Prior hypothermia attenuates malignant hyperthermia in susceptible swine

This study was designed to determine the extent by which mild or moderate hyperthermia attenuates the triggering of malignant hypothermia (MH) induced by the combined administration of halothane and succinylcholine. Sixteen susceptible swine were initially anesthetized with nontriggering drugs and then either kept normothermic (approximately equal to 38 degrees C, n = 6) or cooled to induce mild (approximately equal to 35 degrees C, n = 6), or moderate (approximately equal to 33 degrees C, n = 4) hypothermia. Next, after a 30-min control period, the normothermic and mildly hypothermic animals were administered 1 minimum alveolar anesthetic concentration (MAC) halothane followed by a bolus dose of succinylcholine (2 mg/kg). Within 10 min all normothermic animals developed fulminant MH, whereas the onset of MH was slowed or was absent in the mildly hypothermic group. To test whether moderate hypothermia could more effectively minimize the signs of a MH episode, this group of animals was exposed to 1.5 MAC halothane followed 10 min later by a 3-mg/kg bolus of succinylcholine. MH was not induced and anesthesia was then changed to nontriggering drugs (ketamine and pancuronium). The animals were then aggressively rewarmed to 38 degrees C: a slight increase in the ETCO2 was detected, but MH episodes did not spontaneously occur. Subsequently, the readministration of halothane and succinylcholine rapidly provoked fulminant MH. We concluded that the induction of mild hypothermia impairs triggering and reduces the progression of MH induced by the combined administration of halothane and succinylcholine, whereas moderate hypothermia was completely protective and thus could be considered for prophylaxis.     

Ischemia-reperfusion induced microvascular dysfunction in skeletal muscle: application of intravital video microscopy

Video microscopy of red cell flow in capillaries at the surface of skeletal muscle provided the opportunity to quantitate ischemia-reperfusion (I-R) induced microcirculatory changes, in vivo. Extensor Digitorum Longus (EDL) muscles of 22 male Wistar rats (300-400 g), anesthetized with sodium pentobarbital (Somnotol, 65 mg kg,-1 IP), were used to measure the number of perfused capillaries (CDper: mm-1) crossing lines drawn perpendicular to the muscle axis, and red blood cell velocity (VRBC: mm/s) within individual capillaries from controls (n = 6), and after 2 hr (n = 4), 3 hr (n = 4), and 4 hr (n = 5) of no-flow ischemia with the muscle temperature maintained at its normal value of 32 degrees C. Ischemia was induced by tightening a tourniquet placed around the limb above the EDL muscle. Measurements were made after 30, 60, and 90 min of reperfusion. To test the usefulness of this skeletal muscle model for evaluating proposed interventions in I-R, the effect of hypothermia (24 degrees C) on the microcirculation following 4 hr ischemia (n = 3) was measured. Edema formation was estimated from the wet/dry weight ratio of the ischemic and contralateral control EDL muscles. Capillary perfusion at the surface of the control muscles was remarkably stable over the 5 hr period studied, while significant changes occurred following the ischemic periods. Significantly lower CDper was measured 30 min following all periods of normothermic ischemia. However, unlike the 2 and 4 hr ischemic periods 3 hr normothermic ischemia resulted in a progressive decline in CDper throughout the reperfusion period. VRBC showed evidence of a hyperemic response following 2 hr normothermic ischemia (control: 0.12 mm/s +/- 0.19 compared to 0.26 mm/s +/- 0.03 following 90 min reperfusion; mean +/- sem). However, no such hyperemia was measured following either 3 or 4 hr normothermic ischemia (i.e., 3 hr control: 0.24 mm/s +/- 0.01 compared to 0.07 mm s +/- 0.003 following 90 min reperfusion). In fact, VRBC was essentially zero 90 min following 4 hr normothermic ischemia (0.01 mm/s +/- 0.01). However, when the muscle was allowed to cool to 24 degrees C during 4 hr ischemia no significant change in either VRBC or CDper was measured compared to pre-ischemic controls. Evidence of edema was found after 3 and 4 hr normothermic ischemia. This study establishes a skeletal muscle model of I-R, which may be useful in testing hypotheses regarding mechanisms of I-R injury, and effectiveness of proposed treatments of I-R.     

