Hypothermic modulation of cerebral ischemic injury during cardiopulmonary bypass in pigs

BACKGROUND: The aim of this study was to determine whether progressive levels of hypothermia (37, 34, 31, or 28 degrees C) during cardiopulmonary bypass (CPB) in pigs reduce the physiologic and metabolic consequences of global cerebral ischemia. METHODS: Sagittal sinus and cortical microdialysis catheters were inserted into anesthetized pigs. Animals were placed on CPB and randomly assigned to 37 degrees C (n = 10), 34 degrees C (n = 10), 31 degrees C (n = 11), or 28 degrees C (n = 10) management. Next 20 min of global cerebral ischemia was produced by temporarily ligating the innominate and left subclavian arteries, followed by reperfusion, rewarming, and termination of CPB. Cerebral oxygen metabolism (CMRO2) was calculated by cerebral blood flow (radioactive microspheres) and arteriovenous oxygen content gradient. Cortical excitatory amino acids (EAA) by microdialysis were measured using high-performance liquid chromatography. Electroencephalographic (EEG) signals were graded by observers blinded to the protocol. After CPB, cerebrospinal fluid was sampled to test for S-100 protein and the cerebral cortex was biopsied. RESULTS: Cerebral oxygen metabolism increased after rewarming from 28 degrees C, 31 degrees C, and 34 degrees C CPB but not in the 37 degrees animals; CMRO2 remained lower with 37 degrees C (1.8 +/- 0.2 ml x min[-1] x 100 g[-1]) than with 28 degrees C (3.1 +/- 0.1 ml x min[-1] x 100 g[-1]; P < 0.05). The EEG scores after CPB were depressed in all groups and remained significantly lower in the 37 degrees C animals. With 28 degrees C and 31 degrees C CPB, EAA concentrations did not change. In contrast, glutamate increased by sixfold during ischemia at 37 degrees C and remained significantly greater during reperfusion in the 34 degrees C and 37 degrees C groups. Cortical biopsy specimens showed no intergroup differences in energy metabolites except two to three times greater brain lactate in the 37 degrees C animals. S-100 protein in cerebrospinal fluid was greater in the 37 degrees C (6 +/- 0.9 microg/l) and 34 degrees C (3.5 +/- 0.5 microg/l) groups than the 31 degrees C (1.9 +/- 0.1 microg/l) and 28 degrees C (1.7 +/- 0.2 microg/l) animals. CONCLUSIONS: Hypothermia to 28 degrees C and 31 degrees C provides significant cerebral recovery from 20 min of global ischemia during CPB in terms of EAA release, EEG and cerebral metabolic recovery, and S-100 protein release without greater advantage from cooling to 28 degrees C compared with 31 degrees C. In contrast, ischemia during 34 degrees C and particularly 37 degrees C CPB showed greater EAA release and evidence of neurologic morbidity. Cooling to 31 degrees C was necessary to improve acute recovery during global cerebral ischemia on CPB.     

