Bernard McDonald

Biotransformation of organic nitrates and vascular smooth muscle cell function.

The organic nitrates are interesting examples of drugs that undergo biotransformation at their site of action to generate the active form of the drug. Furthermore, tolerance to the vasodilator effects of organic nitrates is associated with impairment of this metabolic activation process. Despite considerable research effort, the intracellular processes and the chemical reaction pathways by which organic nitrates are converted to their active form are still unresolved. This review by Brian Bennett and colleagues summarizes the characteristics of organic-nitrate biotransformation in vascular smooth muscle, the difficulties encountered when assessing this biotransformation, and the evidence for the role of two identified vascular biotransformation systems (glutathione-S-transferases and the cytochrome P450 system) in the metabolic activation of organic nitrates.

Inhibition of NADPH-cytochrome P450 reductase and glyceryl trinitrate biotransformation by diphenyleneiodonium sulfate.

We reported previously that the flavoprotein inhibitor diphenyleneiodonium sulfate (DPI) irreversibly inhibited the metabolic activation of glyceryl trinitrate (GTN) in isolated aorta, possibly through inhibition of vascular NADPH-cytochrome P450 reductase (CPR). We report that the content of CPR represents 0.03 to 0.1% of aortic microsomal protein and that DPI caused a concentration- and time-dependent inhibition of purified cDNA-expressed rat liver CPR and of aortic and hepatic microsomal NADPH-cytochrome c reductase activity. Purified CPR incubated with NADPH and GTN under anaerobic, but not aerobic conditions formed the GTN metabolites glyceryl-1,3-dinitrate (1,3-GDN) and glyceryl-1,2-dinitrate (1,2-GDN). GTN biotransformation by purified CPR and by aortic and hepatic microsomes was inhibited > 90% after treatment with DPI and NADPH. DPI treatment also inhibited the production of activators of guanylyl cyclase formed by hepatic microsomes. We also tested the effect of DPI on the hemodynamic-pharmacokinetic properties of GTN in conscious rats. Pretreatment with DPI (2 mg/kg) significantly inhibited the blood pressure lowering effect of GTN and inhibited the initial appearance of 1,2-GDN (1-5 min) and the clearance of 1,3-GDN. These data suggest that the rapid initial formation of 1,2-GDN is related to mechanism-based GTN biotransformation and to enzyme systems sensitive to DPI inhibition. We conclude that vascular CPR is a site of action for the inhibition by DPI of the metabolic activation of GTN, and that vascular CPR is a novel site of GTN biotransformation that should be considered when investigating the mechanism of GTN action in vascular tissue.

Biotransformation of glyceryl trinitrate by rat aortic cytochrome P450

Denitration of glyceryl trinitrate (GTN) by the microsomal fraction of rat aorta was found to be NADPH dependent and followed apparent first-order kinetics (T1/2 70.1 min). Biotransformation of GTN was regioselective for glyceryl-1,2-dinitrate formation, and was inhibited by carbon monoxide, SKF-525A, and oxygen. In aortic microsomes prepared from phenobarbital-pretreated rats, biotransformation was increased 7-fold, and was regioselective for glyceryl-1,3-dinitrate formation. These data strongly suggest the involvement of aortic cytochrome P450 in the biotransformation of GTN.

Clinical Impact of Mild Acute Kidney Injury After Cardiac Surgery

BACKGROUND Dialysis-dependent renal failure occurs infrequently after cardiac surgery but leads to substantial morbidity and mortality. In contrast, milder degrees of acute kidney injury (AKI), based on small increases in serum creatinine, occur frequently but the independent impact of mild AKI on outcome remains unclear. METHODS Between January 2010 and December 2012, 3,869 consecutive patients undergoing cardiac surgery comprised the study cohort. Acute kidney injury was defined according to the AKI Network criteria as stage I, II, or III. A nonparsimonious multivariable logistic regression model including preoperative and intraoperative variables was constructed to determine a propensity score for the development of stage I AKI followed by a greedy matching algorithm to create 1:1 propensity-matched pairs. RESULTS The incidence of stage I AKI in the entire cohort was 22.4%. Stage I AKI patients were more likely to be older; to have diabetes mellitus, hypertension, preoperative renal dysfunction, and poorer left ventricle function; and to require more urgent surgery and longer cardiopulmonary bypass. After propensity matching, the 833 matched pairs were similar in terms of all of the above characteristics (all p > 0.5). Within the matched cohort, AKI patients had higher mortality (2.6% versus 1.2%, p = 0.01), higher incidence of neurologic dysfunction (15.2% versus 8.1%, p < 0.001), and longer duration of mechanical ventilation (41.7 ± 125.0 versus 19.3 ± 58.6 hours, p < 0.001). Intensive care unit stay (5.2 ± 10.7 versus 2.7 ± 3.8 days, p < 0.0001), and hospital length of stay (17.9 ± 20.1 versus 14.7 ± 18.3 days, p = 0.0007) was significantly longer for matched AKI patients. CONCLUSIONS Patients with even mild degrees of AKI have increased mortality and morbidity compared with their matched counterparts. Interventions that prevent or mitigate AKI after cardiac surgery can yield substantial clinical benefit.

