Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest Trial (GOT ICE): A Randomized Clinical Trial Comparing Outcomes After Aortic Arch Surgery.

BACKGROUND: Deep hypothermia has been the standard for hypothermic circulatory arrest (HCA) during aortic arch surgery. However, centers worldwide have shifted toward lesser hypothermia with antegrade cerebral perfusion. This has been supported by retrospective data, but there has yet to be a multicenter, prospective randomized study comparing deep versus moderate hypothermia during HCA. METHODS: This was a randomized single-blind trial (GOT ICE [Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest]) of patients undergoing arch surgery with HCA plus antegrade cerebral perfusion at 4 US referral aortic centers (August 2016-December 2021). Patients were randomized to 1 of 3 hypothermia groups: DP, deep (≤20.0 °C); LM, low-moderate (20.1-24.0 °C); and HM, high-moderate (24.1-28.0 °C). The primary outcome was composite global cognitive change score between baseline and 4 weeks postoperatively. Analysis followed the intention-to-treat principle to evaluate if: (1) LM noninferior to DP on global cognitive change score; (2) DP superior to HM. The secondary outcomes were domain-specific cognitive change scores, neuroimaging findings, quality of life, and adverse events. RESULTS: A total of 308 patients consented; 282 met inclusion and were randomized. A total of 273 completed surgery, and 251 completed the 4-week follow-up (DP, 85 [34%]; LM, 80 [34%]; HM, 86 [34%]). Mean global cognitive change score from baseline to 4 weeks in the LM group was noninferior to the DP group; likewise, no significant difference was observed between DP and HM. Noninferiority of LM versus DP, and lack of difference between DP and HM, remained for domain-specific cognitive change scores, except structured verbal memory, with noninferiority of LM versus DP not established and structured verbal memory better preserved in DP versus HM (P = 0.036). There were no significant differences in structural or functional magnetic resonance imaging brain imaging between groups postoperatively. Regardless of temperature, patients who underwent HCA demonstrated significant reductions in cerebral gray matter volume, cortical thickness, and regional brain functional connectivity. Thirty-day in-hospital mortality, major morbidity, and quality of life were not different between groups. CONCLUSIONS: This randomized multicenter study evaluating arch surgery HCA temperature strategies found low-moderate hypothermia noninferior to traditional deep hypothermia on global cognitive change 4 weeks after surgery, although in secondary analysis, structured verbal memory was better preserved in the deep group. The verbal memory differences in the low- and high-moderate groups and structural and functional connectivity reductions from baseline merit further investigation and suggest opportunities to further optimize brain perfusion during HCA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02834065.

Transcriptomic Profiling of circRNAs in rat Hippocampus after Deep Hypothermic Circulatory Arrest.

Neurologic abnormalities occurring after deep hypothermic circulatory arrest (DHCA) remain a significant concern. However, molecular mechanisms leading to DHCA-related cerebral injury are still ill-defined. Circular RNAs (circRNAs) are a class of covalently closed non-coding RNAs and can play important roles in different types of cerebral injury. This study aimed to investigate circRNAs expression profiles in rat hippocampus after DHCA and explore the potential functions of circRNAs in DHCA-related cerebral injury. Hence, the DHCA procedure in rats was established and a transcriptomic profiling of circRNAs in rat hippocampus was done. As a result, a total of 35192 circRNAs were identified. Among them, 339 circRNAs were dysregulated, including 194 down-regulated and 145 up-regulated between DHCA and sham group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed based on the host genes of all dysregulated circRNAs. Also, 4 circRNAs were validated by RT-qPCR (rno_circ_0028462, rno_circ_0037165, rno_circ_0045161 and rno_circ_0019047). Then a circRNA-microRNA (miRNA) interaction network involving 4 candidate circRNAs was constructed. Furthermore, functional enrichment analysis of the miRNA-targeting mRNAs of every candidate circRNA was conducted to gain insight into each of the 4 circRNAs. Our study provided a better understanding of circRNAs in the mechanisms of DHCA-related cerebral injury and some potential targets for neuroprotection.

Hypothermic Circulatory Arrest in Adult Aortic Arch Surgery: A Review of Hypothermic Circulatory Arrest and its Anesthetic Implications.

Diseases affecting the aortic arch often require surgical intervention. Hypothermic circulatory arrest (HCA) enables a safe approach during open aortic arch surgeries. Additionally, HCA provides neuroprotection by reducing cerebral metabolism and oxygen requirements. However, HCA comes with significant risks (eg, neurologic dysfunction, stroke, and coagulopathy), and the cardiac anesthesiologist must completely understand the surgical techniques, possible complications, and management strategies.

