Intraoperative Oxygen Treatment, Oxidative Stress, and Organ Injury Following Cardiac Surgery: A Randomized Clinical Trial.

Importance: Liberal oxygen (hyperoxia) is commonly administered to patients during surgery, and oxygenation is known to impact mechanisms of perioperative organ injury. Objective: To evaluate the effect of intraoperative hyperoxia compared to maintaining normoxia on oxidative stress, kidney injury, and other organ dysfunctions after cardiac surgery. Design, Setting, and Participants: This was a participant- and assessor-blinded, randomized clinical trial conducted from April 2016 to October 2020 with 1 year of follow-up at a single tertiary care medical center. Adult patients (>18 years) presenting for elective open cardiac surgery without preoperative oxygen requirement, acute coronary syndrome, carotid stenosis, or dialysis were included. Of 3919 patients assessed, 2501 were considered eligible and 213 provided consent. Of these, 12 were excluded prior to randomization and 1 following randomization whose surgery was cancelled, leaving 100 participants in each group. Interventions: Participants were randomly assigned to hyperoxia (1.00 fraction of inspired oxygen [FiO2]) or normoxia (minimum FiO2 to maintain oxygen saturation 95%-97%) throughout surgery. Main Outcomes and Measures: Participants were assessed for oxidative stress by measuring F2-isoprostanes and isofurans, for acute kidney injury (AKI), and for delirium, myocardial injury, atrial fibrillation, and additional secondary outcomes. Participants were monitored for 1 year following surgery. Results: Two hundred participants were studied (median [IQR] age, 66 [59-72] years; 140 male and 60 female; 82 [41.0%] with diabetes). F2-isoprostanes and isofurans (primary mechanistic end point) increased on average throughout surgery, from a median (IQR) of 73.3 (53.1-101.1) pg/mL at baseline to a peak of 85.5 (64.0-109.8) pg/mL at admission to the intensive care unit and were 9.2 pg/mL (95% CI, 1.0-17.4; P = .03) higher during surgery in patients assigned to hyperoxia. Median (IQR) change in serum creatinine (primary clinical end point) from baseline to postoperative day 2 was 0.01 mg/dL (-0.12 to 0.19) in participants assigned hyperoxia and -0.01 mg/dL (-0.16 to 0.19) in those assigned normoxia (median difference, 0.03; 95% CI, -0.04 to 0.10; P = .45). AKI occurred in 21 participants (21%) in each group. Intraoperative oxygen treatment did not affect additional acute organ injuries, safety events, or kidney, neuropsychological, and functional outcomes at 1 year. Conclusions: Among adults receiving cardiac surgery, intraoperative hyperoxia increased intraoperative oxidative stress compared to normoxia but did not affect kidney injury or additional measurements of organ injury including delirium, myocardial injury, and atrial fibrillation. Trial Registration: ClinicalTrials.gov Identifier: NCT02361944.

Effect of Regional Analgesia Techniques on Opioid Consumption and Length of Stay After Thoracic Surgery.

BACKGROUND: We examined how intercostal nerve block (ICNB) with standard bupivacaine and ICNB with extended-release liposomal bupivacaine, compared with thoracic epidural analgesia (TEA), were associated with postoperative opioid pain medication consumption and hospital length of stay (LOS) after thoracic surgery. METHODS: We studied 1935 patients who underwent thoracic surgery between January 1, 2010, and November 30, 2017, at a tertiary academic center. Primary and secondary outcomes were postoperative opioid consumption expressed as morphine milligram equivalents (MMEs) at 24, 48, and 72 hours after surgery, the LOS, and total MME consumption from surgery to discharge. RESULTS: Of these patients, 888 (45.9%) received TEA, 730 (37.7%) ICNB with standard bupivacaine, 127 (6.6%) ICNB with liposomal bupivacaine, and 190 (9.8%) no regional analgesia. Compared with epidural analgesia, in 2017, ICNB liposomal bupivacaine provided similar pain control in terms of MME consumption at 24 and 72 hours, but decreased MME consumption at 48 hours (odds ratio [OR] = 0.33; confidence interval [CI] = 0.14-0.81) and at discharge (OR = 0.28; CI = 0.12-0.68) and was associated with a higher likelihood for a shorter LOS (hazard ratio = 3.46; CI = 2.42-4.96). Compared with TEA, ICNB with standard bupivacaine and no regional analgesia use showed varying impact on MME consumption between 24 and 72 hours after surgery, and their use was not associated with a significantly reduced MME consumption at discharge but with a shorter hospital LOS. CONCLUSIONS: Multimodal analgesia involving regional anesthetic alternatives to TEA could help manage postoperative pain in thoracic surgery patients.