Preoperative anaemia is a risk factor for mortality and morbidity following aortic valve surgery.

OBJECTIVES The impact of anaemia on patients undergoing aortic valve surgery has not been well studied. We sought to evaluate the effect of anaemia on early outcomes following aortic valve replacement (AVR). METHODS All patients undergoing non-emergent aortic valve surgery (n = 2698) with or without other concomitant procedures between 1997 and 2010 were included. Preoperative anaemia was defined as per World Health Organization guidelines as haemoglobin (Hb) < 130 g/l in men and Hb < 120 g/l in women. Multivariable analyses were used to determine the association between preoperative anaemia and postoperative outcomes. RESULTS The prevalence of preoperative anaemia was 32.2%. Patients with anaemia were older (71 ± 12 vs 66 ± 13 years, P < 0.001), more likely to have urgent surgery, recent MI, higher creatinine level and impaired preoperative left ventricular function. Overall unadjusted mortality was 2.8% in non-anaemic patients vs 8% in anaemic patients. Anaemic patients were more likely to require renal replacement therapy (11 vs 3%, P < 0.0001) and prolonged ventilation (24 vs 10%, P < 0.0001). Following multivariable adjustment, lower preoperative Hb was an independent predictor of mortality (odds ratio 1.19, 95% CI: 1.04-1.34, P = 0.007) and composite morbidity (odds ratio 1.36, 95% CI: 1.05-1.77, P = 0.02) after AVR. Mortality and composite morbidity were significantly higher with lower levels of preoperative Hb. CONCLUSIONS Preoperative anaemia is a common finding in patients undergoing aortic valve surgery and is an important and potentially modifiable risk factor for postoperative morbidity and mortality.

Impact of anesthetic handover on mortality and morbidity in cardiac surgery: a cohort study.

OBJECTIVE Clinical handover is a critical moment in patient care. The authors tested the hypothesis that handover of anesthesia care is associated with increased mortality and morbidity in patients undergoing cardiac surgery. DESIGN This was a single-center, retrospective cohort study of prospectively collected data. SETTING The study was conducted in a quaternary care cardiac surgery center and university research hospital. PARTICIPANTS All patients undergoing cardiac surgical procedures between April 1, 1999 and October 31, 2009 were included in the study. INTERVENTIONS Propensity-score matching was used to adjust for differences between patients who received intraoperative handover of anesthesia care and those who did not, and in-hospital mortality and morbidity were compared using multivariate logistic modeling. MEASUREMENTS AND MAIN RESULTS 14,421 patients met the inclusion criteria for this study; handover occurred in 966 cases (6.7%). After propensity-score matching, 7,137 patients were included for analysis. In-hospital mortality was 5.4% in the handover group and 4.0% in the non-handover group (match-adjusted odds ratio, 1.425; 95% confidence interval, 1.013-2.006; p = 0.0422); the incidence of major morbidity was 18.5% in the handover group and 15.6% in the non-handover group (match-adjusted odds ratio, 1.274; 95% confidence interval, 1.037-1.564; p = 0.0212). CONCLUSIONS Handover of anesthetic care during cardiac surgery is associated with a 43% greater risk of in-hospital mortality and 27% greater risk of major morbidity. Further studies are required to explore this relationship and to systematically evaluate and improve the process of handover.

Role of nutrition support in adult cardiac surgery: a consensus statement from an International Multidisciplinary Expert Group on Nutrition in Cardiac Surgery

Nutrition support is a necessary therapy for critically ill cardiac surgery patients. However, conclusive evidence for this population, consisting of well-conducted clinical trials is lacking. To clarify optimal strategies to improve outcomes, an international multidisciplinary group of 25 experts from different clinical specialties from Germany, Canada, Greece, USA and Russia discussed potential approaches to identify patients who may benefit from nutrition support, when best to initiate nutrition support, and the potential use of pharmaco-nutrition to modulate the inflammatory response to cardiopulmonary bypass. Despite conspicuous knowledge and evidence gaps, a rational nutritional support therapy is presented to benefit patients undergoing cardiac surgery.