Risk Factors for Stroke Development After Thoracic Aortic Surgery.

OBJECTIVES: Stroke after thoracic aortic surgery is a complication that is associated with poor outcomes. The aim is to characterize the intraoperative risk factors for stroke development. DESIGN: A retrospective analysis. SETTING: Tertiary, high-volume cardiac surgery center. PARTICIPANTS: Patients who had surgical repair of thoracic aortic diseases from January 1, 2017, through December 31, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 704 patients were included, of whom 533 had ascending aortic aneurysms, and 171 had type A aortic dissection. The incidence of postoperative stroke was 4.5% (95% CI 2.9%-6.6%) for ascending aortic aneurysms compared with 12.3% (95% CI 7.8%-18.16%) in type-A aortic dissections. Patients who developed postoperative strokes had significantly lower intraoperative hemoglobin median (7.5 gm/dL [IQR 6.8-8.6] v 8.55 gm/dL [IQR 7.3-10.0]; p < 0.001). The median cardiopulmonary bypass time was 185 minutes (IQR 136-328) in the stroke group versus 156 minutes (IQR 113-206) in the nonstroke group (p = 0.014). Circulatory arrest was used in 57.8% versus 38.5% of the nonstroke patients (p = 0.017). The initial temperature after leaving the operating room was lower, with a median of 35.0°C (IQR 34-35.92) in the stroke group versus 35.5°C (IQR 35-36) in the nonstroke cohort (p = 0.021). CONCLUSIONS: This single-center study highlighted the potential importance of intra-operative factors in preventing stroke. Lower hemoglobin, longer duration of cardiopulmonary bypass, deep hypothermic circulatory arrest, and postoperative hypothermia are potential risk factors for postoperative stroke. Further studies are needed to prevent this significant complication in patients with thoracic aortic diseases.

Does methylprednisolone provide protective effect in total aortic arch replacement requiring hypothermia circulatory arrest and selective cerebral perfusion?

BACKGROUND: Glucocorticoids (GC)were applied in total aortic arch replacement (TAAR) at various dosages in many centers, but with limited evidence. METHODS: The retrospective study was aimed to evaluate whether methylprednisolone was associated with better postoperative outcomes in patients undergoing TAAR. Patients undergoing TAAR with moderate hypothermia and selective cerebral perfusion between 2017.1 to 2018.12 in Fuwai hospital were classified into three groups according to doses of methylprednisolone given in the surgery: large-GC group (1500-3000 mg); medium-GC group (500-1000 mg) and no-GC group (0 mg). Postoperative outcomes were compared among three groups. Multivariable analysis was performed to identify the association of methylprednisolone with outcomes. RESULTS: Three hundred twenty-eight patients were enrolled. Two hundred twenty-eight were in the large-GC group, 34 were in the medium-GC group, and 66 were in the no-GC group. The incidences of major adverse outcomes in large-GC, medium-GC and no-GC groups were 22.8%, 17.6% and 18.2%, respectively, with no statistical difference. A significant difference was observed in post-cardiopulmonary bypass (CPB) fresh frozen plasma (FFP) transfusion (p < .001) and chest drainage volume (p < .001). Multivariable analysis demonstrated that methylprednisolone was not associated with better outcomes (p = .455), while large doses of methylprednisolone were significantly associated with excessive chest drainage (over 2000 mL) [OR (99% CI) 4.282 (1.66-11.044), p < .001] and excessive post-CPB FFP transfusion (over 400 mL) [OR (99% CI) 2.208 (1.027-4.747), p = .008]. CONCLUSIONS: Large doses of methylprednisolone (1500-3000 mg) did not show a protective effect in TAAR with moderate hypothermia arrest plus selective cerebral perfusion and might increase postoperative bleeding and FFP transfusion.

The dynamic changes in autophagy activity and its role in lung injury after deep hypothermic circulatory arrest.