Thermoregulatory vasoconstriction impairs active core cooling

BACKGROUND: Many clinicians now consider hypothermia indicated during neurosurgery. Active cooling often will be required to reach target temperatures < 34 degrees C sufficiently rapidly and nearly always will be required if the target temperature is 32 degrees C. However, the efficacy even of active cooling might be impaired by thermoregulatory vasoconstriction, which reduces cutaneous heat loss and constrains metabolic heat to the core thermal compartment. The authors therefore tested the hypothesis that the efficacy of active cooling is reduced by thermoregulatory vasoconstriction. METHODS: Patients undergoing neurosurgical procedures with hypothermia were anesthetized with either isoflurane/nitrous oxide (n = 13) or propofol/fentanyl (n = 13) anesthesia. All were cooled using a prototype forced-air cooling device until core temperature reached 32 degrees C. Core temperature was measured in the distal esophagus. Vasoconstriction was evaluated using forearm minus fingertip skin-temperature gradients. The core temperature triggering a gradient of 0 degree C identified the vasoconstriction threshold. RESULTS: In 6 of the 13 patients given isoflurane, vasoconstriction (skin-temperature gradient = 0 degrees C) occurred at a core temperature of 34.4 +/- 0.9 degree C, 1.7 +/- 0.58 h after induction of anesthesia. Similarly, in 7 of the 13 patients given propofol, vasoconstriction occurred at a core temperature of 34.5 +/- 0.9 degree C, 1.6 +/- 0.6 h after induction of anesthesia. In the remaining patients, vasodilation continued even at core temperatures of 32 degrees C. Core cooling rates were comparable in each anesthetic group. However, patients in whom vasodilation was maintained cooled fastest. Patients in whom vasoconstriction occurred required nearly an hour longer to reach core temperatures of 33 degrees C and 32 degrees C than did those in whom vasodilation was maintained (P < 0.01). CONCLUSIONS: Vasoconstriction did not produce a full core temperature "plateau," because of the extreme microenvironment provided by forced-air cooling. However, it markedly decreased the rate at which hypothermia developed. The approximately 1-h delay in reaching core temperatures of 33 degrees C and 32 degrees C could be clinically important, depending on the target temperature and the time required to reach critical portions of the operation.     

Hyperoxia increases paradoxical sleep rhythm in the pontine cat

Pontine cat is an ectothermic preparation, whose central temperature can artificially be lowered from 36 degrees C to 26 degrees C; this gradual hypothermia is accompanied by a dramatic increase in paradoxical sleep (PS). Two main hypotheses might explain this result: executive systems of PS might be switched on gradually by cold-sensitive thermodetectors, whereas inhibitory monoaminergic mechanisms appear to be warm-sensitive. On the other hand, energy saving mechanisms peculiar to hypothermia might promote PS appearance. Indeed, in normal animals, PS is selectively suppressed both by hyperthermia and hypoxia. The inhibitory effect of hypoxia might explain why hypothermia, which protects the brain against hypoxic alterations, might facilitate PS. If this last hypothesis is correct, the putative increase in cerebral oxygen supply might increase PS. For this reason, we submitted eight pontine carotid-deafferented cats, kept at the same central temperature (34 +/- 0.5 degrees C: temperature clamp) to periodic hyperoxia (PaO2 = 58 +/- 7 kPa) or room air (PaO2 = 17 +/- 2 kPa) alternatively during 4- or 12-h periods. Hyperoxia induced an 85% increase in PS, mainly due to an increase in PS rhythm (PS cycle duration was 65 +/- 4 min in normoxia and 45 +/- 4 min in hyperoxia, p<0.0001). In five animals, after hyperoxia, PS cycle returned gradually back to control values in 4 to 12 h. These findings show that PS is exquisitely sensitive to conditions that impair oxidative metabolism. The role of cholinergic executive PS systems as putative metabolic-sensitive neurons remains to be established.     

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.     

The arterial to end-tidal carbon dioxide gradient increases with uncorrected but not with temperature-corrected PaCO2 determination during mild to moderate hypothermia