Mean platelet volume and cardiac-surgery-associated acute kidney injury: a retrospective study.

PURPOSE: Increased mean platelet volume (MPV) may indicate platelet activation, platelet aggregation, and a resulting prothrombotic state. Such changes in the postoperative period have been associated with organ injury and adverse outcomes. We hypothesized that changes in MPV after cardiac surgery are associated with both a higher risk of acute kidney injury (AKI) and mortality. METHODS: In this retrospective study, we evaluated consecutive patients undergoing adult cardiac surgery patients between 12 December 2011 and 5 June 2018. The change in MPV was derived by calculating the difference between the baseline MPV before surgery and the average postoperative MPV just prior to the occurrence of AKI. We defined postoperative AKI according to Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Acute Kidney Injury as either a ≥ 50% increase in serum creatinine in the first ten postoperative days, or an increase of ≥ 0.3 mg·dL-1 during any 48-hr window across the ten-day postoperative period. Multivariable logistic regression analysis was used to examine the association between MPV change and postoperative AKI and mortality. RESULTS: Of the 4,204 patients studied, 1,373 (32.7%) developed postoperative AKI, including 83 (2.0%) and 38 (0.9%) who developed stages II and III AKI, respectively. Compared with patients who had an increase in median postoperative MPV of 0.2 femtolitre (fL), those with an increase of 0.8 fL had an 80% increase in the odds of developing AKI (adjusted odds ratio [aOR], 1.80; 95% confidence interval [CI],1.36 to 2.38; P < 0.001) and were almost twice as likely to progress to a higher severity AKI (aOR, 1.66; 95% CI, 1.28 to 2.16; P < 0.001). Change in MPV was not associated with mortality (aOR,1.32; 95% CI, 0.92 to 1.89; P = 0.14). CONCLUSION: Increased MPV change in the postoperative period was associated with both increased risk and severity of AKI, but not mortality.

RéSUMé: OBJECTIF: Un volume plaquettaire moyen (VPM) augmenté peut être indicatif d'une activation plaquettaire, d'une agrégation plaquettaire, et de l'état prothrombotique qui en résulte. De tels changements en période postopératoire ont été associés à des lésions aux organes et à des devenirs défavorables. Nous avons émis l'hypothèse que des changements du VPM après une chirurgie cardiaque seraient associés à un risque plus élevé d'insuffisance rénale aiguë et de mortalité. MéTHODE: Dans cette étude rétrospective, nous avons évalué des patients adultes consécutifs subissant une chirurgie cardiaque entre le 12 décembre 2011 et le 5 juin 2018. Le changement de VPM a été dérivé en calculant la différence entre le VPM de base avant la chirurgie et le VPM postopératoire moyen juste avant la survenue de l'IRA. Nous avons défini une IRA postopératoire sur la base des Directives Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Acute Kidney Injury (Les maladies rénales: Guide d'exercice clinique pour améliorer les devenirs globaux pour l'insuffisance rénale aiguë) en tant qu'une augmentation ≥ 50 % de la créatine sérique au cours des dix premiers jours postopératoires, ou une augmentation de ≥ 0,3 mg·dL−1 pendant toute fenêtre de 48 h au cours des dix premiers jours postopératoires. Une analyse multivariée de régression logistique a été utilisée pour examiner l'association entre le changement de VPM et l'IRA postopératoire et la mortalité. RéSULTATS: Parmi les 4204 patients à l'étude, 1373 (32,7 %) ont souffert d'IRA postopératoire, y compris 83 (2,0 %) et 38 (0,9 %) qui ont développé des IRA de stade II et III, respectivement. Par rapport aux patients ayant manifesté une augmentation du VPM postopératoire médian de 0,2 femtolitre (fL), ceux affichant une augmentation de 0,8 fL ont démontré une augmentation de 80 % de la probabilité d'IRA (rapport de cotes ajusté [RCA], 1,80; intervalle de confiance [IC] 95 %, 1,36 à 2,38; P < 0,001) et couraient un risque pratiquement deux fois plus élevé de voir leur IRA progresser à un stade plus grave (RCA, 1,66; IC 95 %, 1,28 à 2,16; P < 0,001). Les changements de VPM n'étaient pas associés à la mortalité (RCA, 1,32; IC 95 %, 0,92 à 1,89; P = 0,14). CONCLUSION: Une augmentation accrue du VPM en période postopératoire a été associée à un risque et une gravité accrus d'IRA, mais pas à la mortalité.