Mild hypothermia fails to protect late hippocampal neuronal loss following forebrain cerebral ischaemia in rats

Anaesthetized male rats (n = 86) from both Long-Evans strain (LES) (n = 43) and Wistar strain (WS) (n = 43) were utilized for the experiments. While three animals from each strain were used as control, 40 rats from each strain underwent up to 10 minutes forebrain ischaemia by bilateral common carotid artery (CCA) occlusion combined with systemic hypotension [Mean Arterial Blood Pressure (MABP) = 50 mm/Hg]. The animals from each strain were divided into four (n = 10) groups. In both strains, groups (n = 10) 1 and 2, temporalis muscle (TM) and body temperatures of the animals were kept at 36-37 degrees C during the experiments. The groups 1 and 2 were killed in 3 and 7 days after the ischaemic insult, respectively. The groups 3 and 4 were also killed 3 and 7 days after the ischaemic insult, but the forebrain ischaemia was carried out under mild cerebral hypothermia (TM temperature = 33 degrees C). Pyramidal neurons of the hippocampal CA1 region from each group was evaluated semiquantitatively. In WS, groups 1 and 2 showed moderate and severe neuronal loss in the CA1 region, respectively. However, in LES while the group 1 (3 days survival) did not show any neuronal loss, group 2 showed moderate neuronal loss of the CA1 region. While in group 3 (3 days survival, hypothermia) WS and LES, hypothermia protected the CA1 region, group 4 of LES showed mild neuronal loss. However WS, group 4 (7 days survival, hypothermia) showed severe neuronal loss of the CA1 region. It was concluded that mild hypothermia during ischaemic insults did not prevent the delayed postischaemic neuronal damage of the hippocampal CA1 region of both strains, and following 10 minutes forebrain ischaemia, male LES rats were found more resistant than male WS rats to neuronal loss of the CA1 region.     

Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat

The purposes of this study were (1) to document the histopathological consequences of moderate traumatic brain injury (TBI) in anesthetized Sprague-Dawley rats, and (2) to determine whether post-traumatic brain hypothermia (30 degrees C) would protect histopathologically. Twenty-four hours prior to TBI, the fluid percussion interface was positioned over the right cerebral cortex. On the 2nd day, fasted rats were anesthetized with 70% nitrous oxide, 1% halothane, and 30% oxygen. Under controlled physiological conditions and normothermic brain temperature (37.5 degrees C), rats were injured with a fluid percussion pulse ranging from 1.7 to 2.2 atmospheres. In one group, brain temperature was maintained at normothermic levels for 3 h after injury. In a second group, brain temperature was reduced to 30 degrees C at 5 min post-trauma and maintained for 3 h. Three days after TBI, brains were perfusion-fixed for routine histopathological analysis. In the normothermic group, damage at the site of impact was seen in only one of nine rats. In contrast, all normothermic animals displayed necrotic neurons within ipsilateral cortical regions lateral and remote from the impact site. Intracerebral hemorrhagic contusions were present in all rats at the gray-white interface underlying the injured cortical areas. Selective neuronal necrosis was also present within the CA3 and CA4 hippocampal subsectors and thalamus. Post-traumatic brain hypothermia significantly reduced the overall sum of necrotic cortical neurons (519 +/- 122 vs 952 +/- 130, mean +/- SE, P = 0.03, Kruskal-Wallis test) as well as contusion volume (0.50 +/- 0.14 vs 2.14 +/- 0.71 mm3, P = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mild hypothermia as a protective therapy during intracranial aneurysm surgery: a randomized prospective pilot trial

OBJECTIVE: To conduct a pilot trial of mild intraoperative hypothermia during cerebral aneurysm surgery. METHODS: One hundred fourteen patients undergoing cerebral aneurysm clipping with (n = 52) (World Federation of Neurological Surgeons score < or =III) and without (n = 62) acute aneurysmal subarachnoid hemorrhage (SAH) were randomized to normothermic (target esophageal temperature at clip application of 36.5 degrees C) and hypothermic (target temperature of 33.5 degrees C) groups. Neurological status was prospectively evaluated before surgery, 24 and 72 hours postoperatively (National Institutes of Health Stroke Scale), and 3 to 6 months after surgery (Glasgow Outcome Scale). Secondary outcomes included postoperative critical care requirements, respiratory and cardiovascular complications, duration of hospitalization, and discharge disposition. RESULTS: Seven hypothermic patients (12%) could not be cooled to within 1 degrees C of target temperature; three of the seven were obese. Patients randomized to the hypothermic group more frequently required intubation and rewarming for the first 2 hours after surgery. Although not achieving statistical significance, patients with SAH randomized to the hypothermic group, when compared with patients in the normothermic group, had the following: 1) a lower frequency of neurological deterioration at 24 and 72 hours after surgery (21 versus 37-41%), 2) a greater frequency of discharge to home (75 versus 57%), and 3) a greater incidence of good long-term outcomes (71 versus 57%). For patients without acute SAH, there were no outcome differences between the temperature groups. There was no suggestion that hypothermia was associated with excess morbidity or mortality. CONCLUSION: Mild hypothermia during cerebral aneurysm surgery is feasible in nonobese patients and is well tolerated. Our results indicate that a multicenter trial enrolling 300 to 900 patients with acute aneurysmal SAH will be required to demonstrate a statistically significant benefit with mild intraoperative hypothermia.     

