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.

Pre- and postoperative anemia, acute kidney injury, and mortality after coronary artery bypass grafting surgery: a retrospective observational study.

BACKGROUND: Preoperative and postoperative anemia have been identified individually as potential risk factors for postoperative complications after coronary artery bypass grafting (CABG) surgery. Their interrelationship with acute kidney injury (AKI) and long-term mortality, however, has not been clearly defined and was the purpose of this study. METHODS: We retrospectively evaluated 6,130 adult patients undergoing CABG surgery performed at a single large academic medical center. Preoperative and postoperative hemoglobin concentrations were used as continuous predictors of postoperative AKI and mortality. Additionally, sex-specific preoperative (< 13 g·dL-1 in men and < 12 g·dL-1 in women) and postoperative anemia (the median of the lowest in-hospital values) were used as categorical predictors. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines, when serum creatinine rose ≥ 50% during the period between day of surgery and postoperative day ten, or when a 0.3 mg·dL-1 (26.5 µmol·L-1) increase was detected in a rolling 48-hr window from the day of surgery to the tenth postoperative day. The association of preoperative and postoperative hemoglobin levels and anemia patterns with postoperative AKI and mortality were assessed via univariable and multivariable Cox proportional hazard analyses with time-varying effects for postoperative serum hemoglobin concentrations. RESULTS: The median preoperative and median minimum postoperative serum hemoglobin concentrations were 13.1 g·dL-1 and 8.8 g·dL-1, respectively. The incidence of AKI was 58%. Overall, 1,880 (30.7%) patients died an average of 6.8 yr after surgery. After adjusting for differences in baseline and clinical characteristics, on any given day, patients with preoperative anemia (multivariable hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.13 to 1.33; P < 0.001) and those with a combination of preoperative and postoperative anemia (multivariable HR, 1.24; 95% CI, 1.09 to 1.40; P < 0.0008) were at an elevated risk for developing postoperative AKI and mortality (preoperative anemia: multivariable HR, 1.29; 95% CI, 1.15 to 1.44; P < 0.001; preoperative and postoperative anemia: multivariable HR, 1.50; 95% CI, 1.25 to 1.79; P < 0.001). CONCLUSIONS: Our findings suggest that preoperative anemia alone and preoperative anemia combined with postoperative anemia are associated with AKI and mortality after CABG surgery.

Elevated Pulse Pressure, Intraoperative Hemodynamic Perturbations, and Acute Kidney Injury After Coronary Artery Bypass Grafting Surgery.

OBJECTIVE: To explore whether baseline pulse pressure (PP) confers an increased risk for acute kidney injury (AKI) independent of intraoperative hypotension or hypertension in patients who undergo coronary artery bypass grafting (CABG) surgery. DESIGN: Retrospective study. SETTING: Single academic center. PARTICIPANTS: 5,808 patients who underwent CABG surgery. MEASUREMENTS AND MAIN RESULTS: Baseline arterial blood pressure was defined as the mean of the first 5 measurements recorded by the automated record keeping system before anesthesia was induced. Weighted duration of intraoperative hypotension and hypertension were defined as the area (min × mmHg) below a mean arterial pressure of 55 mmHg and above a mean arterial pressure of 100 mmHg. Multivariable logistic and proportional odds regression analyses were performed to determine whether baseline PP and weighted duration of intraoperative hypotension and hypertension were independently associated with postoperative AKI. Of the 5,808 patients, PP was <40 mmHg in 90 (1.6%), 40-to-80 mmHg in 2,463 (42.4 %), and >80 mmHg in 3,255 (56%) patients. The incidence of AKI was 57.7%, which included 7.4% (249 patients) and 2.8% (93 patients) who experienced stages 2 and 3 AKI, respectively. In the risk-adjusted analyses, baseline PP was associated with higher odds for postoperative AKI (odds ratio for every 20 mmHg increase in PP, 1.15; 95% confidence interval 1.10-1.21; p < 0.0001) and a higher severity of postoperative AKI (proportional odds ratio, 1.13; 95% confidence interval 1.03-1.24; p = 0.0098). There was no evidence that weighted duration of intraoperative hypotension or hypertension was associated with postoperative AKI or that either interacted with the association of baseline PP with AKI. CONCLUSIONS: Baseline PP was significantly associated with postoperative AKI after CABG surgery, independent of weighted duration of intraoperative hypotension or hypertension.