CYP2D6 Genotype-guided Metoprolol Therapy in Cardiac Surgery Patients: Rationale and Design of the Pharmacogenetic-guided Metoprolol Management for Postoperative Atrial Fibrillation in Cardiac Surgery (PREEMPTIVE) Pilot Study.

OBJECTIVES: The Preemptive Pharmacogenetic-guided Metoprolol Management for Atrial Fibrillation in Cardiac Surgery (PREEMPTIVE) pilot trial aims to use existing institutional resources to develop a process for integrating CYP2D6 pharmacogenetic test results into the patient electronic health record, to develop an evidence-based clinical decision support tool to facilitate CYP2D6 genotype-guided metoprolol administration in the cardiac surgery setting, and to determine the impact of implementing this CYP2D6 genotype-guided integrated approach on the incidence of postoperative atrial fibrillation (AF), provider, and cost outcomes. DESIGN: One-arm Bayesian adaptive design clinical trial. SETTING: Single center, university hospital. PARTICIPANTS: The authors will screen (including CYP2D6 genotype) up to 600 (264 ± 144 expected under the adaptive design) cardiac surgery patients, and enroll up to 200 (88 ± 48 expected) poor, intermediate, and ultrarapid CYP2D6 metabolizers over a period of 2 years at a tertiary academic center. INTERVENTIONS: All consented and enrolled patients will receive the intervention of CYP2D6 genotype-guided metoprolol management based on CYP2D6 phenotype classified as a poor, intermediate, extensive (normal), or ultrarapid metabolizer. MEASUREMENTS AND MAIN RESULTS: The primary outcome will be the incidence of postoperative AF. Secondary outcomes relating to rates of CYP2D6 genotype-guided prescription changes, costs, lengths of stay, and implementation metrics also will be investigated. CONCLUSIONS: The PREEMPTIVE pilot study is the first perioperative pilot trial to provide essential information for the design of a future, large-scale trial comparing CYP2D6 genotype-guided metoprolol management with a nontailored strategy in terms of managing AF. In addition, secondary outcomes regarding implementation, clinical benefit, safety, and cost-effectiveness in patients undergoing cardiac surgery will be examined.

Future Technology.

Mitral regurgitation is the most common valvular disease and significant (moderate/severe) mitral regurgitation is found in 2.3% of the population older than 65 years. New transcatheter minimally invasive technologies are being developed to address mitral valve disease in patients deemed too high a risk for conventional open-heart surgery. There are several features of the mitral valve (saddle-shaped noncalcified annulus with irregular leaflet geometry) that make a transcatheter approach to repair or replacing the valve more challenging compared with the aortic valve. Several devices are under investigation for transcatheter mitral valve replacement, and also for mitral valve repair targeting the mitral valve leaflets, chordae tendinae, and mitral annulus. The MitraClip device is the only Food and Drug Administration-approved device to treat mitral regurgitation by targeting the mitral leaflets. There are eight minimally invasive devices being studied in humans that target the mitral annulus, and at least two devices being studied in animal models. There are 5 devices in clinical trials for minimally invasive approaches targeting the chordae tendinae. More than 10 different transcatheter mitral valves are in various stages of development and clinical trials. These transcatheter mitral valves can be delivered either through a transseptal, transapical, transaortic, or left atriotomy approach. It seems likely that transcatheter treatment approaches to mitral valve disease will become more common, at least in the sick and elderly patient population.

Fish Oil and Perioperative Bleeding.

