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PubMed2006

Aprotinin improves cerebral protection: evidence from a survival porcine model.

OBJECTIVE: Aprotinin is a serine protease inhibitor used during cardiac surgery to reduce blood loss and preserve platelet function. It has also been shown to reduce leukocyte activation during and after cardiopulmonary bypass. The goal of the study was to test the hypothesis that aprotinin could reduce cerebral injury after low-flow cardiopulmonary bypass and deep hypothermic circulatory arrest. METHODS: Sixteen piglets (mean weight, 13.6 +/- 1.3 kg) were randomly assigned to receive aprotinin or placebo (8 animals per group) before a 120-minute period of deep hypothermic circulatory arrest (15 degrees C) or 25 mL x kg(-1) x min(-1) low-flow cardiopulmonary bypass (25 degrees C or 34 degrees C). Piglets had a cranial window placed over the parietal cerebral cortex for direct examination of the microcirculation by means of intravital microscopy. Rhodamine-stained leukocytes were observed in postcapillary venules, with analysis for adhesion and rolling. Plasma was labeled with fluorescein isothiocyanate-dextran for assessment of functional capillary density. Neurologic and histologic scores were used as the primary outcome measures. RESULTS: During rewarming, the mean number of both rolling and adherent leukocytes was significantly lower after aprotinin administration (P < .05). At 5 and 15 minutes of rewarming, functional capillary density recovered faster with aprotinin treatment (P < .05). Functional outcome (neurologic deficit score) on postoperative day 1 was significantly improved in aprotinin-treated piglets (P < .05). CONCLUSIONS: Aprotinin reduces inflammation and improves neurologic outcome after a prolonged period of deep hypothermic circulatory arrest or low-flow cardiopulmonary bypass.

Animals↗
PubMed2006

Anticonvulsant properties of hypothermia in experimental status epilepticus.

Status epilepticus in patients often does not respond to first-line anticonvulsants, and subsequent treatment escalation with continuous intravenous anesthetics may be associated with significant side-effects. Therefore, alternative treatment regimens are urgently needed. Hypothermia has been shown to reduce excitatory transmission and may thus serve as an interesting adjunct in the management of status epilepticus. In the current experiments, three treatment groups were compared. Animals with self-sustaining status epilepticus were treated with external cooling for 3 h, with low-dose diazepam, or with a combination of both. The effect of these regimens on epileptic activity was compared with untreated controls. Animals that underwent cooling were rewarmed, and all animals were monitored for 5 h to assess occurrence and severity of motor seizures and frequency and amplitude of spontaneous epileptic discharges. Cooling alone significantly reduced number and severity of motor seizures but did not alter epileptic discharges. Cooling in addition to low-dose diazepam significantly diminished amplitudes and frequencies of epileptic discharges, while diazepam alone had only a minor reducing effect on discharge amplitudes. However, at later stages of status epilepticus, diazepam significantly reduced motor seizures. Following rewarming, the discharge frequency tended to increase again, suggesting partial reversibility. The current experiments show that in status epilepticus hypothermia exhibits anticonvulsant effects which are most pronounced if co-administered with low-dose diazepam. The results still require confirmation in other animal models and also clinical studies are urgently needed. However, our data indicate that cooling could well become a future adjunct in the treatment of status epilepticus in patients.

Animals↗
PubMed2004

Differential regulation of glomerular and interstitial endothelial nitric oxide synthase expression in the kidney of hibernating ground squirrel.

