Methemoglobin as a marker of acute anemic stress in cardiac surgery.

Biological evidence supports plasma methemoglobin as a biomarker for anemia-induced tissue hypoxia. In this translational planned substudy of the multinational randomized controlled transfusion thresholds in cardiac surgery (TRICS-III) trial, which included adults undergoing cardiac surgery requiring cardiopulmonary bypass with a moderate-to-high risk of death, we investigated the relationship between perioperative hemoglobin concentration (Hb) and methemoglobin; and evaluated its association with postoperative outcomes. The primary endpoint was a composite of death, myocardial infarction, stroke, and severe acute kidney injury at 28 days. We observe weak non-linear associations between decreasing Hb and increasing methemoglobin, which were strongest in magnitude at the post-surgical time point. Increased levels of post-surgical methemoglobin were associated with a trend toward an elevated risk for stroke and exploratory neurological outcomes. Our generalizable study demonstrates post-surgical methemoglobin may be a marker of anemia-induced organ injury/dysfunction, and may have utility for guiding personalized approaches to anemia management. Clinicaltrials.gov registration NCT02042898.

Safety of a Restrictive versus Liberal Approach to Red Blood Cell Transfusion on the Outcome of AKI in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

BACKGROUND: Safely reducing red blood cell transfusions can prevent transfusion-related adverse effects, conserve the blood supply, and reduce health care costs. Both anemia and red blood cell transfusion are independently associated with AKI, but observational data are insufficient to determine whether a restrictive approach to transfusion can be used without increasing AKI risk. METHODS: In a prespecified kidney substudy of a randomized noninferiority trial, we compared a restrictive threshold for red blood cell transfusion (transfuse if hemoglobin<7.5 g/dl, intraoperatively and postoperatively) with a liberal threshold (transfuse if hemoglobin<9.5 g/dl in the operating room or intensive care unit, or if hemoglobin<8.5 g/dl on the nonintensive care ward). We studied 4531 patients undergoing cardiac surgery with cardiopulmonary bypass who had a moderate-to-high risk of perioperative death. The substudy's primary outcome was AKI, defined as a postoperative increase in serum creatinine of ≥0.3 mg/dl within 48 hours of surgery, or ≥50% within 7 days of surgery. RESULTS: Patients in the restrictive-threshold group received significantly fewer transfusions than patients in the liberal-threshold group (1.8 versus 2.9 on average, or 38% fewer transfusions in the restricted-threshold group compared with the liberal-threshold group; P<0.001). AKI occurred in 27.7% of patients in the restrictive-threshold group (624 of 2251) and in 27.9% of patients in the liberal-threshold group (636 of 2280). Similarly, among patients with preoperative CKD, AKI occurred in 33.6% of patients in the restrictive-threshold group (258 of 767) and in 32.5% of patients in the liberal-threshold group (252 of 775). CONCLUSIONS: Among patients undergoing cardiac surgery, a restrictive transfusion approach resulted in fewer red blood cell transfusions without increasing the risk of AKI.

Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery.

BACKGROUND: We reported previously that, in patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive transfusion strategy was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or 28 days after surgery, whichever came first. We now report the clinical outcomes at 6 months after surgery. METHODS: We randomly assigned 5243 adults undergoing cardiac surgery to a restrictive red-cell transfusion strategy (transfusion if the hemoglobin concentration was <7.5 g per deciliter intraoperatively or postoperatively) or a liberal red-cell transfusion strategy (transfusion if the hemoglobin concentration was <9.5 g per deciliter intraoperatively or postoperatively when the patient was in the intensive care unit [ICU] or was <8.5 g per deciliter when the patient was in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis occurring within 6 months after the initial surgery. An expanded secondary composite outcome included all the components of the primary outcome as well as emergency department visit, hospital readmission, or coronary revascularization occurring within 6 months after the index surgery. The secondary outcomes included the individual components of the two composite outcomes. RESULTS: At 6 months after surgery, the primary composite outcome had occurred in 402 of 2317 patients (17.4%) in the restrictive-threshold group and in 402 of 2347 patients (17.1%) in the liberal-threshold group (absolute risk difference before rounding, 0.22 percentage points; 95% confidence interval [CI], -1.95 to 2.39; odds ratio, 1.02; 95% CI, 0.87 to 1.18; P=0.006 for noninferiority). Mortality was 6.2% in the restrictive-threshold group and 6.4% in the liberal-threshold group (odds ratio, 0.95; 95% CI, 0.75 to 1.21). There were no significant between-group differences in the secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy for red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis at 6 months after surgery. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).

Risk of Acute Kidney Injury in Patients Randomized to a Restrictive Versus Liberal Approach to Red Blood Cell Transfusion in Cardiac Surgery: A Substudy Protocol of the Transfusion Requirements in Cardiac Surgery III Noninferiority Trial.