Deep hypothermic circulatory arrest (DHCA) can cause acute lung injury (ALI), and its pathogenesis mimics ischaemia/reperfusion (I/R) injury. Autophagy is also involved in lung I/R injury. The present study aimed to elucidate whether DHCA induces natural autophagy activation and its role in DHCA-mediated lung injury. Here, rats were randomly assigned to the Sham or DHCA group. The sham group (n = 5) only received anaesthesia and air intubation. DHCA group rats underwent cardiopulmonary bypass (CPB) followed by the DHCA procedure. The rats were then sacrificed at 3, 6 and 24 h after the DHCA procedure (n = 5) to measure lung injury and autophagy activity. Chloroquine (CQ) was delivered to evaluate autophagic flux. DHCA caused lung injury, which was prominent 3-6 h after DHCA, as confirmed by histological examination and inflammatory cytokine quantification. Lung injury subsided at 24 h. Autophagy was suppressed 3 h but was exaggerated at 6 h. At both time points, autophagic flux appeared uninterrupted. To further assess the role of autophagy in DHCA-mediated lung injury, the autophagy inducer rapamycin and its inhibitor 3-methyladenine (3-MA) were applied, and lung injury was reassessed. When rapamycin was administered at an early time point, lung injury worsened, whereas administration of 3-MA at a late time point ameliorated lung injury, indicating that autophagy contributed to lung injury after DHCA. Our study presents a time course of lung injury following DHCA. Autophagy showed adaptive yet protective suppression 3 h after DHCA, as induction of autophagy caused worsening of lung tissue. In contrast, autophagy was exaggerated 6 h after DHCA, and autophagy inhibition attenuated DHCA-mediated lung injury.

Metabolomic profiling demonstrates evidence for kidney and urine metabolic dysregulation in a piglet model of cardiac surgery-induced acute kidney injury.

Acute kidney injury (AKI) is a common cause of morbidity after congenital heart disease surgery. Progress on diagnosis and therapy remains limited, however, in part due to poor mechanistic understanding and a lack of relevant translational models. Metabolomic approaches could help identify novel mechanisms of injury and potential therapeutic targets. In the present study, we used a piglet model of cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB/DHCA) and targeted metabolic profiling of kidney tissue, urine, and serum to evaluate metabolic changes specific to animals with histological acute kidney injury. CPB/DHCA animals with acute kidney injury were compared with those without acute kidney injury and mechanically ventilated controls. Acute kidney injury occurred in 10 of 20 CPB/DHCA animals 4 h after CPB/DHCA and 0 of 7 control animals. Injured kidneys showed a distinct tissue metabolic profile compared with uninjured kidneys (R2 = 0.93, Q2 = 0.53), with evidence of dysregulated tryptophan and purine metabolism. Nine urine metabolites differed significantly in animals with acute kidney injury with a pattern suggestive of increased aerobic glycolysis. Dysregulated metabolites in kidney tissue and urine did not overlap. CPB/DHCA strongly affected the serum metabolic profile, with only one metabolite that differed significantly with acute kidney injury (pyroglutamic acid, a marker of oxidative stress). In conclusion, based on these findings, kidney tryptophan and purine metabolism are candidates for further mechanistic and therapeutic investigation. Urine biomarkers of aerobic glycolysis could help diagnose early acute kidney injury after CPB/DHCA and warrant further evaluation. The serum metabolites measured at this early time point did not strongly differentiate based on acute kidney injury.NEW & NOTEWORTHY This project explored the metabolic underpinnings of postoperative acute kidney injury (AKI) following pediatric cardiac surgery in a translationally relevant large animal model of cardiopulmonary bypass with deep hypothermic circulatory arrest. Here, we present novel evidence for dysregulated tryptophan catabolism and purine catabolism in kidney tissue and increased urinary glycolysis intermediates in animals who developed histological AKI. These pathways represent potential diagnostic and therapeutic targets for postoperative AKI in this high-risk population.

Rotational Thromboelastometry-Guided Transfusion Protocol to Reduce Allogeneic Blood Transfusion in Proximal Aortic Surgery With Deep Hypothermic Circulatory Arrest.

