Prolonged Hypothermic Circulatory Arrest Research Articles

Prolonged Circulatory Arrest is Not Associated with Stroke or Mortality after Pulmonary Thromboendarterectomy

Purpose Patients with chronic thromboembolic pulmonary hypertension (CTEPH) frequently present with extensive distal clot burden, which adds complexity to pulmonary thromboendarterectomy (PTE). Complete endarterectomy often necessitates prolonged periods of hypothermic circulatory arrest (HCA), the ramifications of which are poorly understood. Objectives were to describe the association of HCA time with post-operative neurologic complications, operative mortality and other major morbidity after PTE. Methods From 2013 to 2019, 163 patients underwent PTE at a single academic institution. Median age was 51 [IQR 23] and 55% (N=89) were female. Operative approach involved profound hypothermia with multiple brief periods of HCA without aortic crossclamping. As event rates were low, the primary outcome was a composite of operative mortality, stroke, respiratory failure requiring tracheostomy and renal failure requiring dialysis. Both univariate and multivariable logistic regression analyses were performed to examine association between HCA and this composite outcome. Results Overall operative mortality was 6.8% (N=11), while 1% of patients (n=2) suffered stroke, 5% (n=8) required dialysis and 10% (n=17) required tracheostomy. In terms of hemodynamic outcomes, median improvement in mean PA pressures was 15mmHg [IQR 16] comparing pre-operative to last post-operative invasive monitoring. Median HCA time was 46 minutes [IQR 32] over a median of 3 [IQR 2] arrest periods at median core temperature of 17°C [IQR 2.2]. When grouped by HCA time less than or greater than 60 minutes, there was no significant difference in the composite outcome (15% versus 12%, p=0.720). Among nine patients with very prolonged HCA time greater than 90 minutes, the composite outcome occurred in one (11%). In a univariate logistic regression analysis, neither HCA time (OR 1.00, CI 0.99-1.01) nor number of arrests (OR 0.98, CI 0.94-1.02) were significant predictors of the composite. In a multivariable model, increasing age was the only significant predictor of the composite (OR 1.05, CI 1.01-1.10). Conclusion Prolonged HCA during PTE does not appear to confer increased risk of neurologic or other major complications. Therefore, more extensive endarterectomy should be pursued, when appropriate, to achieve the best hemodynamic outcome for patients with distal and bilateral disease.

Inhibition of microRNA-29c protects the brain in a rat model of prolonged hypothermic circulatory arrest

ObjectiveWe sought to investigate the cerebroprotection of a novel microRNA mechanism by targeting peroxisome proliferator-activated receptor gamma coactivator 1-alpha in a rat model of prolonged deep hypothermia circulatory arrest. MethodsThe right carotid artery and jugular vein of male Sprague–Dawley rats were cannulated for cardiopulmonary bypass. Circulatory arrest was conducted for 60 minutes when the pericranial temperature was cooled to 18°C. The sham group received the surgical procedure without cardiopulmonary bypass and deep hypothermia circulatory arrest; the deep hypothermia circulatory arrest group received cardiopulmonary bypass and deep hypothermia circulatory arrest; lentivirus control vector or lentiviral vector containing antagomiR-29c was given to the deep hypothermia circulatory arrest + vector group or the deep hypothermia circulatory arrest + antagomiR-29c group by intracerebroventricular administration 5 days before cardiopulmonary bypass (n = 8, for each of the 4 groups). Neurologic function was evaluated by the modified hole board test and beam balance task during 14 postoperative days. Expressions of caspase-3, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and miR-29c in the hippocampus were measured by Western blot and quantitative reverse transcription polymerase chain reaction. Malondialdehyde was measured using the Malondialdehyde Assay Kit (Beyotime, Jiangsu, China). ResultsPretreatment with antagomiR-29c significantly decreased the expression of microRNA-29c and increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the hippocampus (P < .05 vs deep hypothermia circulatory arrest group). The level of malondialdehyde in the hippocampus was lower in the deep hypothermia circulatory arrest + antagomiR-29c group (P < .05 vs deep hypothermia circulatory arrest group). The neurologic functions were markedly protected in rats pretreated with antagomiR-29c as evidenced by improvement of vestibulomotor and cognitive performance during the early postoperative period. In the deep hypothermia circulatory arrest + antagomiR-29c group, histologic scores of the hippocampus were improved and the level of caspase-3 in the hippocampus was lower (P < .05 vs deep hypothermia circulatory arrest group). ConclusionsInhibition of miR-29c attenuates neurologic injuries induced by prolonged deep hypothermia circulatory arrest through a peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathway.