Effects of Graded Hypothermia on Hypoxic-ischemic Brain Damage in the Neonatal Rat

Objective To investigate the effect of graded hypothermia on neuropathologic alterations of neonatal rat brain after exposed to hypoxic-ischemic insult at 37℃,33℃,31℃,and 28℃,respectively,and to observe the effect of hypothermia on 72-kDa heat shock protein (HSP72) expression after hypoxic-ischemic insult.Methods Seven days old Wistar rats were subjected to unilateral common carotid artery ligation followed by exposure to hypoxia in 8% oxygen for 2 hours at 37℃,33°C,31℃,and 28℃,respectively.The brain temperature was monitored indirectly by inserting a mini-thermocouple probe into the temporal muscle during hypoxia.After hypoxia-ischemia their mortality was assessed.Neuronal damage was assessed with HE staining 72 hours after hypoxia.HSP72 expression at 0.5,24,and 72 hours of recovery was immunohis-tochemically assessed using a monoclonal antibody to HSP72.Results Hypoxia-ischemia caused 10.5% (2/19) of mortality in rat of 37°C group,but no death occurred in 33℃,31℃ or 28℃ groups.HE staining showed neuropathologic damage was extensive in rats exposed to hypoxia-ischemia at 37℃ (more than 80.0%).The incidence of severe brain damage was significantly decreased in 33℃ (53.3%) and 31℃ groups (44.4%),and no histologic injury was seen in the 28℃ group of rats.Expression of HSP72 was manifest and persistent in the rat brain of 37°C group,but minimum in the rat brain of 28℃ group.Conclusion Mild and moderate hypothermia might prevent cerebral visible neuropathologic damage associated with hypoxic-ischemic injury by decreasing stress response.     

Transgenic A1 adenosine receptor overexpression markedly improves myocardial energy state during ischemia-reperfusion

A1 adenosine (A1AR) activation may reduce ischemia-reperfusion injury. Metabolic and functional responses to 30 min global normothermic ischemia and 20 min reperfusion were compared in wild-type and transgenic mouse hearts with approximately 100-fold overexpression of coupled cardiac A1ARs. 31P-NMR spectroscopy revealed that ATP was better preserved in transgenic v wild-type hearts: 53 +/- 11% of preischemic ATP remained after ischemia in transgenic hearts v only 4 +/- 4% in wild-type hearts. However, recovery of ATP after reperfusion was similar in transgenic (46 +/- 5%) and wild-type hearts (37 +/- 12%). Reductions in phosphocreatine (PCr) and cytosolic pH during ischemia were similar in both groups. However, recovery of PCR on reperfusion was higher in transgenic (67 +/- 8%) v wild-type hearts (36 +/- 8%), and recovery of pH was greater in transgenic (pH = 7.11 +/- 0.05) v wild-type hearts (pH = 6.90 +/- 0.02). Bioenergetic state ([ATP]/[ADP].[Pi]) was higher in transgenic v wild-type hearts during ischemia-reperfusion. Time to ischemic contracture was prolonged in transgenic (13.6 +/- 0.8 min) v wild-type hearts (10.4 +/- 0.3 min). Degree of contracture was lower and recovery of function in reperfusion higher in transgenic v wild-type hearts. In conclusion, A1AR overexpression reduces ATP loss and improves bioenergetic state during severe ischemic insult and reperfusion. These changes may contribute to improved functional tolerance.     