OBJECTIVES: To determine the impact of a rotational thromboelastometry (ROTEM)-guided transfusion protocol on the use of blood products, patient outcomes, coagulation factor concentrates, and costs. DESIGN: A single-center retrospective cohort study. SETTING: A tertiary university hospital. PATIENTS: Adults undergoing proximal aortic surgery with deep hypothermic circulatory arrest. INTERVENTION: ROTEM-guided transfusion protocol compared with clinically-guided transfusion. MEASUREMENTS AND MAIN RESULTS: Two hundred seventeen patients were included; seventy-one elective and 24 emergency patients in the clinically-guided group, and 59 elective and 63 emergency patients in the ROTEM-guided transfusion protocol group. In the ROTEM-guided transfusion protocol group, a significant reduction in transfusion of red blood cells (5 [3-8] v 2 [0-4], p < 0.001), platelet concentrate (2 [2-3] v 1 [1-2], p < 0.001), and plasma (1,980 mL [1,320-3,300] v 800 mL [0-1,000], p < 0.001) was seen in elective surgery. Emergency patients received fewer red blood cells (7 [5-10] v 5 [2-10], p = 0.040), platelet concentrate (3 [2-4] v 2 [2-3], p = 0.023), and plasma (3,140 mL [1,980-3,960] v 1,000 mL [0-1,400], p < 0.001). Prothrombin complex concentrate and fibrinogen concentrate were increased significantly in elective and emergency patients. The surgical reexploration for bleeding rate was decreased in elective patients 33.8% v 5.1%. CONCLUSION: The implementation of a ROTEM-guided transfusion protocol might have the potential to decrease blood product transfusion and may improve patient outcomes.

Duration of regional cerebral oxygen saturation under 40% is a risk factor for neurological injury following pulmonary thromboendarterectomy: A prospective observational study.

BACKGROUND: Deep hypothermic circulatory arrest (DHCA) is nowadays commonly used in pulmonary thromboendarterectomy (PTE). Neurological injury related to DHCA severely impairs the prognosis of patients. However, the risk factors and predictors of neurological injury are still unclear. METHODS: We conducted a prospective observational study, including 82 patients diagnosed as chronic thromboembolic pulmonary hypertension and underwent PTE alone in our center from December 2016 to May 2021. Demographic characteristics, clinical and surgical data, and neurological adverse events were recorded prospectively. Univariate and multivariate analyses were conducted to identify the predictors of neurological injury. RESULTS: Eleven (13.4%) patients exhibited neurological injuries after surgery. Univariate analysis showed that the duration of regional cerebral oxygen saturation (rSO2 ) under 40% (p < .001), the minimum rSO2 (p = .006), and the percentage of decrease in rSO2 (p = .011) were significantly associated with neurological injury. Multivariate analysis showed that the duration of rSO2 under 40% was an independent predictor for postoperative neurological injury (odds ratio = 3.896, 95% confidence interval: 1.812-8.377, p < .001). The receiver operating characteristic curve showed that when the cut-off value was 1.25 min, its sensitivity for predicting neurological injury was 63.6% with a specificity of 88.7%. CONCLUSIONS: The duration of rSO2 under 40% is an independent predictor for neurological injury following PTE. For complicated lesions, more times of circulatory arrest were much safer and more reliable than a prolonged time of a single circulatory arrest. The circulation should be restored as soon as possible, when the rSO2 under 40% is detected, rather than waiting for 5 min.

Predictors of Neurological Outcome Following Infant Cardiac Surgery Without Deep Hypothermic Circulatory Arrest.

The aim of this study is to describe the clinical characteristics, perioperative course and neuroimaging abnormalities of infants with congenital heart disease (CHD) undergoing heart surgery without deep hypothermic circulatory arrest (DHCA) and identify variables associated with neurological outcome. Infants with CHD undergoing open-heart surgery without DHCA between 2009 and 2017 were identified from a cardiac surgery database. Full-term infants < 10 weeks of age at the time of surgery who had both a pre- and postoperative brain magnetic resonance imaging exam (MRI) were included. Clinical characteristics and perioperative variables were collected from the electronic medical record. Brain Injury Scores (BIS) were assigned to pre- and postoperative brain MRIs. Variables were examined for association with neurological outcome at 12 months of age or greater. Forty-two infants were enrolled in the study, of whom 69% (n = 29) had a neurological assessment ≥ to 12 months of age. Adverse neurological outcome was associated with longer intensive care unit (ICU) stay (P = 0.003), lengthier mechanical ventilation (P = 0.031), modified Blalock-Taussig (MBT) shunt procedure (P = 0.005) and postoperative seizures (P = 0.005). Total BIS scores did not predict outcome but postoperative infarction and/or intraparenchymal hemorrhage (IPH) was associated with worse outcome by multivariable analysis (P = 0.018). Infants with CHD undergoing open-heart surgery without DHCA are at increased risk of worse neurological outcome when their ICU stay is prolonged, mechanical ventilation is extended, MBT shunt is performed or when postoperative seizures are present. Cerebral infarctions and IPH on postoperative MRI are also associated with worse outcome.

NMDA Receptor Antagonism for Neuroprotection in a Canine Model of Hypothermic Circulatory Arrest.