Invited Commentary

Invited Commentary

Decreased DNA Disruption in the Porcine Neocortex with Erythromycin Preconditioning during Prolonged Hypothermic Circulatory Arrest: Evidence for Neuroprotection.

We have previously reported that the neocortex is selectively vulnerable to injury in an acute porcine model of hypothermic circulatory arrest (HCA) at 18°C. In view of recent evidence showing that pharmacologic preconditioning with a single dose of erythromycin induces tolerance against transient global cerebral ischemia in rats, we hypothesized that erythromycin would reduce the number of apoptotic neurons in the neocortex in an acute porcine model of HCA at 18°C. Fourteen piglets underwent 75 min of HCA at 18°C following pretreatment with erythromycin (25 mg/kg, IV) (n = 8) or vehicle (Normal Saline 0.9%) (n = 6), applied 12 hr before arrest. Three served as normal controls. After gradual rewarming to a temperature of 36°C, treatment animals were sacrificed and brains were perfusion-fixed and cryopreserved. Neuronal apoptosis after HCA was observed morphologically with hematoxylin and eosin staining, and characterized by in situ DNA fragmentation using terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end-labeling (TUNEL) histochemistry. Pre-ischemic conditioning with a single dose of the antibiotic erythromycin reduced neuronal apoptosis in the neocortex of the porcine brain. TUNEL-positive cells indicating DNA fragmentation and neuronal injury were significantly greater in the neocortex of animals treated with 18°C HCA (2.55 ± 1.17) compared to animals undergoing HCA after erythromycin preconditioning (1.76 ± 0.91) (p ≤ 0.001). These results suggest that cerebral protection during HCA may be achieved with erythromycin pharmacological preconditioning in the porcine model.

Erythromycin induced neuroprotection during prolonged deep hypothermic circulatory arrest in an acute porcine model

Methods Piglets were treated with erythromycin (25 mg/kg, iv) (n = 8) or vehicle (n = 6) and subjected to 75 minutes of DHCA at 18°C, 12 hours after pretreatment. Three served as normal controls. After gradual rewarming, treatment animals were sacrificed and brains were perfusion-fixed and cryopreserved. Motor cortex was dissected from the left hemisphere and paraffin embedded for histologic staining with hematoxylin and eosin (HE). To assess neuronal damage, HE-stained paraffin sections (10 μm) were examined by light microscopic examination at x400 magnification. Layer V of the motor cortex was counted. Neuronal injury was recorded when there was evidence of eosinophilic cytoplasm, cytoplasmic vacuolation, cell body shrinkage or nuclear pyknosis. Neuronal injury was scored on a scale of 0-5.

A modified protocol for retrograde cerebral perfusion: magnetic resonance spectroscopy in pigs