Background Fish oil is among the most common natural supplements for treatment of hypertriglyceridemia or prevention of cardiovascular disease. However, concerns about theoretical bleeding risk have led to recommendations that patients should stop taking fish oil before surgery or delay in elective procedures for patients taking fish oil by some health care professionals. Methods and Results We tested the effect of fish oil supplementation on perioperative bleeding in a multinational, placebo-controlled trial involving 1516 patients who were randomized to perioperative fish oil (eicosapentaenoic acid+docosahexaenoic acid; 8-10 g for 2-5 days preoperatively, and then 2 g/d postoperatively) or placebo. Primary outcome was major perioperative bleeding as defined by the Bleeding Academic Research Consortium. Secondary outcomes include perioperative bleeding per thrombolysis in myocardial infarction and International Society on Thrombosis and Hemostasis definitions, chest tube output, and total units of blood transfused. Participants' mean (SD) age was 63 (13) years, and planned surgery included coronary artery bypass graft (52%) and valve surgery (50%). The primary outcome occurred in 92 patients (6.1%). Compared with placebo, risk of Bleeding Academic Research Consortium bleeding was not higher in the fish oil group: odds ratio, 0.81; 95% CI, 0.53-1.24; absolute risk difference, 1.1% lower (95% CI, -3.0% to 1.8%). Similar findings were seen for secondary bleeding definitions. The total units of blood transfused were significantly lower in the fish oil group compared with placebo (mean, 1.61 versus 1.92; P<0.001). Evaluating achieved plasma phospholipid omega-3 polyunsaturated fatty acids levels with supplementation (on the morning of surgery), higher levels were associated with lower risk of Bleeding Academic Research Consortium bleeding, with substantially lower risk in the third (odds ratio, 0.30 [95% CI, 0.11-0.78]) and fourth (0.36 [95% CI, 0.15-0.87]) quartiles, compared with the lowest quartile. Conclusions Fish oil supplementation did not increase perioperative bleeding and reduced the number of blood transfusions. Higher achieved n-3-PUFA levels were associated with lower risk of bleeding. These novel findings support the need for reconsideration of current recommendations to stop fish oil or delay procedures before cardiac surgery. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00970489.

Point-of-Care Ultrasound Facilitated Detection of Femoral Occlusive Septic Emboli During Mitral Valve Surgery: A Case Report.

Acute lower extremity ischemia from septic emboli is a surgical emergency. Timely diagnosis and management are critical to improve patient outcome. However, traditional diagnostic modalities such as intraoperative angiogram are time-consuming, require special equipment and personnel, and introduce contrast exposure for critically ill patients. There are limited reports of utilization of point-of-care ultrasound to detect peripheral septic emboli. We present a case where femoral occlusive septic emboli were identified by point-of-care ultrasound after mitral valve replacement. This facilitated early surgical embolectomy and limb salvage. We suggest that perioperative point-of-care ultrasonography should be used as a first-line screening test in patients with acute lower extremity ischemia.

The Risk of Oxygen during Cardiac Surgery (ROCS) trial: study protocol for a randomized clinical trial.

BACKGROUND: Anesthesiologists administer excess supplemental oxygen (hyper-oxygenation) to patients during surgery to avoid hypoxia. Hyper-oxygenation, however, may increase the generation of reactive oxygen species and cause oxidative damage. In cardiac surgery, increased oxidative damage has been associated with postoperative kidney and brain injury. We hypothesize that maintenance of normoxia during cardiac surgery (physiologic oxygenation) decreases kidney injury and oxidative damage compared to hyper-oxygenation. METHODS/DESIGN: The Risk of Oxygen during Cardiac Surgery (ROCS) trial will randomly assign 200 cardiac surgery patients to receive physiologic oxygenation, defined as the lowest fraction of inspired oxygen (FIO2) necessary to maintain an arterial hemoglobin saturation of 95 to 97%, or hyper-oxygenation (FIO2 = 1.0) during surgery. The primary clinical endpoint is serum creatinine change from baseline to postoperative day 2, and the primary mechanism endpoint is change in plasma concentrations of F2-isoprostanes and isofurans. Secondary endpoints include superoxide production, clinical delirium, myocardial injury, and length of stay. An endothelial function substudy will examine the effects of oxygen treatment and oxidative stress on endothelial function, measured using flow mediated dilation, peripheral arterial tonometry, and wire tension myography of epicardial fat arterioles. DISCUSSION: The ROCS trial will test the hypothesis that intraoperative physiologic oxygenation decreases oxidative damage and organ injury compared to hyper-oxygenation in patients undergoing cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02361944 . Registered on the 30th of January 2015.