BACKGROUND: Hypothermic circulatory arrest (HCA) is associated with neurologic morbidity, in part mediated by activation of the N-methyl-D-aspartate glutamate receptor causing excitotoxicity and neuronal apoptosis. Using a canine model, we hypothesized that the N-methyl-D-aspartate receptor antagonist MK801 would provide neuroprotection and that MK801 conjugation to dendrimer nanoparticles would improve efficacy. MATERIALS AND METHODS: Male hound dogs were placed on cardiopulmonary bypass, cooled to 18°C, and underwent 90 min of HCA. Dendrimer conjugates (d-MK801) were prepared by covalently linking dendrimer surface OH groups to MK801. Six experimental groups received either saline (control), medium- (0.15 mg/kg) or high-dose (1.56 mg/kg) MK801, or low- (0.05 mg/kg), medium-, or high-dose d-MK801. At 24, 48, and 72 h after HCA, animals were scored by a standardized neurobehavioral paradigm (higher scores indicate increasing deficits). Cerebrospinal fluid was obtained at baseline, eight, 24, 48, and 72 h after HCA. At 72 h, brains were examined for histopathologic injury in a blinded manner (higher scores indicate more injury). RESULTS: Neurobehavioral deficit scores were reduced by low-dose d-MK801 on postoperative day two (P < 0.05) and by medium-dose d-MK801 on postoperative day 3 (P = 0.05) compared with saline controls, but free drug had no effect. In contrast, high-dose free MK801 significantly improved histopathology scores compared with saline (P < 0.05) and altered biomarkers of injury in cerebrospinal fluid, with a significant reduction in phosphorylated neurofilament-H for high-dose MK801 versus saline (P < 0.05). CONCLUSIONS: Treatment with MK-801 demonstrated significant improvement in neurobehavioral and histopathology scores after HCA, although not consistently across doses and conjugates.

Inflammatory profile in a canine model of hypothermic circulatory arrest.

BACKGROUND: Hypothermic circulatory arrest (HCA) is a technique used for complex repair of the aorta, but it can be associated with neurologic morbidity. To better understand the molecular changes that underlie ischemic brain injury, we assessed gene expression and cytokine/chemokine polypeptide concentration in brain tissue and cerebrospinal fluid (CSF) of canines that underwent two hours of HCA. MATERIALS AND METHODS: Adult male canines were cannulated peripherally for cardiopulmonary bypass, cooled to 18°C, and arrested for two hours. Animals were euthanized two, eight, or 24 hours post-HCA (n = 8 per group), and their brains were compared to brains from eight normal canines, using gene expression microarray analysis, cytokine assay, and histopathology. RESULTS: Two to eight hours after HCA, pro-inflammatory cytokine mRNAs increased markedly, and gene expression was enriched within signaling pathways related to neuroinflammation or ischemic injury. Concentrations of pro-inflammatory cytokine polypeptides IL-6, IL-8, IL-1ß, and CCL2 were very low in normal canine brain, whereas anti-inflammatory IL-10 and TGF-ß1 were expressed at moderate levels. Pro-inflammatory cytokine concentrations rose robustly in cerebral tissue and CSF after HCA. IL-6 and IL-8 peaked at eight hours and declined at 24 hours, while IL-1ß and CCL2 remained elevated. Concentrations of anti-inflammatory IL-10 and TGF-ß1 were maintained after HCA, with a significant increase in TGF-ß1 at 24 hours. CONCLUSIONS: These cytokines represent potential diagnostic markers for ischemic neurologic injury that could be used to assess neurologic injury in patients undergoing HCA. The cellular mechanisms underlying this pro-inflammatory, ischemic-induced injury represent potential targets for neuroprotection in the future.

Deep Hypothermic Circulatory Arrest in the Pediatric Population Undergoing Cardiac Surgery With Electroencephalography Monitoring: A Systematic Review and Meta-Analysis.