Retrograde cerebral perfusion (RCP) has been employed to protect the brain during cardiovascular surgery, requiring temporary hypothermic circulatory arrest (HCA). However, the protocol used for RCP remains to be modified if prolonged HCA is expected. The aim of this study was to determine the efficacy of a modified protocol for this purpose. After establishment of HCA at 15°C, 14 pigs were subjected to 90-min RCP using either the conventional protocol (i.e. alpha-stat strategy, 25-mmHg perfusion pressure and occluded inferior vena cava, Group I, n = 7) or the new protocol (i.e. pH-stat strategy, 40-mmHg perfusion pressure and unoccluded inferior vena cava, Group II, n = 7). After being rewarmed to 37°C, pigs were perfused for another 60 min. Phosphorus-31 magnetic resonance spectroscopy was used to track the changes of brain high-energy phosphates [i.e. adenosine triphosphate and phosphocreatine (PCr)] and intracellular pH (pHi). At the end, brain water content was measured. During RCP, high-energy phosphates decreased in both groups, whereas adenosine triphosphate decreased much faster in Group I (10.4 ± 4.3 vs 30.4 ± 4.4% of the baseline, P = 0.007, 60-min RCP). After rewarming, the recovery of high-energy phosphates and pHi was much slower in Group I (PCr: 55.7 ± 9.1 vs 78.4 ± 5.1% of the baseline, P = 0.046; adenosine triphosphate: 26.6 ± 10.6 vs 64.8 ± 4.6% of the baseline, P = 0.007; pHi: 6.5 ± 0.4 vs 7.1 ± 0.1, P = 0.021 at 30-min normothermic perfusion after rewarming). Brain tissue water content was significantly higher in Group I (81.1 ± 0.4 vs 79.5 ± 0.4%, P = 0.016). Application of the modified RCP protocol significantly improved cerebral energy conservation during HCA and accelerated energy recovery after rewarming.

Antegrade selective cerebral perfusion and moderate hypothermia in aortic arch surgery: clinical outcomes in elderly patients

To evaluate the outcome in elderly patients (≥ 75 years) undergoing elective aortic arch surgery with the aid of selective antegrade cerebral perfusion (SACP) and moderate hypothermic circulatory arrest (HCA). A series of 95 patients ≥ 75 years (median age 77 years, median EuroSCORE 28) undergoing elective aortic arch surgery with SACP and moderate HCA were analysed with regard to clinical outcome. Risk factors for serious adverse events (mortality, neurological injury) were determined. Sixty-three patients (66%) underwent ascending aorta and hemiarch replacement, whereas 32 patients (34%) underwent ascending aorta and total arch replacement. Isolated arch replacement was rare. Additionally, 27% of patients underwent aortic valve replacement and 26% underwent root replacement. In-hospital mortality was 7%. Permanent neurological deficits occurred in 5%, transient neurological deficits occurred in 2%. Median SACP time was 24 min. Univariate analysis revealed femoral cannulation site (OR: 3.4; CI: 1.25-9.22, P = 0.016) as well as HCA ≥ 40 min (OR: 4.21; CI: 1.83-12.58, P = 0.001) as predictors of serious adverse events (mortality, neurological injury). Summarizing, elective aortic arch surgery in elderly patients using SACP and moderate HCA provides excellent results regarding mortality and postoperative neurological outcome. Prolonged HCA time and femoral cannulation were the only predictors of serious adverse events (mortality, neurological injury).

Aortic Arch Debranching: Advanced And Hybrid Techniques

Aortic arch procedures have traditionally involved complex surgery with increased risk of mortality and morbidity. Throughout the last decade, however, novel and safe surgical approaches aimed at debranching the great vessels with definitive aortic arch repair have been developed. Currently, hybrid arch procedures allow for open or minimally invasive aortic access to be complemented by endovascular stent-graft techniques, which may eliminate the need for prolonged hypothermic circulatory arrest and its associated complications. Hybrid thoracic aortic and arch repairs have become the preferred approach, with open procedures performed only if hybrid approaches are not possible for technical reasons. In the future, aortic pathology may also benefit from the development of branched and fenestrated endografts that would be deployed in a modular fashion. This article describes the rationale, procedural steps, and recent outcomes data of novel aortic arch procedures.