Platelet Counts and Postoperative Stroke After Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Declining platelet counts may reveal platelet activation and aggregation in a postoperative prothrombotic state. Therefore, we hypothesized that nadir platelet counts after on-pump coronary artery bypass grafting (CABG) surgery are associated with stroke. METHODS: We evaluated 6130 adult CABG surgery patients. Postoperative platelet counts were evaluated as continuous and categorical (mild versus moderate to severe) predictors of stroke. Extended Cox proportional hazard regression analysis with a time-varying covariate for daily minimum postoperative platelet count assessed the association of day-to-day variations in postoperative platelet count with time to stroke. Competing risks proportional hazard regression models examined associations between day-to-day variations in postoperative platelet counts with timing of stroke (early: 0-1 days; delayed: ≥2 days). RESULTS: Median (interquartile range) postoperative nadir platelet counts were 123.0 (98.0-155.0) × 10/L. The incidences of postoperative stroke were 1.09%, 1.50%, and 3.02% for platelet counts >150 × 10/L, 100 to 150 × 10/L, and <100 × 10/L, respectively. The risk for stroke increased by 12% on a given postoperative day for every 30 × 10/L decrease in platelet counts (adjusted hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01-1.24; P= .0255). On a given day, patients with moderate to severe thrombocytopenia were almost twice as likely to develop stroke (adjusted HR, 1.89; 95% CI, 1.13-3.16; P= .0155) as patients with nadir platelet counts >150 × 10/L. Importantly, such thrombocytopenia, defined as a time-varying covariate, was significantly associated with delayed (≥2 days after surgery; adjusted HR, 2.83; 95% CI, 1.48-5.41; P= .0017) but not early postoperative stroke. CONCLUSIONS: Our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and postoperative stroke, and timing of stroke after CABG surgery.

Platelet Counts, Acute Kidney Injury, and Mortality after Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Cardiac surgery requiring cardiopulmonary bypass is associated with platelet activation. Because platelets are increasingly recognized as important effectors of ischemia and end-organ inflammatory injury, the authors explored whether postoperative nadir platelet counts are associated with acute kidney injury (AKI) and mortality after coronary artery bypass grafting (CABG) surgery. METHODS: The authors evaluated 4,217 adult patients who underwent CABG surgery. Postoperative nadir platelet counts were defined as the lowest in-hospital values and were used as a continuous predictor of postoperative AKI and mortality. Nadir values in the lowest 10th percentile were also used as a categorical predictor. Multivariable logistic regression and Cox proportional hazard models examined the association between postoperative platelet counts, postoperative AKI, and mortality. RESULTS: The median postoperative nadir platelet count was 121 × 10/l. The incidence of postoperative AKI was 54%, including 9.5% (215 patients) and 3.4% (76 patients) who experienced stages II and III AKI, respectively. For every 30 × 10/l decrease in platelet counts, the risk for postoperative AKI increased by 14% (adjusted odds ratio, 1.14; 95% CI, 1.09 to 1.20; P < 0.0001). Patients with platelet counts in the lowest 10th percentile were three times more likely to progress to a higher severity of postoperative AKI (adjusted proportional odds ratio, 3.04; 95% CI, 2.26 to 4.07; P < 0.0001) and had associated increased risk for mortality immediately after surgery (adjusted hazard ratio, 5.46; 95% CI, 3.79 to 7.89; P < 0.0001). CONCLUSION: The authors found a significant association between postoperative nadir platelet counts and AKI and short-term mortality after CABG surgery.

Baseline Pulse Pressure, Acute Kidney Injury, and Mortality After Noncardiac Surgery.

BACKGROUND: Increased pulse pressure (PP) is an important independent predictor of cardiovascular outcome and acute kidney injury (AKI) after cardiac surgery. The objective of this study was to determine whether elevated baseline PP is associated with postoperative AKI and 30-day mortality after noncardiac surgery. METHODS: We evaluated 9125 adult patients who underwent noncardiac surgery at Duke University Medical Center between January 2006 and December 2009. Baseline arterial blood pressure was defined as the mean of the first 5 measurements recorded by the automated record keeping system before inducing anesthesia. Multivariable logistic regression analysis was performed to determine whether baseline PP adjusted for other perioperative risk factors was independently associated with postoperative AKI and 30-day mortality. RESULTS: Of the 9125 patients, the baseline PP was <40 mm Hg in 1426 (15.6%), 40-80 mm Hg in 6926 (75.9%), and >80 mm Hg in 773 (8.5%) patients. The incidence of AKI was 19.8%, which included 8.4% (151 patients) and 4.2% (76 patients) who experienced stage II and III AKI, respectively. In the risk-adjusted model for postoperative AKI, elevated baseline PP was associated with higher odds for postoperative AKI (adjusted odds ratio [OR] for every 20 mm Hg increase in PP, 1.17; 95% confidence interval [CI], 1.10-1.25; P < .0001). Also elevated baseline preoperative PP was significantly associated with mild (stage I; OR, 1.19; 95% CI, 1.11-1.27; P < .0001), but not with more advanced stages of postoperative AKI or with an incremental risk for 30-day mortality. CONCLUSIONS: We found a significant association between elevated baseline PP and postoperative AKI in patients who underwent noncardiac surgery. However, elevated PP was not significantly associated with more advanced stages of postoperative AKI or 30-day mortality in these patients.

Neurocognitive Dysfunction After Short (<20 Minutes) Duration Hypothermic Circulatory Arrest.