Hibernating animals transiently reduce renal function during their hypothermic periods (torpor), while completely restoring it during their periodical rewarming to euthermia (arousal). Moreover, structural integrity of the kidney is preserved throughout the hibernation. Nitric oxide (NO) generated by endothelial nitric oxide synthase (eNOS) is a crucial vasodilatory mediator and a protective factor in the kidney. We investigated renal NOS expression in hibernating European ground squirrels after 1 day and 7 days of torpor (torpor short, TS, and torpor long, TL, respectively), at 1.5 and at 10 h of rewarming (arousal short, AS, and arousal long, AL, respectively), and in continuously euthermic animals after hibernation (EU). For that purpose, we performed NOS activity assay, immunohistochemistry and real-time PCR analysis. Immunohistochemistry revealed a decreased glomerular eNOS expression in hibernating animals (TS, TL, AS, and AL) compared to non-hibernating animals (EU, p < 0.05), whereas no difference was found in the expression of interstitial eNOS. Expression of iNOS and nNOS did not differ between all groups. The reduced glomerular eNOS was associated with a significantly lower eNOS mRNA levels and NOS activity of whole kidney during torpor and arousal (TS, TL, AS, and AL) compared to EU. In all methods used, torpid and aroused squirrels did not differ. These results demonstrate differential regulation of eNOS in glomeruli and interstitium of hibernating animals, which is unaffected during arousal. The differential regulation of eNOS may serve to reduce ultrafiltration without jeopardizing tubular structures during hibernation.

Animals↗
PubMed2002

Monitoring bladder temperatures in the OR.

Temperature monitoring via the urinary bladder has become common in the OR, often replacing monitoring at the rectal site. A systematic, integrated review and synthesis of the literature was undertaken to assess the validity of using the urinary bladder as a site for temperature measurement in the OR. During steady thermal states, bladder temperature performed well, providing temperatures similar to those of core sites. In contrast, poor performance was demonstrated during rapid thermal changes, such as during the rapid cooling and rewarming phases of cardiopulmonary bypass. At such times, a significant lag in response rate at the bladder site was noted by multiple investigators. This delayed responsiveness during thermally dynamic states, however, may provide information regarding the adequacy of rewarming during bypass at sites intermediate between the core and periphery. Limited research indicates that urinary bladder temperature may be influenced by urine flow rate, and additional research is required in this area. The cost effectiveness of this method of temperature measurement requires investigation as well.

Body Temperature↗
PubMed1988

Hemodynamic and morphologic alterations after experimental administration of protamine sulfate.

The hemodynamic, hematologic, and morphologic effects induced by protamine sulfate have been studied in 28 dogs divided into 6 groups. All of the groups were given heparin (3 mg/kg body weight) and Groups I, II, III, and IV were given protamine (5 mg/kg body weight). Group I (control group) was not subjected to extracorporeal circulation. The other groups had the following interventions: Group II, cardiopulmonary bypass without aortic clamp, hypothermia, or cardioplegia; Groups III and V, hypothermia of 25 degrees C, aortic clamping for 25 minutes, administration of cardioplegic solution, and slow rewarming; and Groups IV and VI, the same as Groups III and V, but with rapid rewarming. After injection of protamine sulfate, there was a decrease in mean arterial pressure due to peripheral vasodilation and an increase in the mean pulmonary pressure due to increased pulmonary vascular resistance; marked diminution of the number of circulating platelets aside from the extracorporeal circulation; a decrease in the contractility of both ventricles with augmented right ventricular work and decreased cardiac output; and right ventricular edema in Groups I, II, III, and IV. These alterations were most evident in Groups III and IV.

Animals↗
PubMed2001

Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection.