Repair of ascending and transverse aortic arch

This is a report to update our experience with repairs of the ascending and transverse arch, with an emphasis on the protective measures, including retrograde cerebral perfusion and blood flow and neurologic monitoring. Retrospective data were collected from January 1991 to February 2010, and analysis was conducted on 1193 patients who had aneurysms involving the ascending aorta and arch. The 30-day mortality rate was 9.3%, but with a normal glomerular filtration rate, the mortality rate was 3%. In univariate analysis of the risk factors for death, the factors were advancing age of greater than 72 years (mortality, 14.8%; P = .002), the presence of coronary artery disease (mortality, 13.5%; P = .02), aortic pathology of acute dissection (mortality, 13.9%; P = .004), the emergency nature of the operation (mortality, 16.1%; P = .0001), and renal function in the lowest 3 quartiles of glomerular filtration rate (mortality, 6.9%, 10%, and 18.3%; P = .03, .0005, and .0001, respectively, with decreasing glomerular filtration rate). The highest quartile for pump time (>179 minutes) had a mortality rate of 18.1% (P = .0001). The overall stroke rate was 3%. In univariate analysis of risk factors for stroke, the stroke rate was 2.8% with and 4.2% without retrograde cerebral perfusion (P = .30), but when circulatory arrest time exceeded 40 minutes, the stroke rate was 1.7% with and 30% without retrograde cerebral perfusion (P = .002). Risk factors included age greater than 62 years (stroke rate, 4%; P = .04), hypertension (stroke rate, 3.7%; P = .03), emergency operations (stroke rate, 4.9%; P = .04), and glomerular filtration rate of less than 56 (stroke rate, 4.3%; P = .05). In multiple logistic regression for risk factors for stroke, age was associated with an odds ratio of 1.04 (P = .008), and emergency conditions had an odds ratio of 2.17 (P = .03). Retrograde cerebral perfusion was associated with a trend toward a reduced incidence of hospital mortality and, in patients receiving prolonged hypothermic circulatory arrest, a reduced incidence of stroke.

Glutamate Excitotoxicity Mediates Neuronal Apoptosis After Hypothermic Circulatory Arrest

Prolonged hypothermic circulatory arrest results in neuronal cell death and neurologic injury. We have previously shown that hypothermic circulatory arrest causes both neuronal apoptosis and necrosis in a canine model. Inhibition of neuronal nitric oxide synthase reduced neuronal apoptosis, while glutamate receptor antagonism reduced necrosis in our model. This study was undertaken to determine whether glutamate receptor antagonism reduces nitric oxide formation and neuronal apoptosis after hypothermic circulatory arrest. Sixteen hound dogs underwent 2 hours of circulatory arrest at 18 degrees C and were sacrificed after 8 hours. Group 1 (n = 8) was treated with MK-801, 0.75 mg/kg intravenously prior to arrest followed by 75 microg/kg/hour infusion. Group 2 dogs (n = 8) received vehicle only. Intracerebral levels of excitatory amino acids and citrulline, an equal coproduct of nitric oxide, were measured. Apoptosis, identified by hematoxylin and eosin staining and confirmed by electron microscopy, was blindly scored from 0 (normal) to 100 (severe injury), while nick-end labeling demonstrated DNA fragmentation. Dogs in groups 1 and 2 had similar intracerebral levels of glutamate. However, MK-801 significantly reduced intracerebral glycine and citrulline levels compared with hypothermic circulatory arrest controls. The MK-801 significantly inhibited apoptosis (7.92 +/- 7.85 vs 62.08 +/- 6.28, group 1 vs group 2, p < 0.001). Our results showed that glutamate receptor antagonism significantly reduced nitric oxide formation and neuronal apoptosis. We provide evidence that glutamate excitotoxicity mediates neuronal apoptosis in addition to necrosis after hypothermic circulatory arrest. Clinical glutamate receptor antagonists may have therapeutic benefits in ameliorating both types of neurologic injury after hypothermic circulatory arrest.