End-tidal carbon dioxide (PETCO2) monitoring is recommended as a basic standard of care and is helpful in adjusting mechanical ventilation. Gas solubility changes with temperature, which might affect the PaCO2 and thereby the gradient between PaCO2 and PETCO2 (PA-ETCO2) under hypothermic conditions. We investigated whether the PA-ETCO2 changes during mild to moderate hypothermia (36 degrees C-32 degrees C) using PaCO2 measured at 37 degrees C (uncorrected PaCO2) and PaCO2 corrected to actual body temperature. We preoperatively investigated 19 patients. After anesthesia had been induced, controlled ventilation was established to maintain normocarbia using constant uncorrected PaCO2 to adjust ventilation (alpha-stat acid-base regimen). Body core temperature was reduced without surgical intervention to 32 degrees C by surface cooling. Continuous PETCO2 was monitored with a mainstream PETCO2 module. The PA-ETCO2 was calculated using the uncorrected and corrected PaCO2 values. During body temperature reduction from 36 degrees C to 32 degrees C, the gradient between PETCO2 and uncorrected PaCO2 increased 2.5-fold, from 4.1 +/- 3.7 to 10.4 +/- 3.8 mm Hg (P < 0.002). The PA-ETCO2 remained unchanged when the corrected PaCO2 was used for the calculation. We conclude that when the alpha-stat acid-base regimen is used to adjust ventilation, the PA-ETCO2 calculated with the uncorrected PaCO2 increases and should be added to the differential diagnosis of widened PA-ETCO2. In contrast, when the corrected PaCO2 is used for the calculation of the PA-ETCO2, the PA-ETCO2 remains unaltered during hypothermia. Implications: We investigated the impact of induced hypothermia (36 degrees C-32 degrees C) on the gradient between PaCO2 and PETCO2 (PA-ETCO2). The PA-ETCO2 increased 2.5-fold when CO2 determinations were not temperature-corrected. Hypothermia should be added to the differential diagnosis of an increased PA-ETCO2 when the alpha-stat acid-base regimen is used.     

Inhibition of shivering increases core temperature afterdrop and attenuates rewarming in hypothermic humans

During severe hypothermia, shivering is absent. To simulate severe hypothermia, shivering in eight mildly hypothermic subjects was inhibited with meperidine (1.5 mg/kg). Subjects were cooled twice (meperidine and control trials) in 8 degrees C water to a core temperature of 35.9 +/- 0.5 (SD) degrees C, dried, and then placed in sleeping bags. Meperidine caused a 3.2-fold increase in core temperature afterdrop (1.1 +/- 0.6 vs. 0.4 +/- 0.2 degree C), a 4.3-fold increase in afterdrop duration (89.4 +/- 31.4 vs. 20.9 +/- 5.7 min), and a 37% decrease in rewarming rate (1.2 +/- 0.5 vs. 1.9 +/- 0.9 degrees C/h). Meperidine inhibited overt shivering. Oxygen consumption, minute ventilation, and heart rate decreased after meperidine injection but subsequently returned toward preinjection values after 45 min postimmersion. This was likely due to the increased thermoregulatory drive with the greater afterdrop and the short half-life of meperidine. These results demonstrate the effectiveness of shivering heat production in attenuating the postcooling afterdrop of core temperature and potentiating core rewarming. The meperidine protocol may be valuable for comparing the efficacy of various hypothermia rewarming methods in the absence of shivering.     

Radiologic changes of the temporomandibular joint after condylar fractures in childhood

We have previously shown that mild hypothermia applied after hypoxia-ischemia in newborn piglets and rats reduces brain injury evaluated 3-7 d after the insult. The aim of the present study was to assess the neuroprotective efficacy of hypothermia with respect to short- (neuropathology) and long-term (neuropathology and sensorimotor function) outcome after hypoxia-ischemia in 7-d-old rats. One hundred fourteen animals from 13 litters survived either 1 or 6 wk after a hypoxic-ischemic insult. The animals were randomized to either 1) normothermic recovery for the whole 1- or 6-wk period or 2) cooling to a rectal temperature of 32.0 degrees C for the first 6 h followed by normothermic recovery with the dam. Hypothermia offered a uniform protection of 27, 35, 28, and 25% in cerebral cortex, hippocampus, basal ganglia, and thalamus, respectively, in the 1-wk survivors (n = 32). The corresponding values for the 6-wk survivors (n = 61) were 22, 28, 37, and 35%. There was a significant correlation between sensorimotor performance and infarct volume (r = 0.66; p < 0.001). However, the sensorimotor function was not significantly improved by hypothermia if all animals were included, but in female pups the total functional score was higher in the hypothermia group (150 +/- 35 versus 100 +/- 34, p < 0.0007) which corresponded to a marked (51%) reduction of the neuropathology score in this subgroup. This is the first neonatal study to show a long-term histopathologic protection of the brain after posthypoxic hypothermia.     