BACKGROUND: Ischemic preconditioning is an endogenous mechanism whereby brief periods of ischemia render neurons resistant to subsequent lethal insults. This protection appears to alter cellular apoptosis and can be induced by potassium channel openers acting on the inner membrane of the mitochondria (mitoK(ATP)). To test the hypothesis that pharmacologic preconditioning could provide neuroprotection, the mitoK(ATP) opener diazoxide was used in a canine model of brain injury induced by hypothermic circulatory arrest (HCA). METHODS: Seventeen dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18 degrees C. After 2 hours of HCA, animals were rewarmed and weaned from CPB. Six dogs received intravenous diazoxide (2.5 mg/kg bolus 15 minutes prior to CPB, then 0.5 mg/min until circulatory arrest, then restarted for the first hour of rewarming). Six animals received vehicle only. Five received diazoxide and the mitoK(ATP) blocker 5-hydroxydecanoate (5-HD). Using a modified Pittsburgh Canine Neurological Scoring System (0 = normal, 500 = brain death), animals were evaluated every 24 hours for 3 days. The brains were removed and histologic sections of four regions characteristically injured in this model were scored (0 = no injury, 4 = infarction) by a neuropathologist in a blinded fashion. RESULTS: Clinical scoring showed marked improvement in the diazoxide group at 48 hours (101 +/- 10.5 vs 165 +/- 14.8, p < 0.01) and 72 hours (54 +/- 9.3 vs 137 +/- 12.1, p < 0.01). This neuroprotection was attenuated when 5-HD was concomitantly administered. Three of four brain regions typically injured in this model (cortex, hippocampus, and entorhinal cortex) had significant neuron preservation in the diazoxide group. Likewise, combined region scores were significantly improved in the treatment group (1.18 +/- 0.2 vs 2.46 +/- 0.2, p < 0.01). CONCLUSIONS: Pretreatment with diazoxide resulted in significant improvement in both clinical neurologic scores and histopathology in our model of HCA. This suggests that pharmacologic preconditioning with the mitoK(ATP) channel opener diazoxide may offer effective neuroprotection during HCA.

Animals↗
PubMed2002

Influence of retrograde cerebral perfusion during aortic arch procedures.

BACKGROUND: Recent reports suggest dramatic improvement in outcome using retrograde cerebral perfusion (RCP) during operations on the arch; however, most investigators have compared contemporary results with historic controls. The purpose of this study was to determine the impact of RCP within the same patient population and time period. METHODS: From 1996 to 2000, 72 consecutive patients underwent an aortic arch procedure using hypothermic circulatory arrest (HCA) (31 acute dissection or rupture, 41 chronic dissection or aneurysm). Supplemental RCP was used in 36 patients, whereas 36 patients had HCA alone. The groups were similar in age, emergent status, and cardiopulmonary bypass time (p > 0.08), but HCA time was higher with RCP (40 +/- 15 minutes versus 29 +/- 14 minutes; p < 0.001). RESULTS: Operative mortality was 10% +/- 4% (+/- 70% confidence limit), and adverse outcomes (death or cerebrovascular accident) occurred in 14% +/- 4%, but there was no difference between HCA alone (8% +/- 5%, 14% +/- 6%) and HCA with RCP (11% +/- 5%, 14% +/- 6%) (p > 0.73). The incidence of transient neurologic dysfunction was also similar (HCA alone, 11% +/- 5%; HCA with RCP, 17% +/- 6%; p > 0.73). Multivariate risk factors for mortality included emergency operation and HCA time (p < 0.02). Risk factors for adverse outcome included emergency operation and atheromatous ascending aorta (p < 0.03). Risk factors for transient neurologic dysfunction included preexisting cerebrovascular disease and rewarming retrograde (femoral) rather than antegrade (through the graft) (p < 0.03). CONCLUSIONS: Supplemental RCP during HCA did not decrease mortality or neurologic complications. Retrograde rewarming through the femoral artery after completion of the distal anastomosis increased transient neurologic dysfunction. Therefore, RCP remains optional, but reperfusion should be antegrade to improve neurologic recovery.

Adult↗
PubMed1986

Cerebral blood flow and metabolism during cardiopulmonary bypass with special reference to effects of hypotension induced by prostacyclin.