Mild hypothermia after cardiac arrest in dogs does not affect postarrest cerebral oxygen uptake/delivery mismatching

PURPOSE: To compare measurements of cerebral arteriovenous oxygen content differences (oxygen extraction ratios, oxygen utilization coefficients) in dogs after cardiac arrest, resuscitated under normothermia vs. mild hypothermia for 1-2 h or 12 h. METHODS: In 20 dogs, we used our model of ventricular fibrillation (no blood flow) of 12.5 min, reperfusion with brief cardiopulmonary bypass, and controlled ventilation, normotension, normoxemia, and mild hypocapnia to 24 h. We compared a normothermic control Group I (37.5 degrees C) (n = 8); with brief mild hypothermia in Group II (core and tympanic membrane temperature about 34 degrees C during the first hour after arrest) (n = 6); and with prolonged mild hypothermia in Group III (34 degrees C during the first 12 h after arrest) (n = 6). RESULTS: In Group I, the cerebral arteriovenous O2 content difference was 5.6 +/- 1.6 ml/dl before arrest; was low during reperfusion (transient hyperemia) and increased (worsened) significantly to 8.8 +/- 2.8 ml/dl at 1 h, remained increased until 18 h, and returned to baseline levels at 24 h after reperfusion. These values were not significantly different in hypothermic Groups II and III. The cerebral venous (saggital sinus) PO2 (PssO2) was about 40 mmHg (range 29-53) in all three groups before arrest and decreased significantly below baseline values, between 1 h and 18 h after arrest; the lowest mean values were 19 +/- 19 mmHg in Group I, 15 +/- 8 in Group II (NS), and 21 +/- 3 in Group III (NS). Postarrest PssO2 values of < or = 20 mmHg were found in 6/8 dogs in Group I, 5/6 in Group II and 4/6 in Group III. Among the 120 values of PssO2 measured between 1 h and 18 h after arrest, 32 were below the critical value of 20 mmHg. CONCLUSIONS: After prolonged cardiac arrest, critically low cerebral venous O2 values suggest inadequate cerebral O2 delivery. Brief or prolonged mild hypothermia after arrest does not mitigate the postarrest cerebral O2 uptake/delivery mismatching.     

Reduction in cerebral ischemic injury in the newborn rat by potentiation of endogenous adenosine

Because of ontogenic influences on the pathophysiologic mechanisms of brain injury in the perinatal brain, and in particular, the incomplete development of adenosine receptor systems, we investigated the potential for adenosine to provide cerebro-protection in a well established newborn rat model of hypoxia-ischemia. Fifteen litters of postnatal d 7 animals were subjected to unilateral carotid ligation and exposure to hypoxia (8% oxygen) for 3 h. Immediately after hypoxia-ischemia, animals received either the adenosine deaminase inhibitor deoxycoformycin (DCF; 2.5 mg/kg intraperitoneally) or the adenosine uptake inhibitor propentofylline (PPF; 10 mg/kg intraperitoneally); paired littermates received an equivalent volume of normal saline. On postnatal d 14, injury or protection was assessed by differences in hemispheric weights, morphometric determinations of infarct area, and histopathologic analyses. DCF resulted in a 34% (p = 0.02) and 31% (p = 0.03) reduction in hemispheric weight disparities and infarct area, respectively; for PPF, these reductions were 46% (p = 0.03) and 32% (p = 0.04), respectively. Light microscopic examinations of striatum, thalamus, hippocampus, and cortex revealed that both drugs significantly improved histologic scores as well. Measurements in six separate litters indicated that neither drug significantly reduced core body temperature for at least 6 h postadministration. These findings indicate that potentiation of endogenous adenosine levels in the perinatal brain can significantly ameliorate brain injury. Each of these treatment strategies was effective even when administered after the hypoxic-ischemic insult. Thus, further investigations of adenosinergic therapies are warranted in this and other perinatal models of cerebral ischemia to elucidate in detail their potential for clinical application.     

Mortality among workers in the pulp-paper industry. A successive follow up of the cohort

Neuropathologic findings are described, for the first time, in a neonatal dog model of circulatory arrest in normothermic conditions, and the findings are compared to those reported in neonatal dogs with hypothermic circulatory arrest. Total circulatory arrest was produced in 3- to 6-day-old anesthetized, paralyzed and ventilated, normothermic dogs either by asphyxiation or cardioplegia. Duration of circulatory arrest was 8-20 min and 10-40 min in asphyxiated and cardioplegic animals, respectively. The animals were resuscitated and maintained under controlled systemic physiologic conditions until neuropathologic examination after 8 or 24 h of recovery. The results suggest that the minimal durations of circulatory arrest for brain damage to occur following asphyxia or cardioplegia are 10 and 15 min, respectively. Ischemic lesions in both groups consisted of neuronal necrosis and involved mainly the brain stem structures, particularly the reticular nuclei and the spinal cord gray matter. The medulla was more severely involved than midbrain and pons. There was a direct correlation between the length of circulatory arrest and the severity of damage in the medulla (P = 0.001) and overall brain stem damage (P = 0.004) in animals with cardioplegia, but not in animals with asphyxia. These findings are compared to the neuropathologic changes previously described in newborn dogs subjected to hypothermic circulatory arrest, in which ischemic lesions are focused on the cerebral cortex and basal ganglia. It is concluded that hypothermia in this model not only prolongs the period of circulatory arrest that is required to produce brain damage, but also shifts the pattern of regional ischemic vulnerability from caudal to more rostral structures.     