Evaluation of Persistent Organ Dysfunction Plus Death As a Novel Composite Outcome in Cardiac Surgical Patients

OBJECTIVES Validated composite outcomes after complicated cardiac surgery are poorly established. Therefore, the authors evaluated a novel composite endpoint, persistent organ dysfunction (POD)+death, which is defined as any need for life-sustaining therapies or death at any time within 28 days from surgery. DESIGN Secondary analysis extracted from a large-scale prospective randomized trial of critically ill cardiac surgery patients. SETTING Multi-institutional, university hospitals. PARTICIPANTS Ninety-five cardiac surgery patients with complicated postoperative courses. INTERVENTIONS Cardiac surgery with cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS At 28 days following surgery, the prevalence of POD was 15%, and 23% of patients had died (POD+death = 38%). Patients alive with POD at day 28 exhibited a significantly higher extent of organ injury and longer ICU (33 v 7 days; p<0.001) and hospital lengths of stay (49 v 21 days; p<0.001) compared to patients without POD at day 28. At 3 and 6 months, quality-of-life scores (by Short Form 36 questionnaire) showed a significantly reduced rating for most components in patients with POD at day 28 compared to those without POD. The 6-month mortality rate was 21% among patients alive with POD at day 28 compared to 5% among patients alive without POD (p = 0.05). The calculated number of patients needed per arm to detect a 25% relative risk reduction for mortality alone was 762 compared to 386 per arm for POD+ death. CONCLUSIONS POD+death at day 28 following cardiac surgery may be a valid composite endpoint and offers statistical efficiencies in terms of sample size calculations for cardiac surgical trials.

How detrimental is reexploration for bleeding after cardiac surgery

Objective: To establish the risk factors and impact of reexploration for bleeding in a large modern cardiac surgical cohort. Methods: At a tertiary referral center, baseline, index procedural, reexploration, outcome, and readmission characteristics of 16,793 consecutive adult cardiac surgery patients were prospectively entered into dedicated clinical databases. Correlates of reexploration for bleeding, as well as its association with outcomes and readmission, were examined with multivariable regression models. Results: The mean patient age was 65.9 ± 12.1 years, and 11,991 patients (71.4%) patients were male. Perioperative mortality was 2.8% (458 of 16,132) in those who did not undergo reexploration for bleeding and 12.0% (81 of 661) in those who underwent reexploration for bleeding, corresponding to an odds ratio of 3.4 ± 0.5 (P <.001) over other predictors of mortality, including Euroscore II. Mortality was highest in patients who underwent reexploration after the day of index surgery (odds ratio, 6.4 ± 1.1). Hospital stay was longer in patients who underwent reexploration for bleeding (median, 12 days, vs 7 days in patients who did not undergo reexploration; P <.001), to an extent beyond any other correlate. Reexploration for bleeding also was independently associated with new‐onset postoperative atrial fibrillation, renal insufficiency, intensive care unit readmission, and wound infection. Risk factors for reexploration for bleeding were tricuspid valve repair, on‐pump versus off‐pump coronary artery bypass grafting, emergency status, cardiopulmonary bypass (CPB) duration, low body surface area, and lowest CPB hematocrit of <24%. Conclusions: Reexploration for bleeding is a lethal and morbid complication of cardiac surgery, with a detrimental effect that surpasses that of any other known potentially modifiable risk factor. All efforts should be made to minimize the incidence and burden of reexploration for bleeding, including further research on transfusion management during CPB.

Impact of Subglottic Suctioning on the Incidence of Pneumonia After Cardiac Surgery: A Retrospective Observational Study

OBJECTIVE Continuous aspiration of subglottic secretions (CASS) has been found to decrease the incidence of pneumonia in the general intensive care unit (ICU) population, but its benefit in cardiac surgery patients is unclear. The present study aimed to determine whether the routine use of CASS in cardiac surgical patients was associated with decreased pneumonia. DESIGN A retrospective, single-center observational study. SETTING The study was conducted in a quaternary care cardiac surgery center and university research hospital. PARTICIPANTS 4,880 patients undergoing cardiac surgery were studied. INTERVENTIONS The control group (no CASS) received a standard endotracheal tube and underwent surgery between April 1, 2007 and March 31, 2009. The intervention group (CASS) received a subglottic suctioning endotracheal tube and underwent surgery between June 1, 2009 and May 31, 2011. The primary outcome was the development of pneumonia, and the secondary outcomes were 30-day in-hospital mortality, ventilation time, need for tracheostomy, ICU length of stay (LOS), and hospital LOS. MEASUREMENTS AND MAIN RESULTS The unadjusted incidence of pneumonia was 1.9% in the CASS group and 5.6% in the control group (p<0.0001). The CASS group also had lower 30-day in-hospital mortality (2.1% v 3.3%; p = 0.007), median ventilation time (8.42 v 7.3 hours; p<0.0001), and shorter median ICU LOS (1.77 v 1.17 days; p<0.0004) compared with the control group. Tracheostomy rates and median hospital LOS did not differ between groups. After adjusting using multivariable modeling, CASS remained an independent risk predictor for pneumonia (odds ratio [OR] 0.342, 95% confidence interval [CI] 0.239-0.490) and ICU LOS (OR 0.817, 95% CI 0.718-0.931). CONCLUSIONS The universal implementation of CASS in a quaternary care cardiac surgical population was associated with a decreased incidence of pneumonia.