Cardiopulmonary bypass and deep hypothermic circulatory arrest in a massively obese patient

As a consequence of the rising global prevalence and magnitude of obesity, a greater proportion of patients presenting for cardiac surgery is morbidly obese. Being overweight (body mass index; BMI 25-29.9 kg/m(2)) or obese (BMI 30-35 kg/m(2)) appears to confer some survival benefit following cardiac surgery. By contrast, morbid obesity (BMI >40 kg/m(2)) is associated with an increased likelihood of postoperative complications and prolonged intensive care unit and hospital length of stay. The physical difficulties encountered when managing this group of patients is exemplified by those undergoing complex, multiple procedures requiring prolonged cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). We present the successful management of a massively obese 19-year-old male (BMI 45 kg/m(2)) with Marfan's syndrome who required aortic root and arch replacement under DHCA. The selection of extracorporeal circuit components to accommodate a large circulating volume and permit high CPB flow rates (>9 l/min) is discussed.

Hypothermic circulatory arrest with 'low flow' lower body perfusion: An experimental study of microcirculatory parameters

Objective: Cerebral perfusion seems to be an adequate tool for neuroprotection under hypothermic circulatory arrest (HCA). To avoid extended cardiopulmonary bypass (CPB) times, moderate temperatures are applied for body arrest, jeopardizing optimal organ protection, especially if prolonged HCA times are anticipated. Therefore, distal aortic perfusion might become an alternative, but experimental data are missing.

Erythropoietin protects the central nervous system during prolonged hypothermic circulatory arrest: An experimental study in a canine model

Erythropoietin protects the central nervous system during prolonged hypothermic circulatory arrest: An experimental study in a canine model

Un niveau réduit d’hématocrite aggrave les lésions cérébrales après un arrêt circulatoire hypothermique prolongé chez le rat

This study tests the hypothesis that low hematocrit (Hct) worsens cerebral injury after prolonged hypothermic circulatory arrest (HCA) in rats, and the mechanism involves variable expression of the genes C-Fos, Bcl-2 and Bax. A rat HCA model was developed, and 40 animals were randomly assigned to four groups: Sham (sham) group, or Hct groups of Hct 10%, Hct 20% and Hct 30%. After 90 min of HCA at 18 degrees C, physiologic variables were recorded and brain morphological changes were evaluated with light and electron microscopy. Expressions of C-Fos, Bcl-2, Bax in various brain areas were measured by the reverse transcriptase polymerase chain reaction and standard immunohistochemistry techniques. The number of injured neurons in the hippocampus CA1 and parietal cortex in the Hct 10% group (CA1: 11.44 +/- 2.52; cortex: 13.65 +/- 2.31) exceeded the mean number of injured neurons in the Hct 20% group (CA1: 8.29 +/- 1.31; cortex: 10.68 +/- 1.24; P < 0.05) and the Hct 30% group. Mean mitochondrial injury scores were greatest at lower Hct levels, while the expression of C-Fos and Bax were highest in the Hct 10% group and lowest in the Hct30% group (P < 0.05). In contrast, the expression of the Bcl-2 mRNA was greatest in the Hct 30% group (P < 0.05). Low Hct worsens cerebral injury after prolonged HCA and CPB in rats, which may relate in part to the variable expression of the genes C-Fos, Bcl-2 and Bax.

Erythropoietin protects the central nervous system during prolonged hypothermic circulatory arrest: An experimental study in a canine model