Terson''s syndrome in a patient with acute promyelocytic leukemia on all-trans retinoic acid treatment

Hypothermia induced by surface cooling has shown to protect vulnerable regions of the brain during an ischemic insult. This study evaluated the neuroprotective efficacy of neurotensin, a potent hypothermic agent, using a 5-min carotid occlusion procedure in the gerbil. In Experiment 1, the dose-response and time course of neurotensin-induced hypothermia were evaluated (n = 5/dose). Central infusion of 10, 20, and 30 micrograms neurotensin were found to significantly decrease core body temperature of conscious gerbils within 30 min of administration. In Experiment 2, gerbils pretreated with 30 micrograms neurotensin were permitted to become hypothermic or were maintained at 37 degrees-38 degrees C (rectal) during ischemic insult. Other gerbils were pretreated with peptide vehicle prior to ischemic insult (at 37 degrees -38 degrees C) or underwent a sham procedure (n = 6/condition). At 24 h after surgery, gerbils were tested for increased locomotor activity in an open-field apparatus. Gerbils pretreated with peptide vehicle or neurotensin and maintained at 37 degrees-38 degrees C during ischemia had significantly higher activity levels compared to the other treated groups. In contrast, gerbils made hypothermic with neurotensin exhibited activity levels similar to sham gerbils. Histological assessment revealed that neurotensin-induced hypothermia protected the CA1 region from ischemic damage.     

Effect of hyperglycemia on brain cell membrane function and energy metabolism during hypoxia-ischemia in newborn piglets

The purpose of this study was to test the hypothesis that hyperglycemia ameliorates changes in brain cell membrane function and preserves cerebral high energy phosphates during hypoxia-ischemia in newborn piglets. A total of 42 ventilated piglets were divided into 4 groups, normoglycemic/normoxic(group 1, n=9), hyperglycemic/normoxic(group 2, n=8), normoglycemic/hypoxic-ischemic(group 3, n=13) and hyperglycemic/hypoxic-ischemic(group 4, n=12) group. Cerebral hypoxia-ischemia was induced by occlusion of bilateral common carotid arteries and simultaneous breathing with 8% oxygen for 30 min. Hyperglycemia (blood glucose 350-400 mg/dl) was maintained for 90 min before and throughout hypoxia-ischemia using modified glucose clamp technique. Changes in cytochrome aa3 were continuously monitored using near infrared spectroscopy. Blood and CSF glucose and lactate were monitored. Na+, K+-ATPase activity, lipid peroxidation products (conjugated dienes), tissue high energy phosphates (ATP and phosphocreatine) levels and brain glucose and lactate levels were determined biochemically in the cerebral cortex. During hypoxia-ischemia, glucose levels in blood and CSF were significantly elevated in hyperglycemic/hypoxic-ischemic group compared with normoglycemic/hypoxic-ischemic group, but lactate levels in blood and CSF were not different between two groups. At the end of hypoxia-ischemia of group 3 and 4, triangle up Cyt aa3, Na+, K+-ATPase activity, ATP and phosphocreatine values in brain were significantly decreased compared with normoxic groups 1 and 2, but were not different between groups 3 and 4. Levels of conjugated dienes and brain lactate were significantly increased in groups 3 and 4 compared with groups 1 and 2, and were significantly elevated in group 4 than in group 3 (0.30+/-0.11 vs. 0.09+/-0.02 micromol g-1 protein, 26.4+/-7.6 vs. 13.1+/-2.6 mmol kg-1, p<0.05). These findings suggest that hyperglycemia does not reduce the changes in brain cell membrane function and does not preserve cerebral high energy phosphates during hypoxia-ischemia in newborn piglets. We speculate that hyperglycemia may be harmful during hypoxia-ischemia due to increased levels of lipid peroxidation in newborn piglet.     

Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation

BACKGROUND and PURPOSE: Mild hypothermia is possibly the single most effective method of cerebroprotection developed to date. However, many questions regarding mild hypothermia remain to be addressed before its potential implementation in the treatment of human stroke. Here we report the results of 2 studies designed to determine the optimal depth and duration of mild hypothermia in focal stroke and its effects on infarct size, neurological outcome, programmed cell death, and inflammation. METHODS: Rats underwent a 2-hour occlusion of the left middle cerebral artery. In the first study (I) animals were kept (intraischemically) at either 37 degreesC (n=8), 33 degreesC (n=8), or 30 degreesC (n=8). Study II consisted of 4 groups: (1) controls (37 degreesC, n=10), (2) 30 minutes of hypothermia started at ischemic onset (33 degreesC, n=9), (3)1 hour (33 degreesC, n=8), and (4) 2 hours (33 degreesC, n=8). Brain temperature was measured by a thermocouple probe placed in the contralateral cortex. After suture removal, all animals were rewarmed and reperfused for 22 hours (I) or 70 hours (II). RESULTS: Mild hypothermia to 33 degreesC or 30 degreesC was neuroprotective (17+/-7% and 27+/-6%, respectively) relative to controls (53+/-8%, P<0.02), but 33 degreesC was better tolerated and recovery from anesthesia was faster. The neurological score of hypothermic animals was significantly better than that of controls (I & II) at both 24 and 72 hours postischemia except for the 30-minute group (II), which showed no improvement. In Study II, 2 hours of hypothermia reduced injury by 59%, 1 hour reduced injury by 84% whereas 30 minutes did not reduce injury. Normalized for infarct size, 2 hours of mild hypothermia decreased neutrophil accumulation by 57% whereas both 1 hour and 30 minutes had no effect. At 72 hours, 1 and 2 hours of mild hypothermia decreased transferase dUTP nick-end labeling (TUNEL) staining by 78% and 99%, respectively, and 30 minutes of hypothermia had no effect. CONCLUSIONS: Intraischemic mild hypothermia must be maintained for 1 to 2 hours to obtain optimal neuroprotection against ischemic cell death due to necrosis and apoptosis.     

Mild posttraumatic hypothermia reduces mortality after severe controlled cortical impact in rats

The effect of posttraumatic hypothermia (brain temperature controlled at 32 degrees C for 4 h) on mortality after severe controlled cortical impact (CCI) was studied in rats. Four posttraumatic brain temperatures were compared: 37 degrees C (n = 10), 36 degrees C (n = 4), 32 degrees C (n = 10), and uncontrolled (UC; n = 6). Rats were anesthetized and subjected to severe CCI (4.0-m/s velocity, 3.0-mm depth) to the exposed left parietal cortex. At 10 min posttrauma the rats were cooled or maintained at their target brain temperature, using external cooling or warming. Brain temperature in the UC group was recorded but not regulated, and rectal temperature was maintained at 37 +/- 0.5 degrees C. After 4 h, rats were rewarmed over a 1-h period to 37 degrees C, extubated, and observed for 24 h. In the 37 and 36 degree C groups, 24-h mortality was 50% (37 degrees C = 5/10, 36 degrees C = 2/4). In the 32 degree C group, 24-h mortality was 10% (1/10). In the UC group, brain temperature was 35.4 +/- 0.6 degrees C during the 4-h treatment period and 24-h mortality was 0% (0/6). Mortality was higher in groups with brain temperatures > or = 36 degrees C versus those with brain temperatures < 36 degrees C (50 vs. 6%, respectively; p < 0.05). Additionally, electroencephalograms (EEG) were recorded in subsets of each temperature group and the percentage of time that the EEG was suppressed (isoelectric) was determined. Percentage of EEG suppression was greater in the hypothermic (32 degrees C, n = 6; UC, n = 4) groups than in the normothermic (36 degrees C, n = 3; 37 degrees C, n = 6) groups (23.3 +/- 14.3 vs. 1.2 +/- 3.1%, respectively; p < 0.05). Posttraumatic hypothermia suppressed EEG during treatment and reduced mortality after severe CCI. The threshold for this protective effect appears to be a brain temperature < 36 degrees C. Thus, even mild hypothermia may be beneficial after severe brain trauma.     