BACKGROUND: It has long been held that the safe duration of hypothermic circulatory arrest (HCA) is at least 25-30 minutes. However, this is based primarily on clinical outcomes research and has not been systematically investigated using more sensitive brain imaging and neurocognitive assessments. METHODS: This exploratory sub-study of the randomized GOT ICE trial, which compared outcomes for deep versus moderate hypothermia during arch surgery, investigated the frequency of neurocognitive and structural and functional magnetic resonance imaging (MRI) deficits with short (<20 minutes) duration HCA. Neurocognitive deficit was defined as >1 standard deviation decline in >1 of 5 cognitive domains on neurocognitive testing. RESULTS: Of 228 GOT ICE patients with complete 4-week cognitive data, 74.6% (n=170/228) had HCA durations <20 minutes, including 59 randomized to deep (<20.0°C), 55 low-moderate (20.1-24.0°C), and 56 high-moderate (24.1-28.0°C) hypothermia. Of these, cognitive deficit was detected 4-weeks post-surgery in ∼40% of patients in all 3 groups [deep: 22/59 (37.3%); low-moderate: 23/55 (41.8%); high-moderate: 24/56 (42.9%)]. Furthermore, in a subset of patients with complete MRI data (n=43), baseline to 4-week post-surgery right frontal lobe functional connectivity change was inversely associated with HCA duration (range 8-17 minutes; p-FWE<0.01). CONCLUSIONS: Even short durations of HCA result in cognitive deficits in ∼40% of patients, independent of systemic hypothermia temperature. HCA duration was inversely associated with frontal lobe functional MRI connectivity, suggesting this brain region may be preferentially sensitive to HCA. Surgeons should be aware that even short durations of HCA may not provide complete neuroprotection following aortic arch surgery.

Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.

INTRODUCTION: Thrombocytopenia after cardiac surgery independently predicts stroke, acute kidney injury and death. To understand the underlying risks and mechanisms, we analysed genetic variations associated with thrombocytopenia in patients undergoing coronary artery bypass grafting (CABG) surgery. MATERIALS AND METHODS: Study subjects underwent isolated on-pump CABG surgery at Duke University Medical Center. Post-operative thrombocytopenia was defined as platelet count < 100 × 109/L. Using a logistic regression model adjusted for clinical risk factors, we performed a genome-wide association study in a discovery cohort (n = 860) and validated significant findings in a replication cohort (n = 296). Protein expression was assessed in isolated platelets by immunoblot. RESULTS: A total of 63 single-nucleotide polymorphisms met a priori discovery thresholds for replication, but only 1 (rs9574547) in the intergenic region upstream of sprouty 2 (SPRY2) met nominal significance in the replication cohort. The minor allele of rs9574547 was associated with a lower risk for thrombocytopenia (discovery cohort, odds ratio, 0.45, 95% confidence interval, 0.30-0.67, p = 9.76 × 10-5) with the overall association confirmed by meta-analysis (meta-p = 7.88 × 10-6). Immunoblotting demonstrated expression of SPRY2 and its dynamic regulation during platelet activation. Treatment with a functional SPRY2 peptide blunted platelet extracellular signal-regulated kinase (ERK) phosphorylation after agonist stimulation. CONCLUSION: We identified the association of a genetic polymorphism in the intergenic region of SPRY2 with a decreased incidence of thrombocytopenia after CABG surgery. Because SPRY2-an endogenous receptor tyrosine kinase inhibitor-is present in platelets and modulates essential signalling pathways, these findings support a role for SPRY2 as a novel modulator of platelet responses after cardiac surgery.

Mast cell activation and arterial hypotension during proximal aortic repair requiring hypothermic circulatory arrest.

OBJECTIVE: Aortic surgeries requiring hypothermic circulatory arrest evoke systemic inflammatory responses that often manifest as vasoplegia and hypotension. Because mast cells can rapidly release vasoactive and proinflammatory effectors, we investigated their role in intraoperative hypotension. METHODS: We studied 31 patients undergoing proximal aortic repair with hypothermic circulatory arrest between June 2013 and April 2015 at Duke University Medical Center. Plasma samples were obtained at different intraoperative time points to quantify chymase, interleukin-6, interleukin-8, tumor necrosis factor alpha, and white blood cell CD11b expression. Hypotension was defined as the area (minutes × millimeters mercury) below a mean arterial pressure of 55 mm Hg. Biomarker responses and their association with intraoperative hypotension were analyzed by 2-sample t test and Wilcoxon rank sum test. Multivariable logistic regression analysis was used to examine the association between clinical variables and elevated chymase levels. RESULTS: Mast cell-specific chymase increased from a median 0.97 pg/mg (interquartile range [IQR], 0.01-1.84 pg/mg) plasma protein at baseline to 5.74 pg/mg (IQR, 2.91-9.48 pg/mg) plasma protein after instituting cardiopulmonary bypass, 6.16 pg/mg (IQR, 3.60-9.41 pg/mg) plasma protein after completing circulatory arrest, and 7.64 pg/mg (IQR, 4.63-12.71 pg/mg) plasma protein after weaning from cardiopulmonary bypass (each P value < .0001 vs baseline). Chymase was the only biomarker associated with hypotension during (P = .0255) and after (P = .0221) cardiopulmonary bypass. Increased temperatures at circulatory arrest and low presurgical hemoglobin levels were independent predictors of increased chymase responses. CONCLUSIONS: Mast cell activation occurs in cardiac surgery requiring cardiopulmonary bypass and hypothermic circulatory arrest and is associated with intraoperative hypotension.