Cerebral blood flow and metabolism of oxygen, glucose, and lactate were studied in 43 patients undergoing aortocoronary bypass. Twenty-five patients received prostacyclin infusion, 50 ng per kilogram of body weight per minute, during cardiopulmonary bypass (CPB), and 18 patients served as a control group. Regional cerebral blood flow (CBF) was studied by intraarterially injected xenon 133 and a single scintillation detector. Oxygen tension, carbon dioxide tension, oxygen saturation, glucose, and lactate were measured in arterial and cerebral venous blood. Mean arterial blood pressure decreased during hypothermia and prostacyclin infusion to less than 30 mm Hg. The regional CBF was, on average, 22 (standard deviation [SD] 4) ml/100 gm/min before CPB. It increased in the control group during hypothermia to 34 (SD 12) ml/100 gm/min, but decreased in the prostacyclin group to 15 (SD 5) ml/100 gm/min. It increased during rewarming in the prostacyclin group. After CPB, regional CBF was about 40 ml/100 gm/min in both groups. The cerebral arteriovenous oxygen pressure difference decreased more in the control group than in the prostacyclin group during hypothermia. The cerebral metabolic rate of oxygen decreased in both groups from approximately 2 ml/100 gm/min to about 1 ml/100 gm/min during hypothermia, increased again during rewarming, and after CPB was at the levels measured before bypass in both groups. There was no difference between the groups in regard to glucose and lactate metabolism.

Adult↗
PubMed1986

The protective effect of profound hypothermia on the canine central nervous system during one hour of circulatory arrest.

Circulatory arrest during profound hypothermia is a safe technique of cardiac surgery when used in selected instances. Despite its proven safety, the degree of cerebral protection offered by this technique is still poorly defined. Ten dogs anesthetized with Pentothal (thiopental sodium) were surface cooled to 32 degrees C. They were placed on cardiopulmonary bypass, cooled to 13 degrees C (cerebral temperature), and then underwent one hour of circulatory arrest. At the end of the arrest period, the dogs were rewarmed, resuscitated, and successfully weaned from bypass. A control group of 6 dogs were subjected to the same protocol but without the one-hour period of circulatory arrest. There were no group differences in animal weight, duration of surface cooling, cardiopulmonary bypass, or rewarming, mean flow, or mean arterial pressure. After a 7-day observation period, the dogs were killed with rapid tissue fixation using formalin. No neurological deficits were noted in any of the dogs during the observation period. The fixed brains were examined by a neuropathologist. No gross or microscopic evidence of cerebral hypoxia was seen in any of the animals. We conclude that one hour of circulatory arrest under profoundly hypothermic temperatures produces no detectable neurological changes or histological evidence of cerebral hypoxia.

Animals↗
PubMed1977

Oxygen consumption during surface-induced deep hypothermia under halothane anesthesia.

The effect of halothane-100% oxygen anesthesia on oxygen consumption was studied in 10 dogs subjected to surface-induced deep hypothermia with 30 minutes of circulatory arrest. The results were compared with previous oxygen consumtion data under ether-100% oxygen anesthesia. Low cardiac output, especially during the rewarming period, low PaO2, and a large arteriovenous oxygen difference during rewarming were significantly different in the halothane group, despite identical oxygen consumption in both groups. These differences could not elucidate the exact cause of postoperative motor disturbances associated with 30 minutes of circulatory arrest in the halothane group. The possibility that there was higher oxygen consumption under halothane anesthesia is discussed.

Anesthesia↗
PubMed1975

The use of Forane anesthesia for surface-induced deep hypothermia.

The effects of Forane anesthesia for deep surface hypothermia with 30 minutes of total circulatory occlusion were evaluated. With 100% O2 6 of 7 dogs developed motor disorders postoperatively, while 3 of 5 with 98% O2/2% CO2 and none with 95% O2/5% CO2 developed motor disorders. Cooling was uneventful except for 1 episode of ventricular fibrillation in the 5% CO2 group at 23 degrees C. Resuscitation was easy, but the early rewarming period was characterized by repeated episodes of ventricular fibrillation and delayed recovery of cardiac function, especially in the 100% O2 group. Blood lactate levels remained low during cooling and gradually increased during rewarming in all groups, with the highest levels in the 100% O2 group and the lowest in the 5% CO2 group. It is concluded that Forane can be used for surface hypothermia with 30 minutes' circulatory occlusion when administered in 95% O2/5% CO2. A Comparison of these results with previously reported series indicates that Forane is inferior to ether but may be superior to halothane for surface hypothermia.

Anesthesia, Inhalation↗
PubMed1998

Effects of oncotic pressure and hematocrit on outcome after hypothermic circulatory arrest.