Effect of the no-flow interval and hypothermia on cerebral blood flow and metabolism during cardiopulmonary resuscitation in dogs

BACKGROUND and PURPOSE: We sought (1) to determine the effect of brief periods of no flow on the subsequent forebrain blood flow during cardiopulmonary resuscitation (CPR) and (2) to test the hypothesis that hypothermia prevents the impact of the no-flow duration on cerebral blood flow (CBF) during CPR. METHODS: No-flow intervals of 1.5, 3, and 6 minutes before CPR at brain temperatures of 28 degreesC and 38 degreesC were compared in 6 groups of anesthetized dogs. Microsphere-determined CBF and metabolism were measured before and during vest CPR adjusted to maintain cerebral perfusion pressure at 25 mm Hg. RESULTS: Increasing the no-flow interval from 1.5 to 6 minutes at 38 degreesC decreased the CBF (18. 6+/-3.6 to 6.1+/-1.7 mL/100 g per minute) and the cerebral metabolic rate (2.1+/-0.3 to 0.7+/-0.2 mL/100 g per minute) during CPR. Cooling to 28 degreesC before and during the arrest eliminated the detrimental effects of increasing the no-flow interval on CBF (16. 8+/-1.0 to 14.8+/-1.9 mL/100 g per minute) and cerebral metabolic rate (1.1+/-0.1 to 1.3+/-0.1 mL/100 g per minute). Unlike the forebrain, 6 minutes of preceding cardiac arrest did not affect brain stem blood flow during CPR. CONCLUSIONS: Increasing the no-flow interval to 6 minutes in normothermic animals decreases the supratentorial blood flow and cerebral metabolic rate during CPR at a cerebral perfusion pressure of 25 mm Hg. Cooling to 28 degreesC eliminates the detrimental impact of the 6-minute no-flow interval on the reflow produced during CPR. The brain-protective effects of hypothermia include improving reflow during CPR after cardiac arrest. The effect of hypothermia and the impact of short durations of no flow on reperfusion indicate that increasing viscosity and reflex vasoconstriction are unlikely causes of the "no-reflow" phenomenon.     

Visceral, hematologic and bacteriologic changes and neurologic outcome after cardiac arrest in dogs. The visceral post-resuscitation syndrome

We studied the post-resuscitation syndrome in 42 healthy dogs after normothermic ventricular fibrillation cardiac arrest (no blood flow) of 7.5, 10, or 12.5 min duration, reversed by standard external cardiopulmonary resuscitation (CPR) (< or = 10 min) and followed by controlled ventilation to 20 h and intensive care to 72 h. We reported previously, in the same dogs, no difference in resuscitability, mortality, or neurologic outcome between the three insult groups. There was no pulmonary dysfunction, but post-arrest cardiovascular failure, of greater severity in the 12.5 min arrest group. This report concerns renal, hematologic, hepatic and bacteriologic changes. Renal function recovered within 1 h after arrest, without permanent dysfunction. Clotting derangements at 1-24 h postarrest reflect transient disseminated intravascular coagulation with hypocoagulability, more severe after longer arrests, which resolved by 24 h after arrest. Hepatic dysfunction was transient but more severe in the animals that did not recover consciousness and correlated with neurologic dysfunction, but not with brain histologic damage. Bacteremia was present in all animals postarrest. We conclude that in the previously healthy organism after cardiac arrest of 7.5-12.5 min no flow, visceral and hematologic changes, although transient, can retard neurologic recovery.     

Conspiring to succeed: the process of a joint military health care merger

The exact mechanism of hypothermic cerebroprotection after traumatic brain injury (TBI) is not fully understood. The present study was conducted to investigate the effects of mild hypothermia on trauma-induced synthesis of nitric oxide (NO), which has been implicated in the pathogenesis of ischemic brain damage associated with glutamate neurotoxicity. Cerebral contusion was created in the rat parietal cortex by a weight-drop method, and extracellular concentrations of the NO end products nitrite and nitrate were measured using in vivo brain microdialysis and capillary electrophoresis under normothermic (37 degrees C) and mild hypothermic (32 degrees C) conditions. In normothermic animals, the level of NO end products increased markedly 10 min after contusion, reaching a maximum level at 20 min. In the hypothermic rats, such increases were absent. Although it is unknown whether endothelial NO synthase, neuronal NO synthase, or both caused the elevation of the NO end products seen in the normothermic animals, the present results indicate that inhibition of NO synthesis may play a part in hypothermic cerebroprotection following TBI.     