Interaction of heart rate and hypothermia on global myocardial contraction of the isolated rabbit heart

We studied the effects of mild hypothermia on cardiac contractility in isolated rabbit hearts perfused with Krebs-Henseleit solution according to the technique of Langendorff. Isovolumetric left ventricular pressure (LVP) was measured with a fluid-filled balloon. Hearts were paced after induction of atrioventricular block. At low heart rates ( < 30 bpm) mild hypothermia (cooling to 30 degrees C) induced a 32% increase in LVp (146.5 +/- 10 mm Hg at 30 degrees C vs 110.7 +/- 13 mm Hg at 37 degrees C) but this positive inotropic response was progressively lost by increasing heart rate. At pacing rates > or = 90 bpm, lower systolic LVP, higher diastolic LVP, and lower positive and negative LV dP/dt were obtained in hypothermic (93 +/- 12 mm Hg, 55 +/- 18 mm Hg, 584 +/- 137 mm Hg/s, and 323 +/- 57 mm Hg/s at 210 bpm, respectively) compared to normothermic hearts (123 +/- 4 mm Hg, 10 +/- 4 mm Hg, 1705 +/- 145.5 mm Hg/s, and 1155 +/- 78 mm Hg/s at 210 bpm, respectively.) The duration of mechanical diastole was reduced or suppressed in these hearts. Exposure to the beta-adrenoreceptor agonist, isoproterenol, improved this diastolic dysfunction during hypothermia and pacing at high rates, suggesting that the sarcoplasmic reticulum Ca2+ uptake might be involved. Our data are also consistent with an increase in myofilament Ca2+ sensitivity that is opposed by isoproterenol during hypothermia.     

The effects of a temperature below 15 degrees C on the myocardial calcium and ultrastructure in donor heart preservation in a canine model

The effects of 6-h hypothermic cardioplegic arrest on myocardial biochemical, morphologic, and functional recovery were investigated in two groups of dogs. Group 1 (n = 6) was subjected to hypothermia of 15 degrees C and group 2 (n = 6) was subjected hypothermia of 5 degrees C. Although the myocardial calcium (Ca) concentration was significantly higher at the end of reperfusion in group 2 compared to group 1, the MB-fraction of creatine kinase, mitochondrial aspartate aminotransferase, recovery of left ventricular systolic function, and mitochondrial morphologic integrity were better in group 2 than in group 1. These findings suggest that hypothermia of 5 degrees C in 6-h cardioplegia is not necessarily coupled with interference in myocardial contractility, despite the Ca overload that occurs during reperfusion.     

Interactions between hypothermia and the latency to ischemic depolarization: implications for neuroprotection

BACKGROUND: The authors postulated that hypothermic neuroprotection can be attributed to a delayed onset of ischemic depolarization. METHODS: Halothane-anesthetized rats were prepared for near-complete forebrain ischemia. Direct current (DC) potential microelectrodes were placed in hippocampal CA1. The pericranial temperature was maintained at 31 degrees C, 33 degrees C, 35 degrees C, or 37 degrees C (n = 6 per group). Bilateral carotid occlusion with systemic hypotension was initiated for 10 min. The time to onset of the DC shift was recorded. In a second experiment, rats were assigned to 37 degrees C or 31 degrees C for 10 min of ischemia, or to 31 degrees C for 14 min of ischemia (n = 8 per group). These durations of ischemia were defined to allow 9 min of ischemic depolarization in the 37 degrees C-10 min and 31 degrees C-14 min groups. Neurologic and histologic outcomes were examined 7 days later. RESULTS: Hippocampal CA1 time to depolarization increased with decreasing temperature (P < 0.0001). Time to depolarization was increased by approximately 4 min in the rats maintained at 31 degrees C compared with those at 37 degrees C. Time to repolarization during reperfusion was not affected by temperature. Increasing the duration of ischemia from 10 min to 14 min with the pericranial temperature maintained at 31 degrees C resulted in a duration of depolarization that was equivalent in the 37 degrees C-10 min and 31 degrees C-14 min groups. However, hippocampal CA1 damage was not increased (31 degrees C-10 min = 4 +/- 1% dead neurons; 31 degrees C-14 min = 6 +/- 1% dead neurons, 95% CI, -1% to 3%; 37 degrees C-10 min = 90 +/- 17% dead neurons). CONCLUSIONS: Despite similar durations of DC depolarization, outcome in hypothermic rats was markedly improved compared with normothermic rats. This indicates that hypothermic neuroprotection can be attributed to mechanisms other than the delay in time to onset of ischemic depolarization.     