BACKGROUND: When safe to do so, avoiding blood transfusions in cardiac surgery can avoid the risk of transfusion-related infections and other complications while protecting a scarce resource and reducing costs. This protocol describes a kidney substudy of the Transfusion Requirements in Cardiac Surgery III (TRICS-III) trial, a multinational noninferiority randomized controlled trial to determine whether the risk of major clinical outcomes in patients undergoing planned cardiac surgery with cardiopulmonary bypass is no greater with a restrictive versus liberal approach to red blood cell transfusion. OBJECTIVE: The objective of this substudy is to determine whether the risk of acute kidney injury is no greater with a restrictive versus liberal approach to red blood cell transfusion, and whether this holds true in patients with and without preexisting chronic kidney disease. DESIGN AND SETTING: Multinational noninferiority randomized controlled trial conducted in 73 centers in 19 countries (2014-2017). PATIENTS: Patients (~4800) undergoing planned cardiac surgery with cardiopulmonary bypass. MEASUREMENTS: The primary outcome of this substudy is perioperative acute kidney injury, defined as an acute rise in serum creatinine from the preoperative value (obtained in the 30-day period before surgery), where an acute rise is defined as ≥26.5 µmol/L in the first 48 hours after surgery or ≥50% in the first 7 days after surgery. METHODS: We will report the absolute risk difference in acute kidney injury and the 95% confidence interval. We will repeat the primary analysis using alternative definitions of acute kidney injury, including staging definitions, and will examine effect modification by preexisting chronic kidney disease (defined as a preoperative estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). LIMITATIONS: It is not possible to blind patients or providers to the intervention; however, objective measures will be used to assess outcomes, and outcome assessors will be blinded to the intervention assignment. RESULTS: Substudy results will be reported by the year 2018. CONCLUSIONS: This substudy will provide generalizable estimates of the risk of acute kidney injury of a restrictive versus liberal approach to red blood cell transfusion in the presence of anemia during cardiac surgery done with cardiopulmonary bypass. TRIAL REGISTRATION: www.clinicaltrials.gov; clinical trial registration number NCT 02042898.

CONTEXTE: En chirurgie cardiaque, éviter les transfusions sanguines, lorsque sécuritaire, contribue à réduire les risques d'infections transfusionnelles et de complications tout en préservant une ressource rare et en réduisant le coût des soins. Ce protocole décrit une étude secondaire qui examine le volet des risques d'insuffisance rénale aiguë (IRA) de l'étude TRICS-III (Transfusion Requirements in Cardiac Surgery III), un essai de non-infériorité multinational, contrôlé et à répartition aléatoire faisant état des exigences applicables à la transfusion sanguine en chirurgie cardiaque. Notre protocole vise plus particulièrement à déterminer si le risque d'atteintes rénales encouru par les patients subissant une chirurgie de pontages coronarien est plus ou moins grand selon que l'on préconise une approche restrictive ou libérale en matière de transfusion sanguine. OBJECTIF: L'objectif de notre étude est de déterminer si le risque d'IRA est plus ou moins grand selon que l'on préconise une approche restrictive ou libérale à l'égard de la transfusion sanguine; et, si c'est le cas, d'établir si ce risque différentiel perdure selon que le patient était ou non atteint d'insuffisance rénale chronique avant l'intervention. CADRE ET TYPE D'ÉTUDE: L'étude consiste en un essai multinational de non-infériorité, contrôlé et à répartition aléatoire, mené entre 2014 et 2017 au sein de 73 centres répartis dans 19 pays. PATIENTS: L'étude compte environ 4 800 patients ayant subi un pontage coronarien. MESURES: Le principal facteur observé est le développement d'une IRA périopératoire, telle que définie par une hausse marquée du taux de créatinine sérique par rapport à la valeur préopératoire (prélevée dans les 30 jours précédant l'intervention). Nous avons défini une « hausse marquée ¼ par un taux de créatinine atteignant au moins 26,5µmol/L dans les 48 heures postopératoires ou son augmentation d'au moins 50 % à l'intérieur des sept premiers jours. MÉTHODOLOGIE: Nous présenterons le risque différentiel absolu d'IRA dans un intervalle de confiance à 95 %. Nous répéterons l'analyse primaire en alternant les définitions de l'IRA (notamment en fonction des différents stades) et examinerons les éventuelles modifications de l'incidence chez des patients atteints d'une insuffisance rénale préexistante (définie par un DFGe préopératoire à moins de 60 ml/min/1,73 m2). LIMITES DE L'ÉTUDE: Il n'est évidemment pas possible de procéder à l'insu des patients ni des fournisseurs de soins lors de l'intervention. Toutefois, des mesures objectives seront utilisées pour évaluer les résultats, et les évaluateurs ne seront aucunement au courant de la répartition des cas. RÉSULTATS: Les résultats de cette étude secondaire seront présentés d'ici 2018. CONCLUSION: Cette étude secondaire fournira des estimations généralisables du risque de développer une IRA lors d'un pontage coronarien selon que, pour traiter l'anémie, l'approche à l'égard de la transfusion sanguine soit restrictive ou libérale.