OBJECTIVE: Cardiac surgery for repair of congenital heart defects poses unique hazards to the developing brain. Deep hypothermic circulatory arrest (DHCA) is a simple and effective method for facilitating a bloodless surgical field during congenital heart defect repair. There are, however, some concerns that prolonged DHCA increases the risk of nervous system injury. The electroencephalogram (EEG) is used in adult and, to a lesser extent, pediatric cardiac procedures as a neuromonitoring method. The present study was performed to assess outcomes following DHCA with EEG monitoring in the pediatric population. DESIGN: In this systematic review and meta-analysis, the PubMed, Cochrane Central Register of Controlled Trials, Scopus, Institute of Science Index, and Embase databases were searched from inception for relevant articles. A fixed- or random-effects model, as appropriate, was used. SETTING: Surgical setting. PARTICIPANTS: Pediatric population (≤18 y old). INTERVENTIONS: DHCA (18°C) with EEG monitoring. MEASUREMENTS AND MAIN RESULTS: Nineteen articles with 1,267 pediatric patients ≤18 years were included. The event rate of clinical and EEG seizures among patients who underwent DHCA was 12.9% and 14.9%, respectively. Mortality was found to have a 6.3% prevalence. A longer duration of DHCA was associated with a higher risk of EEG seizure and neurologic abnormalities. In addition, seizures were associated with increased neurologic abnormalities and neurodevelopmental delay. CONCLUSIONS: EEG and neurologic abnormalities were common after DHCA. A longer duration of DHCA was found to lead to more EEG seizure and neurologic abnormalities. Moreover, EEG seizures were more common than clinical seizures. Seizures were found to be associated with increased neurologic abnormalities and neurodevelopmental delay.

Deep hypothermic circulatory arrest in cyanotic piglets is associated with increased neuronal necrosis.

BACKGROUND: The contribution of neonatal cyanosis, inherent to cyanotic congenital heart disease, to the magnitude of neurologic injury during deep hypothermic circulatory arrest has not been fully delineated. This study investigates the impact of cyanosis and deep hypothermic circulatory arrest on brain injury. METHODS: Neonatal piglets were randomised to placement of a pulmonary artery to left atrium shunt to create cyanosis or sham thoracotomy. At day 7, animals were randomised to undergo deep hypothermic circulatory arrest or sham. Arterial oxygen tension and haematocrit were obtained. Neurobehavioural performance was serially assessed. The animals were sacrificed on day 14. Brain tissue was assessed for neuronal necrosis using a 5-point histopathologic score. RESULTS: Four experimental groups were analysed (sham, n = 10; sham + deep hypothermic circulatory arrest, n = 8; shunt, n = 9; shunt + deep hypothermic circulatory arrest, n = 7). Cyanotic piglets had significantly higher haematocrit and lower partial pressure of oxygen at day 14 than non-cyanotic piglets. There were no statistically significant differences in neurobehavioural scores at day 1. However, shunt + deep hypothermic circulatory arrest piglets had evidence of greater neuronal injury than sham animals (median (range): 2 (0-4) versus 0 (0-0), p = 0.02). DISCUSSION: Cyanotic piglets undergoing deep hypothermic circulatory arrest had increased neuronal injury compared to sham animals. Significant injury was not seen for either cyanosis or deep hypothermic circulatory arrest alone relative to shams. These findings suggest an interaction between cyanosis and deep hypothermic circulatory arrest and may partially explain the suboptimal neurologic outcomes seen in children with cyanotic heart disease who undergo deep hypothermic circulatory arrest.

Anticoagulation management during pulmonary endarterectomy with cardiopulmonary bypass and deep hypothermic circulatory arrest.

INTRODUCTION: Pulmonary endarterectomy requires cardiopulmonary bypass and deep hypothermic circulatory arrest, which may prolong the activated clotting time. We investigated whether activated clotting time-guided anticoagulation under these circumstances suppresses hemostatic activation. METHODS: Individual heparin sensitivity was determined by the heparin dose-response test, and anticoagulation was monitored by the activated clotting time and heparin concentration. Perioperative hemostasis was evaluated by thromboelastometry, platelet aggregation, and several plasma coagulation markers. RESULTS: Eighteen patients were included in this study. During cooling, tube-based activated clotting time increased from 719 (95% confidence interval = 566-872 seconds) to 1,273 (95% confidence interval = 1,136-1,410 seconds; p < 0.01) and the cartridge-based activated clotting time increased from 693 (95% confidence interval = 590-796 seconds) to 883 (95% confidence interval = 806-960 seconds; p < 0.01), while thrombin-antithrombin showed an eightfold increase. The heparin concentration showed a slightly declining trend during cardiopulmonary bypass. After protamine administration (protamine-to-heparin bolus ratio of 0.82 (0.71-0.90)), more than half of the patients showed an intrinsically activated coagulation test and intrinsically activated coagulation test without heparin effect clotting time >240 seconds. Platelet aggregation through activation of the P2Y12 (adenosine diphosphate test) and thrombin receptor (thrombin receptor activating peptide-6 test) decreased (both -33%) and PF4 levels almost doubled (from 48 (95% confidence interval = 42-53 ng/mL) to 77 (95% confidence interval = 71-82 ng/mL); p < 0.01) between weaning from cardiopulmonary bypass and 3 minutes after protamine administration. CONCLUSION: This study shows a wide variation in individual heparin sensitivity in patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest. Although activated clotting time-guided anticoagulation management may underestimate the level of anticoagulation and consequently result in a less profound inhibition of hemostatic activation, this study lacked power to detect adverse outcomes.