Thermoregulatory and metabolic responses following cardiac surgery

The thermoregulatory responses in 13 haemodynamically stable patients were evaluated over a 7-h period following coronary artery bypass graft surgery. Cutaneous vasoconstriction was defined by a forearm-to-fingertip skin temperature gradient (delta Tskin) > or = 4 degrees C and muscular hyperactivity was assessed by integrating the electromyographic signals (iEMG). Blood gases and lactate were measured in arterial, mixed venous and femoral venous blood. After arrival in ICU, we observed: (1) mild central hypothermia (Tc = 34.8 +/- 0.6 degrees C) and elevated peripheral vascular resistance in all the patients; (2) delta Tskin > or = 4 degrees C in 11 of 13 patients that persisted until a median Tc of 37.1 degrees C was achieved; (3) a transient increase in iEMG (+ 18%) was accompanied by an increase in total body O2 uptake (+ 28%); (4) elevated muscle O2 extraction rate (56 +/- 18% after 3 h) and lactate release. These data suggest that residual hypothermia in sedated patients after cardiac surgery elicits appropriate thermoregulatory responses that are associated with transient O2 supply/uptake mismatch within skeletal muscles.     

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.     

Increased portal endothelin-1 level is associated with the liver function after cardiopulmonary bypass in rabbits: influence of hypothermia on the damage

The purpose of this study was to prove the hypothesis that ET-1 production is increased in the splanchnic-hepato circulation during cardiopulmonary bypass (CPB) with or without hypothermia and this greatly affects hepatocellular function after surgery. Twelve Japanese white rabbits were used. In group I (n = 6), the rectal temperature was kept at 37.0 degrees C during CPB (90 min). In group II (n = 6), the rectal temperature was lowered to 26 degrees C during the first 30 minutes and then increased to 37 degrees C for the following 60 minutes. In group I, surface liver tissue blood flow (LBF) remained stable during CPB. While, in group II, LBF was significantly reduced to 66.9% of baseline values during hypothermic CPB, but it increased during the rewarming phase to 84.3% of the baseline value (p = 0.0070). At the end of CPB, portal ET-1 levels were increased in both groups, but they were significantly higher in group II (7.32 +/- 0.50 pg/ml and 9.29 +/- 0.61 pg/ml, respectively). Serum GOT, GPT, LDH and arterial ammonia levels were also higher in group II. Portal ET-1 levels had a significant positive correlation with those liver enzymes. Histopathological examination after CPB showed severe damage of the hepatic parenchyma in zone 3 associated with microvesicular fatty infiltration in group II.     