BACKGROUND: A recent study found that a higher-perfusate hematocrit was associated with improved neurologic recovery after deep hypothermic circulatory arrest. The current study examined the relative contributions of oxygen delivery and colloid oncotic pressure to this result, as well as the efficacy of different colloidal agents and modified ultrafiltration. METHODS: Twenty-six piglets were randomized into five groups (n = 5 or 6 animals per group): control group 1--blood and crystalloid prime, hematocrit of 20%; group 2--blood and hetastarch prime, hematocrit of 20%; group 3--blood and pentafraction prime, hematocrit of 20%; group 4--blood and crystalloid prime with 10 minutes of modified ultrafiltration; group 5--whole blood prime, hematocrit of 30%. All groups underwent 60 minutes of deep hypothermic circulatory arrest at 15 degrees C. RESULTS: Groups 2 and 3 showed less body weight gain (analysis of variance, p = 0.001; group 2 versus group 1, p = 0.0009; group 3 versus group 1, p = 0.0009) and body water content after cardiopulmonary bypass (analysis of variance, p = 0.001; group 2 versus group 1, p = 0.003; group 3 versus group 1, p = 0.013). Group 5 showed more rapid recovery of phosphocreatine and intracellular acidosis, as measured by magnetic resonance spectroscopy, during rewarming than group 1 did (phosphocreatine, p = 0.0329; intracellular acidosis, p = 0.0462). Group 3 also showed accelerated recovery of intracellular acidosis (p = 0.0411). Cytochrome a,a3 recovery, determined by near-infrared spectroscopy, was significantly better in group 5 than in group 1 and worse in group 2 than in group 1 after rewarming. The neurologic deficit score and overall performance category score were best in group 5 (neurologic deficit score, p = 0.012; overall performance category score, p = 0.046) on the first postoperative day. Group 3 also had a better overall performance category score than group 1 did (p = 0.0068). Only group 1 and 2 animals showed histologic damage. CONCLUSIONS: Both higher hematocrit and higher colloid oncotic pressure with pentafraction improve cerebral recovery after deep hypothermic circulatory arrest. The higher hematocrit improves cerebral oxygen delivery but does not reduce total body edema. Modified ultrafiltration after cardiopulmonary bypass is less effective than having a higher initial prime hematocrit or colloid oncotic pressure.

Animals↗
PubMed1998

Anesthetic technique influences brain temperature during cardiopulmonary bypass in dogs.

BACKGROUND: Because different anesthetics have different effects on cerebral blood flow and cerebral metabolism, we hypothesized that they also may have different effects on brain temperature during hypothermic cardiopulmonary bypass (CPB) and subsequent rewarming. METHODS: Sixteen dogs were anesthetized either with inhaled halothane, 1.0 minimum alveolar concentration (ie, an anesthetic that should increase cerebral blood flow and minimally affect cerebral metabolism; n = 8), or with intravenous high-dose pentobarbital (ie, an anesthetic that should reduce cerebral blood flow and cerebral metabolism by approximately one half; n = 8). Normocapnia (alpha-stat technique) and a blood pressure near 90 mm Hg were maintained. Thermistors were placed in the esophagus (ie, the body core), in the parietal epidural space, and in the parietal brain parenchyma at depths of 1 and 2 cm. Initially, all temperatures were controlled at 38.0 degrees +/- 0.2 degrees C (mean +/- standard deviation). Thereafter, atrial-femoral artery CPB was initiated, and after 15 minutes at 38 degrees C, the core temperature was decreased to 28 degrees C over approximately 21 minutes. After 30 minutes at 28 degrees C, the core temperature was returned to 38 degrees C over approximately 21 minutes and was maintained at 38 degrees C for the next 30 minutes. RESULTS: In halothane-anesthetized dogs, the mean brain-to-core temperature gradient always was 1.0 degrees C or less for all brain sites during all phases of CPB. In contrast, in pentobarbital-anesthetized dogs, the mean brain temperature during active cooling typically exceeded the core temperature by 1.7 degrees to 2.2 degrees C. This brain-to-core temperature gradient persisted into the period of stable hypothermia. During the rewarming phase of CPB, the mean brain temperature was 2.9 degrees to 3.4 degrees C cooler than the core temperature. This trend of relative cerebral hypothermia persisted well into the period in which the core temperature was 38 degrees C. CONCLUSIONS: Deep barbiturate anesthesia resulted in a brain-to-core temperature gradient during CPB that was of a magnitude greater than the 1 degrees C previously reported to modulate ischemic neurologic injury. We speculate that the timely administration of barbiturates (eg, during the latter stages of CPB) may be useful as part of a cerebroprotective regimen in humans undergoing CPB, in part because the barbiturates influence brain temperature.