Mild hypothermia: therapeutic window after experimental cerebral ischemia

The treatment of cerebral ischemia remains a formidable challenge in neuroscience today. Mild hypothermia has been shown to be an effective neuroprotective agent. Despite the great volume of published research, the therapeutic window of mild hypothermia has not been precisely elucidated. Using a model of reversible focal cerebral ischemia in the rat, this study was undertaken to define the optimal duration of hypothermic application and the maximal postischemic delay in hypothermic application before which optimal therapeutic effect is noted. Focal ischemia was induced by temporary occlusion of the middle cerebral artery and both carotid arteries in Sprague-Dawley rats for a period of 3 hours. In the first study, mild hypothermia (32-33 degrees C) was induced at the onset of ischemia in four groups of rats for varying lengths of time ranging from 1 to 4 hours. The animals were killed after 3 days, and their brains were sliced and stained. Infarcted volume was measured using a computerized image analyzer. The infarct volumes were 211 +/- 4.5, 214.2 +/- 8.0, 199.5 +/- 5.3, 171.3 +/- 9.1, and 169.8 +/- 6.5 mm3 (mean +/- standard error of the mean, n = 6 per group) for the control, 1-hour, 2-hour, 3-hour, and 4-hour groups, respectively. On the basis of the results from the above study, a 3-hour duration of hypothermia was then applied to animals at 0, 15, 30, or 45 minutes after the ischemic onset. The volumes of infarction for these four respective groups were: 171.3 +/- 9.1, 173 +/- 5.7, 179.3 +/- 5.2, and 206.2 +/- 8.4 mm3 (mean +/- standard error of the mean, n = 6 per group). These results demonstrated that optimal duration of mild hypothermia was at least 3 hours (P < 0.001) when applied within the first 30 minutes after the onset of ischemia (P < 0.001).     

Experimental hypothermia: effects of core cooling and rewarming on hemodynamics, coronary blood flow, and myocardial metabolism in dogs

Conflicting results have been reported as to the extent that cardiovascular function can be reestablished after rewarming from hypothermia. We measured hemodynamic function, myocardial metabolism and tissue water content in dogs core-cooled to 25 degrees C and later rewarmed. At 25 degrees C left ventricular (LV) systolic pressure (LVSP) was 54% +/- 4%, maximum rate of LV pressure rise (LV dP/dtmax) 44% +/- 5%, aortic pressure (AOP) 50% +/- 6%, heart rate (HR) 40% +/- 0%, cardiac output (CO) 37% +/- 5%, myocardial blood flow (MBF) 34% +/- 5%, and myocardial oxygen consumption (MVO2) 8% +/- 1%, compared to precooling. Stroke volume (SV) and LV end-diastolic pressure (LVEDP) were unchanged. As normothermia (37 degrees C) was reestablished, the depression of cardiac function and myocardial metabolism remained the same as that at 25 degrees C: LVSP 71% +/- 6%, LV dP/dtmax 73% +/- 7%, SV 60% +/- 9%, AOP 70% +/- 6%, CO 57% +/- 9%, MBF 53% +/- 8%, and MVO2 44% +/- 8% HR, in contrast, recovered to precooling values. The arterial concentrations of glucose and free fatty acids (FFA) did not change significantly during the experimental period, whereas an increase in lactate of nonmyocardial origin appeared after rewarming. Increased myocardial contents of creatine phosphate and water were found during both hypothermia and rewarming. The present study demonstrates a persistent depression of cardiac function after hypothermia and rewarming in spite of adequate energy stores. Thus, a direct influence on myocardial contractile function by the cooling and rewarming process is suggested.     

Long-term development in the mandible and incisor crowding with and without an orthodontic stabilising appliance

Dimensional alteration of hepatic microvessels was demonstrated during reperfusion after normothermic hepatic ischemia. Using a specially designed cover glass, it was possible to relocate selected sites of observation and microvessels repeatedly throughout the whole reperfusion time. Twenty minutes of hepatic ischemia resulted in a decrease of sinusoidal diameter (mean +/- SEM; 10.0 +/- 0.3 microns at baseline, 8.2 +/- 0.2 microns after ischemia) and diameter of postsinusoidal venules (26.4 +/- 1.2 at baseline, 23.0 +/- 1.0 after ischemia). In the control group (no ischemia induced) no changes of these parameters were observed. Thus, the reduction of hepatic microvascular cross section was present during the early phase of reperfusion. Hepatic dysfunction was characterized by increased serum activity of liver enzymes and reduction of bile flow in the ischemia-exposed animals. It has been suggested that postischemic dimensional microvascular changes are involved in postischemic liver dysfunction.