Reducing lipid peroxidation stress of erythrocyte membrane by alpha-tocopherol nicotinate plays an important role in improving blood rheological properties in type 2 diabetic patients with retinopathy

STUDY OBJECTIVE: To test the hypothesis that warming intravenous (i.v.) fluids in conjunction with convective warming results in less intraoperative hypothermia (core temperature < 36.0 degrees C) than that seen with convective warming alone. DESIGN: Prospective, randomized study. SETTING: University affiliated tertiary care teaching hospital. PATIENTS: 61 ASA physical status, I, II, and III adults undergoing major surgery and general anesthesia with isoflurane. INTERVENTIONS: All patients received convective warming. Group 1 patients received warmed fluids (setpoint 42 degrees C). Group 2 patients received room temperature fluids (approximately 21 degrees C). MEASUREMENTS AND MAIN RESULTS: Lowest and final intraoperative distal esophageal temperatures were higher (p < 0.05) in Group 1 (mean +/- SEM: 35.8 +/- 0.1 degrees C and 36.6 +/- 0.1 degrees C) versus Group 2 (35.4 +/- 0.1 degrees C and 36.1 +/- 0.1 degrees C, respectively). Compared with Group 1, more Group 2 patients were hypothermic at the end of anesthesia (10 of 26 patients, or 38.5% vs. 4 of 30 patients, or 13%; p < 0.05). After 30 minutes in the recovery room, there were no differences in temperature between groups (36.7 +/- 0.1 degrees C and 36.5 +/- 0.1 degrees C in Groups 1 and 2, respectively). Intraoperative cessation of convective warming because of core temperature greater than 37 degrees C was required in 33% of Group 1 patients (vs. 11.5% in Group 2; p = 0.052). CONCLUSIONS: The combination of convective and fluid warming was associated with a decreased likelihood of patients leaving the operating room hypothermic. However, average final temperatures were greater than 36 degrees C in both groups, and intergroup differences were small. Care must be taken to avoid overheating the patient when both warming modalities are employed together.     

Effect of brain, body, and magnet bore temperatures on energy metabolism during global cerebral ischemia and reperfusion monitored by magnetic resonance spectroscopy in rats

To record brain temperature for comparison with rectal and temporalis muscle temperatures in preliminary studies before MR spectroscopy experiments, a thermistor was inserted into the basal ganglia in eight anesthetized, ventilated, and physiologically monitored rats. The rats were placed in an MR spectrometer and subjected to 60 min of global cerebral ischemia and 2 h of reperfusion without radiofrequency (RF) pulsing. Body temperature was maintained at 37.5-38.0 degrees C (normothermia) or 36.5-37.0 degrees C (mild hypothermia). Brain temperature during ischemia, which dropped to 31.9 +/- 0.3 (hypothermia) and 33.6 +/- 0.5 degrees C (normothermia), correlated with temporalis muscle temperature (r2 = 0.92) but not with body or magnet bore temperature measurements. Ischemia reduced brain temperature approximately 1.7 degrees C in rats subjected to mild hypothermia (1 degree reduction of body temperature). Parallel MR spectroscopy experiments showed no significant difference in energy metabolites between normothermic and hypothermic rats during ischemia. However, the metabolic recovery was more extensive 20-60 min after the onset of reperfusion in hypothermic rats, although not thereafter (P < 0.05). Mild hypothermia speeds metabolic recovery temporarily during reperfusion but does not retard energy failure during global ischemia in rats.     

Effects of mild (33 degrees C) and moderate (29 degrees C) hypothermia on cerebral blood flow and metabolism, lactate, and extracellular glutamate in experimental head injury