Intraoperative cerebral oxygenation, oxidative injury, and delirium following cardiac surgery.

BACKGROUND: Delirium affects 20-30% of patients after cardiac surgery and is associated with increased mortality and persistent cognitive decline. Hyperoxic reperfusion of ischemic tissues increases oxidative injury, but oxygen administration remains high during cardiac surgery. We tested the hypothesis that intraoperative hyperoxic cerebral reperfusion is associated with increased postoperative delirium and that oxidative injury mediates this association. METHODS: We prospectively measured cerebral oxygenation with bilateral oximetry monitors in 310 cardiac surgery patients, quantified intraoperative hyperoxic cerebral reperfusion by measuring the magnitude of cerebral oxygenation above baseline after any ischemic event, and assessed patients for delirium twice daily in the ICU following surgery using the confusion assessment method for ICU (CAM-ICU). We examined the association between hyperoxic cerebral reperfusion and postoperative delirium, adjusted for the extent of cerebral hypoxia, the extent of cerebral hyperoxia prior to any ischemia, and additional potential confounders and risk factors for delirium. To assess oxidative injury mediation, we examined the association between hyperoxic cerebral reperfusion and delirium after further adjusting for plasma levels of F2-isoprostanes and isofurans at baseline and ICU admission, the association between hyperoxic cerebral reperfusion and these markers of oxidative injury, and the association between these markers and delirium. RESULTS: Ninety of the 310 patients developed delirium following surgery. Every 10%·hour of intraoperative hyperoxic cerebral reperfusion was independently associated with a 65% increase in the odds of delirium (OR, 1.65 [95% CI, 1.12-2.44]; P=0.01). Hyperoxia prior to ischemia was also independently associated with delirium (1.10 [1.01-1.19]; P=0.02), but hypoxia was not (1.12 [0.97-1.29]; P=0.11). Increased hyperoxic cerebral reperfusion was associated with increased concentrations of F2-isoprostanes and isofurans at ICU admission, increased concentrations of these markers were associated with increased delirium, and the association between hyperoxic cerebral reperfusion and delirium was weaker after adjusting for these markers of oxidative injury. CONCLUSIONS: Intraoperative hyperoxic cerebral reperfusion was associated with increased postoperative delirium, and increased oxidative injury following hyperoxic cerebral reperfusion may partially mediate this association. Further research is needed to assess the potential deleterious role of cerebral hyper-oxygenation during surgery.

Perioperative intravenous acetaminophen attenuates lipid peroxidation in adults undergoing cardiopulmonary bypass: a randomized clinical trial.

BACKGROUND: Cardiopulmonary bypass (CPB) lyses erythrocytes and induces lipid peroxidation, indicated by increasing plasma concentrations of free hemoglobin, F2-isoprostanes, and isofurans. Acetaminophen attenuates hemeprotein-mediated lipid peroxidation, reduces plasma and urine concentrations of F2-isoprostanes, and preserves kidney function in an animal model of rhabdomyolysis. Acetaminophen also attenuates plasma concentrations of isofurans in children undergoing CPB. The effect of acetaminophen on lipid peroxidation in adults has not been studied. This was a pilot study designed to test the hypothesis that acetaminophen attenuates lipid peroxidation in adults undergoing CPB and to generate data for a clinical trial aimed to reduce acute kidney injury following cardiac surgery. METHODS AND RESULTS: In a prospective double-blind placebo-controlled clinical trial, sixty adult patients were randomized to receive intravenous acetaminophen or placebo starting prior to initiation of CPB and for every 6 hours for 4 doses. Acetaminophen concentrations measured 30 min into CPB and post-CPB were 11.9 ± 0.6 µg/mL (78.9 ± 3.9 µM) and 8.7 ± 0.3 µg/mL (57.6 ± 2.0 µM), respectively. Plasma free hemoglobin increased more than 15-fold during CPB, and haptoglobin decreased 73%, indicating hemolysis. Plasma and urinary markers of lipid peroxidation also increased during CPB but returned to baseline by the first postoperative day. Acetaminophen reduced plasma isofuran concentrations over the duration of the study (P = 0.05), and the intraoperative plasma isofuran concentrations that corresponded to peak hemolysis were attenuated in those subjects randomized to acetaminophen (P = 0.03). Perioperative acetaminophen did not affect plasma concentrations of F2-isoprostanes or urinary markers of lipid peroxidation. CONCLUSIONS: Intravenous acetaminophen attenuates the increase in intraoperative plasma isofuran concentrations that occurs during CPB, while urinary markers were unaffected. TRIAL REGISTRATION: ClinicalTrials.gov NCT01366976.