Changing of haemostatic system in a pig model during different types of hypothermic circulatory arrest.

BACKGROUND: Hypothermic circulatory arrest is usually used in aortic surgery, congenital heart defect repairs and other complex surgeries. It is frequently associated with excessive postoperative bleeding and the transfusion of allogeneic blood products. The physiopathology of hypothermic circulatory arrest-induced coagulopathy has never been systematically studied. The aim of the study was to investigate this phenomenon in a pig model. METHODS: Ten pigs were randomly assigned to 30 min of hypothermic circulatory arrest at either 15 °C (n = 5) or 25 °C (n = 5). Detection of apoptosis and haemostatic system assays were performed in this experiment. Enzyme-linked immunosorbent assays were performed at ten time points in each group to study the changes in the coagulation system in hypothermic circulatory arrest. All of the statistical analyses were performed in SPSS software, version 18.0, and as bilateral tests, and p < 0.05 was considered statistically significant. RESULTS: There was no significant difference in the effect of different types of hypothermic circulatory arrest on routine laboratory tests and tissue sample analysis (p > 0.05, for all). Our results demonstrated that more severe systemic activation of the coagulation system (TAT and F1+2) was applied in the deep hypothermic circulatory arrest group but not in the moderate hypothermic circulatory arrest group (TAT/p = 0.01, F1+2/p = 0.03). However, this activation of the coagulation system (AT III and PC) was not associated with changes in the anticoagulation pathway (AT III/p = 0.24, PC/p = 0.33). In addition, analysis of biomarkers of the haemostatic system revealed that the consumption of coagulation is more concentrated on extrinsic coagulation factors (FVII/p = 0.01). CONCLUSIONS: Moderate hypothermic circulatory arrest is more suitable for patients with coagulation dysfunction. We believe the application of deep hypothermic circulatory arrest should pay more attention to changes in coagulation rather than the anticoagulation pathway. Extrinsic coagulation factor supplementation is more effective after deep hypothermic circulatory arrest.

Sex-Related Differences in Patients Undergoing Thoracic Aortic Surgery.

BACKGROUND: Contemporary outcomes after surgical management of thoracic aortic disease have improved; however, the impact of sex-related differences is poorly understood. METHODS: A total of 1653 patients (498 [30.1%] female) underwent thoracic aortic surgery with hypothermic circulatory arrest between 2002 and 2017 in 10 institutions of the Canadian Thoracic Aortic Collaborative. Outcomes of interest were in-hospital death, stroke, and a modified Society of Thoracic Surgeons-defined composite for mortality or major morbidity (stroke, renal failure, deep sternal wound infection, reoperation, prolonged ventilation). Multivariable logistic regression was used to determine independent predictors of these outcomes. RESULTS: Women were older (mean±SD, 66±13 years versus 61±13 years; P<0.001), with more hypertension and renal failure, but had less coronary disease, less previous cardiac surgery, and higher ejection fraction than men. Rates of aortic dissection were similar between women and men. Rates of hemiarch, and total arch repair were similar between the sexes; however, women underwent less aortic root reconstruction including aortic root replacement, Ross, or valve-sparing root operations (29% versus 45%; P<0.001). Men experienced longer cross-clamp and cardiopulmonary bypass times, but similar durations of circulatory arrest, methods of cerebral perfusion, and nadir temperatures. Women experienced a higher rate of mortality (11% versus 7.4%; P=0.02), stroke (8.8% versus 5.5%; P=0.01), and Society of Thoracic Surgeons-defined composite end point for mortality or major morbidity (31% versus 27%; P=0.04). On multivariable analyses, female sex was an independent predictor of mortality (odds ratio, 1.81; P<0.001), stroke (odds ratio, 1.90; P<0.001), and Society of Thoracic Surgeons-defined composite end point for mortality or major morbidity (odds ratio, 1.40; P<0.001). CONCLUSIONS: Women experience worse outcomes after thoracic aortic surgery with hypothermic circulatory arrest. Further investigation is required to better delineate which measures may reduce sex-related outcome differences after complex aortic surgery.