Current data suggest that erythropoietin protects the brain and the spinal cord from ischemic and traumatic injury. In this study, we determined whether erythropoietin protects the central nervous system during prolonged hypothermic circulatory arrest in an experimental canine model. Ten adult beagle dogs were randomly and intravenously injected with either 5000 U/kg recombinant human erythropoietin or normal saline. Each dog was then subjected to a cardiopulmonary bypass and 120 minutes of deep hypothermic circulatory arrest (18 degrees C). The level of tau proteins in the cerebrospinal fluid, a modified marker of neurologic deficit in dogs, and the histopathologic characteristics of the brains and spinal cords were then examined. The level of tau proteins was significantly lower in the erythropoietin-treated group than in the untreated group at 6 hours (20 +/- 12 vs 144 +/- 54 pg/mL; P = .036) and 12 hours (64 +/- 35 vs 478 +/- 103 pg/mL; P = .01) after the operation. The total Neurologic Deficit Score was 59 +/- 31 (0, normal; 500, brain death) in the erythropoietin-treated group, compared with 376 +/- 30 in the untreated group (P = .0117). Histopathologic examination revealed that ischemic neuronal changes and apoptosis in the hippocampus CA1 were significantly lower in the erythropoietin-treated group (P < .01 and P = .028, respectively). This study showed that erythropoietin protected the central nervous system during prolonged hypothermic circulatory arrest, partly by preventing both necrosis (ischemic neuronal changes) and apoptosis.

Impact of different cerebral perfusion temperatures in an experimental pig model of prolonged hypothermic circulatory arrest and selective antegrade cerebral perfusion

Impact of different cerebral perfusion temperatures in an experimental pig model of prolonged hypothermic circulatory arrest and selective antegrade cerebral perfusion

Low hematocrit causes worsened cerebral injury after prolonged hypothermic circulatory arrest in rats: possible involvement of C-Fos, Bcl-2 and Bax

Low hematocrit causes worsened cerebral injury after prolonged hypothermic circulatory arrest in rats: possible involvement of C-Fos, Bcl-2 and Bax

Acute regional neuronal injury following hypothermic circulatory arrest in a porcine model

Although deep hypothermic circulatory arrest (HCA) is routinely used to interrupt normal perfusion of the brain and prevent subsequent cerebral ischemic injury during cardiac surgery, it is associated with various forms of neurologic disturbances. Neurologic sequelae after prolonged HCA include motor, memory and cognitive deficits. The present study was designed to assess acute regional neuronal injury after HCA in an animal model. Six piglets underwent 75 min of HCA at 18 degrees C. Four piglets served as normal controls. After gradual rewarming and reperfusion, treatment animals were killed and their brains were perfusion-fixed and cryopreserved. Regional patterns of neuronal apoptosis after HCA was characterized by in situ DNA fragmentation using terminal deoxyneucleotidyl-transferase-mediated biotin-dUTP nick end-labeling (TUNEL) histochemistry. Hematoxylin and eosin histology was used to characterize cell damage morphologically. TUNEL-positive cells were scored on a scale of 0 to 5. Grade 0: no TUNEL-positive cells; Grade 1: <10%, Grade 2: 10-25%, Grade 3: 25-50%, Grade 4: 50-75%; and Grade 5: >75%. TUNEL-positive cells indicating DNA-fragmentation were scored in the precentral gyrus (motor neocortex), postcentral gyrus (sensory neocortex), hippocampus, cerebellum, thalamus and ventral medulla of HCA treated animals and were significantly greater than in normal controls (P<or=0.05). Significantly higher concentrations of TUNEL-positive cells were observed in the sensory and motor neocortex and hippocampus, compared to the cerebellum, thalamus and medulla, indicating an increased selective vulnerability of these brain subregions (P<or=0.05). Despite significant DNA fragmentation indicated by high-concentrations TUNEL-positive cells, no morphologic evidence of apoptosis or necrosis was observed in this acute model. The data indicate that sensory and motor neocortex and hippocampal neurons are selectively vulnerable to neurologic injury after HCA as indicated by elevated levels of TUNEL-positive cells in these brain regions. It is noteworthy that evidence of significant neuronal injury is observed in the acute state. The absence of morphological evidence of apoptosis or necrosis with high levels of TUNEL-positive cells, strongly suggests activation of the apoptotic mechanisms at this early stage. These findings are compatible with data showing morphological evidence of apoptosis in these regions after a more prolonged period in a chronic animal model. The mechanisms underlying neuronal injury, and potential neuroprotective strategies remain to be elucidated.