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery.

BACKGROUND: The effect of a restrictive versus liberal red-cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS: In this multicenter, open-label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red-cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red-cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red-cell transfusion and other clinical outcomes. RESULTS: The primary outcome occurred in 11.4% of the patients in the restrictive-threshold group, as compared with 12.5% of those in the liberal-threshold group (absolute risk difference, -1.11 percentage points; 95% confidence interval [CI], -2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive-threshold group and 3.6% in the liberal-threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red-cell transfusion occurred in 52.3% of the patients in the restrictive-threshold group, as compared with 72.6% of those in the liberal-threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between-group differences with regard to the other secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy regarding red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).

Comparison of remifentanil and low-dose fentanyl for fast-track cardiac anesthesia: a prospective randomized study.

BACKGROUND: Different anesthetic techniques have been used for fast tracking in cardiac anesthesia. Remifentanil, with its unique pharmacokinetic profile, could be an ideal drug for fast tracking. Possible limitations of remifentanil are rapid onset of postoperative pain after discontinuation of the drug infusion, which may increase the risk of an ischemic event. We conducted this randomized study to compare the efficacy of remifentanil versus low doses of fentanyl in fast-track cardiac anesthesia. It has been hypothesized that remifentanil would provide a safe anesthesia with no impact on myocardial function and with positive effects on extubation time and mobilization. METHODS: We compared the postoperative course of patients, the remifentanil group (RG) and the low-dose fentanyl group (LDFG), in whom remifentanil and low-dose fentanyl, respectively, were used for fast-track cardiac anesthesia. The study was designed as a prospective randomized study. The primary outcomes were changes in the cardiac index and creatine kinase MB fraction (CKMB), extubation times, mobilization times, and lengths of stay in the intensive care unit (ICU) and the hospital. Frequency of myocardial infarction (MI), reoperations due to excessive bleeding, renal impairment, and cerebral complications were registered as well. RESULTS: Seventy-one patients were enrolled in the study, and 7 were excluded due to difficult airway, bleeding, and technical difficulties. The RG comprised 33 patients and the LDFG comprised of 31 patients. There were no differences between the groups in terms of age, Euroscore, types of surgery, extracorporeal circulation, and aortic cross-clamp time. We did not find significant difference in cardiac index, CKMB, extubation times, mobilization times, length of stay in the ICU and in the hospital between the groups. Postoperative complications such as MI, rates of reoperations, renal and cerebral complications and incidence of atrial fibrillation did not show any significant differences. CONCLUSIONS: Remifentanil fast-track anesthesia for cardiac patients has no negative impact on myocardial function. Both remifentanil and low-dose fentanyl are equally effective and safe for fast-track cardiac anesthesia. The study did not highlight any statistical superiority of remifentanil anesthesia over low-dose fentanyl anesthesia.

Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial.

OBJECTIVES: To evaluate the long term effects of perioperative beta blockade on mortality and cardiac morbidity in patients with diabetes undergoing major non-cardiac surgery. DESIGN: Randomised placebo controlled and blinded multicentre trial. Analyses were by intention to treat. SETTING: University anaesthesia and surgical centres and one coordinating centre. PARTICIPANTS: 921 patients aged > 39 scheduled for major non-cardiac surgery. INTERVENTIONS: 100 mg metoprolol controlled and extended release or placebo administered from the day before surgery to a maximum of eight perioperative days. MAIN OUTCOME MEASURES: The composite primary outcome measure was time to all cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure. Secondary outcome measures were time to all cause mortality, cardiac mortality, and non-fatal cardiac morbidity. RESULTS: Mean duration of intervention was 4.6 days in the metoprolol group and 4.9 days in the placebo group. Metoprolol significantly reduced the mean heart rate by 11% (95% confidence interval 9% to 13%) and mean blood pressure by 3% (1% to 5%). The primary outcome occurred in 99 of 462 patients in the metoprolol group (21%) and 93 of 459 patients in the placebo group (20%) (hazard ratio 1.06, 0.80 to 1.41) during a median follow-up of 18 months (range 6-30). All cause mortality was 16% (74/462) in the metoprolol group and 16% (72/459) in the placebo group (1.03, 0.74 to 1.42). The difference in risk for the proportion of patients with serious adverse events was 2.4% (- 0.8% to 5.6%). CONCLUSIONS: Perioperative metoprolol did not significantly affect mortality and cardiac morbidity in these patients with diabetes. Confidence intervals, however, were wide, and the issue needs reassessment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN58485613.