Dramatic increase in serum trypsinogens, SPINK1 and hCGß in aortic surgery patients after hypothermic circulatory arrest.

The concentrations of several diagnostic markers have been found to increase dramatically in critically ill patients with a severe disturbance of normal physiological homeostasis, without indication of the diseases they are normally associated with. To prevent false diagnoses and inappropriate treatments of critically ill patients, it is important that the markers aiding the selection of second-line treatments are evaluated in such patients and not only in the healthy population and patients with diseases the markers are associated with. The levels of trypsinogen isoenzymes, the trypsin inhibitor serine peptidase inhibitor Kazal type 1 (SPINK1), hCG and hCGß, which are used as pancreatitis and cancer markers, were analyzed by immunoassays from serum samples of 17 adult patients who have undergone surgery of the ascending aorta during hypothermic circulatory arrest (HCA) with optional selective cerebral perfusion. Highly elevated levels of trypsinogen-1, -2 and -3, SPINK1 and hCGß were observed in patients after HCA. This was accompanied by increased concentrations of S100ß and NSE. In conclusion, this study highlights the importance of critically evaluating the markers used for aiding selection of second line of treatments in critically ill patients.

Predictors of Acute Kidney Injury Following Aortic Arch Surgery.

BACKGROUND: Acute kidney injury (AKI) following open aortic arch surgery is a frequent complication associated with increased morbidity and mortality. The primary purpose of this study was to evaluate risk factors for postoperative AKI in patients who underwent open aortic arch surgery utilizing hypothermic circulatory arrest (HCA). MATERIALS AND METHODS: Included were 295 patients undergoing surgery between January 2011 and March 2018. AKI was defined according to Kidney Disease: Improving Global Outcomes guidelines. Preoperative and intraoperative variables were stratified by no AKI versus any AKI, and bivariate analysis was performed. Multivariable logistic regression analysis used statistically and clinically significant characteristics from the bivariate analysis. RESULTS: Of the 295 patients, 93 (32%) developed AKI. In the bivariate analysis, significant predictors of AKI included the following: history of hypertension (P < 0.001), diabetes (P = 0.03), operative urgency (P = 0.009), cardiopulmonary bypass (CPB) time (P < 0.0001), HCA time (0.02), total intraoperative transfusions (P = 0.002), and concomitant procedures (coronary artery bypass grafting, or mitral/tricuspid interventions, P = 0.0009). In the multivariable analysis, significant predictors of AKI were history of hypertension (P = 0.03) and CPB time (P = 0.02). Age, operative urgency, circulatory arrest time, and any intraoperative transfusion were not significant in the multivariable analysis. CONCLUSION: In conclusion, given that CPB time is the only modifiable risk factor identified in the analysis, approaches to reducing bypass time should continue to be the focus of decreasing risk for postoperative AKI in HCA cases.

Remote ischaemic preconditioning may prolong permissible period of hypothermic circulatory arrest in a porcine model.

Objectives. The hypothermic circulatory arrest (HCA) is still of paramount importance in aortic arch surgery, but the safe period of the arrest is limited. Remote ischaemic preconditioning (RIPC) prepares the cerebral tissue for ischaemic insult. Prolongation of the permissible period of HCA with RIPC may have a major impact on the outcome of aortic operations requiring cessation of blood flow by decreasing the rate of neurological deficits. Design. Twenty pigs were randomised into the RIPC group (n = 10) and the control group (n = 10). The RIPC group underwent four cycles of transient hind limb ischaemia. Both groups underwent cooling with cardiopulmonary bypass to 11 °C followed by a 45-minute HCA and re-warming to 36 °C. Cerebral blood flow was measured with a transit time ultrasonic flowmeter from the right common carotid artery, and the arteriovenous oxygen difference was calculated from sagittal sinus and arterial blood samples. Measurements were taken at several time points during cooling and warming. Temperature coefficient (Q10) was calculated to determine estimated permissible periods of HCA. Results. The Q10 was 2.27 (1.98-2.58) for the RIPC group and 1.87 (1.61-2.25) for the control group. The permissible period of HCA at 18 °C was 26 minutes (20-33) in the RIPC group and 17 minutes (13-25) in the control group (p = .063)(Data expressed in medians and interquartile ranges). Conclusions. RIPC tends to suppress cerebral metabolism during cooling with cardiopulmonary bypass and may prolong estimated permissible period of HCA.