Anesthesia↗
PubMed1999

Increased temperature reduces the protective effect of University of Wisconsin solution in the heart.

BACKGROUND: The protective effect of University of Wisconsin solution (UW) for hypothermic storage of donor hearts has been demonstrated in the laboratory. However, clinical usage is associated with occasional primary graft failures. We postulated that this could be related to adverse effects of UW on the coronary vasculature during cardiac implantation and rewarming. We therefore assessed recovery of contractile function and coronary flow in rat hearts after cardioplegic arrest using UW compared with St. Thomas' solution (ST) at 4 degrees C or 25 degrees C. METHODS: Cardioplegia was induced in isolated rat hearts using either UW or ST at 4 degrees C. Hearts were then maintained at 4 degrees C or 25 degrees C. In some hearts, UW at 4 degrees C was used for inducing arrest followed by flushing with ST at 4 degrees C and then rewarming to 25 degrees C. After 40 minutes of arrest, recovery of function and coronary flow were measured. Nuclear track emulsion was used to assess microvascular competence. RESULTS: Compared with ST-treated hearts, UW-treated hearts showed significant reduction in recovery of function at 25 degrees C (76.2% +/- 4.0% versus 25.0% +/- 4.1%; p < 0.01) but not at 4 degrees C (88.0% +/- 1.6% versus 87.1% +/- 2.6%). Recovery of coronary flow in the UW-treated hearts at 25 degrees C was significantly lower than that in the ST-treated hearts at 25 degrees C (71.7% +/- 3.0% versus 94.5% +/- 6.3%; p < 0.01). At 25 degrees C, microvascular competence was reduced in the UW group compared with the ST group. At 25 degrees C, flushing out UW with ST resulted in greater recovery of function compared with UW throughout (73.4% +/- 7.1% versus 25.0% +/- 4.1%; p < 0.01). CONCLUSIONS: University of Wisconsin solution provides effective donor heart protection under hypothermic conditions but can be deleterious at warmer temperatures.

Adenosine↗
PubMed1999

Effects of perfusion mode on regional and global organ blood flow in a neonatal piglet model.

BACKGROUND: Organ injury (brain, kidney, and heart) has been reported in up to 30% of pediatric open heart surgery patients after conventional hypothermic non-pulsatile cardiopulmonary bypass (CPB) support with or without deep hypothermic circulatory arrest (DHCA). The effects of pulsatile (with a Food and Drug Administration approved modified roller pump) versus non-pulsatile perfusion on regional and global cerebral, renal, and myocardial blood flow were investigated during and after CPB with 60 minutes of DHCA in a neonatal piglet model. METHODS: Piglets, mean weight 3 kg, were used in both pulsatile (n = 7) and non-pulsatile (n = 7) groups. After initiation of CPB, all animals were subjected to hypothermia for 25 minutes, reducing the rectal temperatures to 18 degrees C, 60 minutes of DHCA followed by 10 minutes of cold reperfusion and 40 minutes of rewarming with a pump flow of 150 mL/kg/min. During cooling and rewarming, alpha-stat acid-base management was used. Differently labeled radioactive microspheres were injected pre-CPB, on normothermic CPB, pre-DHCA, post-DHCA, and after CPB to measure the regional and global cerebral, renal, and myocardial blood flows. RESULTS: Global cerebral blood flow was significantly higher in the pulsatile group compared to the non-pulsatile group at normothermic CPB (100.4 +/- 6.3 mL/100 gm/min versus 70.2 +/- 8.1 mL/100 gm/min, p < 0.05) and pre-DHCA (77.2 +/- 5.2 mL/100 gm/min versus 56.1 +/- 6.7 mL/100 gm/min, p < 0.05). Blood flow in cerebellum, basal ganglia, brain stem, and right and left cerebral hemispheres had an identical pattern with the global cerebral blood flow. Renal blood flow appeared higher in the pulsatile group compared to the non-pulsatile group during CPB, but the results were statistically significant only at post-CPB (94.8 +/- 9 mL/100 gm/min versus 22.5 +/- 22 mL/100 gm/min, p < 0.05). Pulsatile flow better maintained the myocardial blood flow compared to the non-pulsatile flow after CPB (316.6 +/- 45.5 mL/100 gm/min versus 188.2 +/- 19.5 mL/100 gm/min, p < 0.05). CONCLUSIONS: Pulsatile perfusion provides superior vital organ blood flow compared to non-pulsatile perfusion in this model.