Hemodynamic instability in patients undergoing pulmonary embolectomy: institutional experience.

OBJECTIVES: Acute pulmonary embolism is a major cause of morbidity and mortality in patients presenting for emergent cardiac surgery with overall mortality ranging from 6% to as high as 85%. While the initial focus of treatment is nonsurgical or percutaneous interventions, surgical treatment continues to be a treatment for patients with refractory thrombus burden or cardiogenic shock. Our institution regularly performs surgical pulmonary embolectomy with improved outcomes compared to current reports. We thus performed a retrospective analysis of outcomes of pulmonary embolectomy patients and anesthetic management. DESIGN: A retrospective review of 40 patients undergoing emergent pulmonary embolectomy over a 4 year period (2008-2012) at our institution was performed to assess for a 2nd period of critical instability. SETTING: The study was conducted at a tertiary, level 1, trauma university medical center. PARTICIPANTS: The study was performed through chart review of patient hospital records. INTERVENTIONS: No interventions were performed. MEASUREMENTS: Anesthetic records were reviewed along with echocardiographic records and surgical reports to assess cardiac function, need for emergent cardiopulmonary bypass, and degree of patient morbidity. CONCLUSIONS: A total of 40 patients were studied. Hemodynamic instability occurred in 12.5% of patients at time of induction requiring emergent cardiopulmonary bypass. Another 17% of patients who remained stable following induction developed subsequent instability requiring emergent cardiopulmonary bypass during pericardial opening or manipulation which has not been previously reported. One patient died during hospitalization. Patients who required emergent bypass following induction of general anesthesia tended to receive higher doses of induction drugs than the other groups. In patients who needed emergent bypass during pericardial manipulation there were no identifiable factors suggesting that these patients remain at risk despite a stable post-induction course.

Heme Oxygenase-1 and Acute Kidney Injury following Cardiac Surgery.

BACKGROUND: Intraoperative hemolysis and inflammation are associated with acute kidney injury (AKI) following cardiac surgery. Plasma-free hemoglobin induces heme oxygenase-1 (HO-1) expression. HO-1 degrades heme but increases in experimental models of AKI. This study tested the hypothesis that plasma HO-1 concentrations are associated with intraoperative hemolysis and are increased in patients that develop AKI following cardiac surgery. METHODS: We measured plasma HO-1, free hemoglobin, and inflammatory markers in 74 patients undergoing cardiopulmonary bypass (CPB). AKI was defined as an increase in serum creatinine concentration of 50% or 0.3 mg/dl within 72 h of surgery. RESULTS: Twenty-eight percent of patients developed AKI. HO-1 concentrations increased from 4.2 ± 0.2 ng/ml at baseline to 6.6 ± 0.5 ng/ml on postoperative day (POD) 1 (p < 0.001). POD1 HO-1 concentrations were 3.1 ng/ml higher (95% CI 1.1-5.1) in AKI patients, as was the change in HO-1 from baseline to POD1 (4.4 ± 1.3 ng/ml in AKI patients vs. 1.5 ± 0.3 ng/ml in no-AKI patients, p = 0.006). HO-1 concentrations remained elevated in AKI patients even after controlling for AKI risk factors and preoperative drug therapy. Peak-free hemoglobin concentrations correlated with peak HO-1 concentrations on POD1 in patients that developed AKI (p = 0.02). Duration of CPB and post-CPB IL-6 and IL-10 concentrations were also associated with increased HO-1 on POD1. CONCLUSION: Plasma HO-1 is increased in patients that develop AKI, and CPB duration, hemolysis, and inflammation are associated with increased HO-1 concentrations following cardiac surgery. Strategies that alter hemolysis and HO-1 expression during cardiac surgery may affect risk for AKI.

Acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass.

OBJECTIVE: Hemolysis, occurring during cardiopulmonary bypass, is associated with lipid peroxidation and postoperative acute kidney injury. Acetaminophen inhibits lipid peroxidation catalyzed by hemeproteins and in an animal model attenuated rhabdomyolysis-induced acute kidney injury. This pilot study tests the hypothesis that acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass. DESIGN: Single-center prospective randomized double-blinded study. SETTING: University-affiliated pediatric hospital. PATIENTS: Thirty children undergoing elective surgical correction of a congenital heart defect. INTERVENTIONS: Patients were randomized to acetaminophen (OFIRMEV [acetaminophen] injection; Cadence Pharmaceuticals, San Diego, CA) or placebo every 6 hours for four doses starting before the onset of cardiopulmonary bypass. MEASUREMENT AND MAIN RESULTS: Markers of hemolysis, lipid peroxidation (isofurans and F2-isoprostanes), and acute kidney injury were measured throughout the perioperative period. Cardiopulmonary bypass was associated with a significant increase in free hemoglobin (from a prebypass level of 9.8 ± 6.2 mg/dL to a peak of 201.5 ± 42.6 mg/dL postbypass). Plasma and urine isofuran and F2-isoprostane concentrations increased significantly during surgery. The magnitude of increase in plasma isofurans was greater than the magnitude in increase in plasma F2-isoprostanes. Acetaminophen attenuated the increase in plasma isofurans compared with placebo (p = 0.02 for effect of study drug). There was no significant effect of acetaminophen on plasma F2-isoprostanes or urinary makers of lipid peroxidation. Acetaminophen did not affect postoperative creatinine, urinary neutrophil gelatinase-associated lipocalin, or prevalence of acute kidney injury. CONCLUSION: Cardiopulmonary bypass in children is associated with hemolysis and lipid peroxidation. Acetaminophen attenuated the increase in plasma isofuran concentrations. Future studies are needed to establish whether other therapies that attenuate or prevent the effects of free hemoglobin result in more effective inhibition of lipid peroxidation in patients undergoing cardiopulmonary bypass.

Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition.

UNLABELLED: Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition. CLINICAL TRIAL REGISTRATION: - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.

Etomidate use and postoperative outcomes among cardiac surgery patients.

BACKGROUND: Although a single dose of etomidate can cause relative adrenal insufficiency, the impact of etomidate exposure on postoperative outcomes is unknown. The objective of this study was to examine the association between a single induction dose of etomidate and clinically important postoperative outcomes after cardiac surgery. METHODS: The authors retrospectively examined the association between etomidate exposure during induction of anesthesia and postoperative outcomes in patients undergoing cardiac surgery from January 2007 to December 2009 by using multivariate logistic regression analyses and Cox proportional hazards regression analyses. Postoperative outcomes of interest were severe hypotension, mechanical ventilation hours, hospital length of stay, and in-hospital mortality. RESULTS: Sixty-two percent of 3,127 patients received etomidate. Etomidate recipients had a higher incidence of preoperative congestive heart failure (23.0 vs. 18.3%; P = 0.002) and a lower incidence of preoperative cardiogenic shock (1.3 vs. 4.0%; P < 0.001). The adjusted odds ratio for severe hypotension and in-hospital mortality associated with receiving etomidate was 0.80 (95% CI, 0.58-1.09) and 0.75 (95% CI, 0.45-1.24), respectively, and the adjusted hazard ratio for time to mechanical ventilation removal and time to hospital discharge was 1.10 (95% CI, 1.00-1.21) and 1.07 (95% CI, 0.97-1.18), respectively. Propensity score analysis did not change the association between etomidate use and postoperative outcomes. CONCLUSIONS: In this study, there was no evidence to suggest that etomidate exposure was associated with severe hypotension, longer mechanical ventilation hours, longer length of hospital stay, or in-hospital mortality. Etomidate should remain an option for induction of anesthesia in cardiac surgery patients.