The effects of mild (33 degrees C) and moderate (29 degrees C) hypothermia were investigated to determine which temperature was more effective against compression-induced cerebral ischemia. Eighteen cats were anesthetized. The animals were divided into three groups according to deep-brain temperature (control, 37 degrees C; mild hypothermia, 33 degrees C; and moderate hypothermia, 29 degrees C). Intracranial pressure (ICP) and cerebral blood flow (CBF) were monitored, the latter by hydrogen clearance. Arteriovenous oxygen difference (AVDO2) and cerebral venous oxygen saturation (ScvO2) were measured in blood samples from the superior sagittal sinus. The cerebral metabolic rate of oxygen (CMRO2) and the cerebral metabolic rate of lactate (CMR lactate) were calculated. Extracellular glutamate was measured by microdialysis. ICP was increased by inflation of an epidural balloon until CBF became zero, and this ischemia was maintained for 5 min, after which the balloon was quickly deflated. All parameters were recorded over 6 h. Evans blue was injected to examine vascular permeability changes. CBF was decreased by 56% by mild hypothermia and by 77% by moderate hypothermia. Mild hypothermia had a coupled metabolic suppression whereas moderate hypothermia significantly increased AVDO2 and decreased ScvO2, producing a low CBF/CMRO2 (relative ischemia). After balloon deflation, all three groups showed reactive hyperemia, which was significantly reduced by mild and moderate hypothermia. CBF then decreased to 50% of pre-inflation values and ScvO2 decreased (post-ischemic hypoperfusion). CBF/CMRO2, ScvO2, and AVDO2 did not differ significantly between the three groups. After balloon deflation, all three groups showed increased CMR lactate, which was significantly reduced by mild and moderate hypothermia. Extracellular glutamate increased in control animals (3.8 +/- 1.72 microM), an effect most effectively suppressed in the mild hypothermia group (1.0 +/- 0.46 microM). Damaged tissue volumes as indicated by Evans blue dye extravasation were 729 +/- 89 mm3 in control, 247 +/- 56 mm3 in mild hypothermia, and 267 +/- 35 mm3 in moderate hypothermia animals. These data suggest that mild hypothermia (33 degrees C) might be the optimal brain temperature to treat compression-related cerebral ischemia.     

Two-color analysis of peripheral lymphocyte surface antigens in inherently healthy adults

We examined the efficacy of relatively low temperature collagenase digestion at 20 degrees C on the yield and viability of islets after long-term cold preservation. Wistar rat pancreases were distended with University of Wisconsin solution via a pancreatic duct at the time of harvesting to which collagenase and 2.5 mM calcium chloride were added. The pancreases were cold-preserved at 4 degrees C for 24 or 48 hr. After storage, they were incubated for collagenase digestion at 37 degrees C or 20 degrees C for various incubation periods to obtain the peak yield. At 20 degrees C, in vitro collagenase activity measured by the FALGPA method was one fourth of that at 37 degrees C, and pancreases were well digested with a prolonged digestion period (60-90 min vs. 15-20 min for the 37 degrees C group). In vitro insulin secretion of islets isolated from freshly removed pancreases was maintained at 20 degrees C for 120 min in University of Wisconsin solution as compared with 30 min at 37 degrees C. Therefore, the preserved pancreases used in this study were incubated either at 37 degrees C or 20 degrees C at various times in order to obtain peak islet yields. The islet yields from 24-hr cold-preserved pancreases at 37 degrees C and 20 degrees C digestion were 573 +/- 59/rat (n = 6) and 497 +/- 84/rat (n = 11), respectively, and those from 48-hr cold-preserved pancreases were 395 +/- 113/rat (n = 6) and 414 +/- 75/rat (n = 6), respectively. The yields from 24- and 48-hr cold-preserved pancreases were significantly low compared with 635 +/- 52/rat for fresh pancreases (n = 15), but there was no significant difference between the 2 methods. The viability of the isolated islets, which was examined by transplantation to streptozotocin-induced diabetic C57BL/6 mice, showed a significant difference in the capacity to ameliorate diabetes. The functional success rate of islet transplantation after 24-hr cold preservation was equally good (8/8 for 37 degrees C group vs. 9/10 for 20 degrees C group), but the rate for those from 48-hr cold-preserved pancreases was significantly better with digestion at 20 degrees C than at 37 degrees C (1/8 for 37 degrees C group vs. 7/8 for 20 degrees C group, P < 0.05). We concluded that viable islets can be isolated from 48-hr cold-preserved pancreases with the low temperature collagenase digestion method, which shows promise as a modality for successful clinical islet transplantation.     

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.     

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.     

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)