Animals↗
PubMed1997

Pyruvate reverses fatty-acid-induced depression of ventricular function and calcium overload after hypothermia in guinea pig hearts.

OBJECTIVE: High levels of free fatty acids have been shown to impair mechanical recovery and calcium homeostasis of isolated rat hearts following hypothermic perfusion. The objective of the present study was to investigate whether inhibition of fatty acid oxidation through activation of pyruvate dehydrogenase by millimolar concentrations of pyruvate could influence functional recovery and Ca2+ homeostasis after a hypothermic insult. METHODS: Ventricular function and myocardial calcium ([Ca]total) were measured in 3 different groups of Langendorff-perfused guinea pig hearts exposed to 40 min hypothermic (15 degrees C) perfusion, followed by 30 min rewarming at 37 degrees C. The hearts were perfused with either 11.1 mM glucose (G), glucose and 1.2 mM palmitate (GP), or glucose, palmitate and 5 mM pyruvate (GPP) as energy substrates. RESULTS: All groups showed marked elevations in [Ca]total during hypothermia (from 0.6-0.7 mumol.g dry wt-1 to 9.3-12.2 mumol.g dry wt-1 at 40 min hypothermia, P < 0.05), associated with a pronounced increase in left ventricular end-diastolic pressure (LVEDP from 0-2 to 50-60 mmHg). Following rewarming, GP-perfused hearts showed significantly lower recovery of mechanical function compared to both G- and GPP-perfused hearts (% recovery of left ventricular developed pressure: 27 +/- 8 vs. 62 +/- 3 and 62 +/- 8%, respectively, P < 0.05). The reduced mechanical recovery of GP-perfused hearts was associated with elevated [Ca]total. In separate experiments we found that addition of 1.2 mM palmitate reduced glucose oxidation ([14C]glucose) from 1.77 +/- 0.28 mumol.min-1.g dry wt-1 (G-perfused hearts) to 0.15 +/- 0.04 mumol.min-1.g dry wt-1 (GP-perfused hearts, P < 0.05), implying that fatty acids had become the major substrate for oxidative phosphorylation. Fatty acid oxidation was, however, less pronounced after further addition of 5 mM pyruvate. Thus, palmitate oxidation ([3H]palmitate) was more than 40% lower in GPP-perfused than in GP-perfused hearts (0.83 +/- 0.22 vs. 1.41 +/- 0.12 mumol.min-1.g dry wt-1, P < 0.05). CONCLUSIONS: The present results demonstrate impaired ventricular function and calcium homeostasis after hypothermia in guinea pig hearts perfused with fatty acids in addition to glucose, as compared to hearts perfused with glucose alone. Furthermore, we show that these unfavourable effects of fatty acids can be overcome by an exogenous supply of pyruvate.

Animals↗
PubMed2002

Vitrification media: toxicity, permeability, and dielectric properties.