Cooling to 10�C and treatment with Cyclosporine A improve cerebral recovery following prolonged hypothermic circulatory arrest in a chronic porcine model

This study was undertaken to assess whether cooling to 10 degrees C and/or treatment with Cyclosporine A (CsA) can reduce neurological injury during prolonged hypothermic circulatory arrest (HCA) in a chronic animal model. In this blinded study, 24 pigs (20-23 kg) were randomized to HCA for 90 min at 20 degrees C (n=8), at 10 degrees C (n=8), or at 10 degrees C with 5 mg/kg CsA (n=8). CsA (or placebo) were given intravenously before and for 3 days after HCA. Hemodynamics and neurophysiological data were monitored periodically throughout the experiment and for 3 h after HCA, as well as intracranial pressure (ICP), which has been shown to correlate with outcome. Daily neurological/behavioral evaluation (mental status, coordination and appetite; 12=normal and 0=coma or death) was carried out until sacrifice on postoperative day (POD) 3. Overall survival rate was 83.3%: one 20 degrees C control, two 10 degrees C controls, and one 10 degrees C/CsA pig died and were replaced. Basic hemodynamic data revealed no significant differences between groups. ICP differed significantly among the groups during the first 3 h postoperatively (P=0.003 by repeated measures ANOVA); it was higher in the 20 degrees C group than in the 10 degrees C/CsA or 10 degrees C control groups. Recovery of visual evoked potentials was significantly better in the 10 degrees C/CsA group than in the 10 degrees C control group; no recovery was seen by 3 h in the 20 degrees C control group. Postoperative behavioral scores also differed significantly between the groups, P=0.03: a good behavioral outcome--a score >9 on POD3--was more prevalent among CsA-treated pigs (75%) than among 10 degrees C controls (50%), or 20 degrees C controls (12.5%, P=0.06). The data suggest that cooling to 10 degrees C and CsA treatment are both of benefit in improving cerebral recovery after HCA when compared with untreated 20 degrees C controls, and may be synergistic.

Ischemic preconditioning or heat shock pretreatment ameliorates neuronal apoptosis following hypothermic circulatory arrest

Objective Hypothermic circulatory arrest has been widely used in complex cardiac and aortic surgery. Stroke and/or neurologic injury can occur after prolonged hypothermic circulatory arrest, possibly due to apoptosis. Ischemic preconditioning has been widely used as a neuroprotective tool, but its application in neuronal injury under hypothermic circulatory arrest has never been studied. Methods Forty male New Zealand white rabbits were placed on closed-chest cardiopulmonary bypass, subjected to hypothermic circulatory arrest, and rewarmed to normothermia. Experimental groups were treated with heat shock or ischemic preconditioning before hypothermic circulatory arrest. Hippocampal CA1 neurons were analyzed histopathologically. Apoptosis was confirmed by TUNEL assay and Western blot analysis, and serum S-100β levels, c-Fos and Bcl-2 antibodies, and caspase-3 and heat shock protein 70 levels were measured. Results After 2-hour hypothermic circulatory arrest and 4-hour reperfusion, apoptosis was observed in hippocampal CA1 neurons with elevation of serum S-100β levels, which could be ameliorated by ischemic preconditioning or heat shock manipulations. TUNEL-positive nuclear expression of caspase-3 increased after hypothermic circulatory arrest (3.08% ± 0.71%, P < .001) and was diminished with ischemic preconditioning (1.61% ± 0.42%) and heat shock (1.72% ± 0.38%) manipulations. Ischemic preconditioning or heat shock manipulations produced diverse patterns of heat shock protein 70, c-Fos, and Bcl-2 protein expression, suggesting that these manipulations provide neuroprotection via different pathways. Conclusions Ischemic preconditioning and heat shock can attenuate hippocampal CA1 neuronal apoptosis after prolonged hypothermic circulatory arrest under cardiopulmonary bypass. The expression of heat shock protein 70 may not play a major role in the first window of ischemic preconditioning-induced neuroprotection.