The aim of this study was to select a cryoprotectant for use in attempts to preserve tissues and organs by vitrification. The first step was to select a cell line with which to compare the toxicity of a range of commonly used cryoprotectants. An immortal vascular endothelial cell (ECV304) was exposed to vitrifying concentrations of four cryoprotectants: dimethyl sulfoxide (Me(2)SO; 45% w/w); 2,3 butanediol (BD; 32%); 1,2-propanediol (PD; 45%); and ethanediol (ED; 45%). Three times of exposure (1, 3, and 9 min) and two temperatures (22 and 2-4 degrees C) were studied. After removal of the cryoprotectant, the ability of the cells to adhere and divide in culture over a 2-day period was measured and expressed as a Cell Survival Index (CSI). There was no measurable loss of cells after exposure to the four cryoprotectants but 3-min exposure to BD, PD, or Me(2)SO at room temperature completely destroyed the ability of the cells to adhere and divide in culture. In contrast, exposure to all four cryoprotectants at 2-4 degrees C for up to 9 min permitted the retention of significant cell function, the CSIs, as a proportion of control, being 76.3+/-7.0% for BD, 63.6+/-7.1% for PD, 37.0+/-4.1 for Me(2)SO, and 33.2+/-3.0 for ED. The permeability properties of the cells for these four cryoprotectants was also measured at each temperature. Permeability to water was high, L(p) approximately equal 10(-7) cm/s/atm at 2-4 degrees C with all the cryoprotectants, but there were substantial differences in solute permeability: BD and PD were the most permeable at 2-4 degrees C (P(s)=4.1 and 3.0 x 10(-6) cm/s, respectively). Equilibration of intracellular cryoprotectant concentration was rapid, due in part to high water permeability; the cells were approximately 80% of their physiological volume after 10 min. Treatment at 2-4 degrees C with BD was the least damaging, but PD was not significantly worse. Exposure to vitrifying concentrations of ED and Me(2)SO, even at 2-4 degrees C, was severely damaging. Segments of rabbit carotid artery were treated with vitrifying concentrations of each of the two most favorable cryoprotectants, BD and PD, for 9 min. It was shown that each cryoprotectant reduced smooth muscle maximum contractility to a similar extent and abolished the acetylcholine response. However, vital staining revealed that exposure to BD also caused substantial damage to the endothelial lining, whereas the endothelium was completely intact after PD exposure, raising the possibility that the effect of PD on NO release may be reversible. In later stages of this project it is planned to use dielectric heating to rewarm the tissues and thereby avoid devitrification. The effects of each cryoprotectant on this mode of heating was therefore studied. Gelatin spheres containing vitrifiable concentrations of each cryoprotectant were rewarmed from -60 degrees C in a radiofrequency applicator. Because the uniformity of heating is related to the dielectric properties of the material, these properties were also measured. PD was the most suitable. These physical measurements, combined with the measurements of toxicity and permeability, indicate that PD is the most favorable cryoprotectant of those tested for use in subsequent stages of this study.

Butylene Glycols↗
PubMed1986

The role of temperature on the development of oscillatory afterpotentials and triggered activity.

Increasing evidence suggests that calcium dependent oscillatory afterpotentials (OAP) may play a pivotal role in the genesis of reperfusion-induced arrhythmias. Many factors may influence the vulnerability of the heart to reperfusion arrhythmias, some of which may possibly affect the development of OAP. Since intramyocardial temperature changes during ischemia and reperfusion, it may be speculated that the rapid rewarming of the ischemic area during reperfusion favors the development of associated arrhythmias. We thought it important to examine the effects of sudden changes in temperature on OAP and subsequent triggered activity. Evidence is presented that raising the bath temperature from 34 degrees C to 37 degrees C causes a transient increase above the control level of the OAP amplitude, and that if the OAP is large enough to reach the threshold a triggered rhythm ensues. These results suggest that sudden rewarming of calcium overloaded cell (as it happens during reperfusion of the ischemic myocardium) may favor the development of abnormal automaticity due to OAP.

Animals↗