Fraser D. Rubens

Acute Kidney Injury After Cardiac Surgery Focus on Modifiable Risk Factors

Background— Acute kidney injury (AKI) after cardiac surgery is a major health issue. Lacking effective therapies, risk factor modification may offer a means of preventing this complication. The objective of the present study was to identify and determine the prognostic importance of such risk factors. Methods and Results— Data from a multicenter cohort of 3500 adult patients who underwent cardiac surgery at 7 hospitals during 2004 were analyzed (using multivariable logistic regression modeling) to determine the independent relationships between 3 thresholds of AKI (>25%, >50%, and >75% decrease in estimated glomerular filtration rate within 1 week of surgery or need for postoperative dialysis) with death rates, as well as to identify modifiable risk factors for AKI. The 3 thresholds of AKI occurred in 24% (n=829), 7% (n=228), and 3% (n=119) of the cohort, respectively. All 3 thresholds were independently associated with a >4-fold increase in the odds of death and could be predicted with several perioperative variables, including preoperative intra-aortic balloon pump use, urgent surgery, and prolonged cardiopulmonary bypass. In particular, 3 potentially modifiable variables were also independently and strongly associated with AKI. These were preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration. Conclusions— AKI after cardiac surgery is highly prevalent and prognostically important. Therapies aimed at mitigating preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration may offer protection against this complication.

Antithrombotic and Thrombolytic Therapy for Valvular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND Antithrombotic therapy in valvular disease is important to mitigate thromboembolism, but the hemorrhagic risk imposed must be considered. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS In rheumatic mitral disease, we recommend vitamin K antagonist (VKA) therapy when the left atrial diameter is > 55 mm (Grade 2C) or when complicated by left atrial thrombus (Grade 1A). In candidates for percutaneous mitral valvotomy with left atrial thrombus, we recommend VKA therapy until thrombus resolution, and we recommend abandoning valvotomy if the thrombus fails to resolve (Grade 1A). In patients with patent foramen ovale (PFO) and stroke or transient ischemic attack, we recommend initial aspirin therapy (Grade 1B) and suggest substitution of VKA if recurrence (Grade 2C). In patients with cryptogenic stroke and DVT and a PFO, we recommend VKA therapy for 3 months (Grade 1B) and consideration of PFO closure (Grade 2C). We recommend against the use of anticoagulant (Grade 1C) and antiplatelet therapy (Grade 1B) for native valve endocarditis. We suggest holding VKA therapy until the patient is stabilized without neurologic complications for infective endocarditis of a prosthetic valve (Grade 2C). In the first 3 months after bioprosthetic valve implantation, we recommend aspirin for aortic valves (Grade 2C), the addition of clopidogrel to aspirin if the aortic valve is transcatheter (Grade 2C), and VKA therapy with a target international normalized ratio (INR) of 2.5 for mitral valves (Grade 2C). After 3 months, we suggest aspirin therapy (Grade 2C). We recommend early bridging of mechanical valve patients to VKA therapy with unfractionated heparin (DVT dosing) or low-molecular-weight heparin (Grade 2C). We recommend long-term VKA therapy for all mechanical valves (Grade 1B): target INR 2.5 for aortic (Grade 1B) and 3.0 for mitral or double valve (Grade 2C). In patients with mechanical valves at low bleeding risk, we suggest the addition of low-dose aspirin (50-100 mg/d) (Grade 1B). In valve repair patients, we suggest aspirin therapy (Grade 2C). In patients with thrombosed prosthetic valve, we recommend fibrinolysis for right-sided valves and left-sided valves with thrombus area < 0.8 cm(2) (Grade 2C). For patients with left-sided prosthetic valve thrombosis and thrombus area ≥ 0.8 cm(2), we recommend early surgery (Grade 2C). CONCLUSIONS These antithrombotic guidelines provide recommendations based on the optimal balance of thrombotic and hemorrhagic risk.

Clinical benefit of steroid use in patients undergoing cardiopulmonary bypass: a meta-analysis of randomized trials

We sought to establish the efficacy and safety of prophylactic steroids in adult patients undergoing cardiopulmonary bypass (CPB). We performed a meta-analysis of randomized trials reporting the effects of prophylactic steroids on clinical outcomes after CPB. Outcomes examined were mortality, myocardial infarction, neurological events, new onset atrial fibrillation, transfusion requirements, postoperative bleeding, duration of ventilation, intensive care unit (ICU) stay, hospital stay, wound complications, gastrointestinal complications, and infectious complications. We included 44 trials randomizing 3205 patients. Steroids reduced new onset atrial fibrillation [relative risk (RR) 0.71, 95% confidence interval (CI) 0.59 to 0.87], postoperative bleeding [weighted mean difference (WMD) -99.6 mL, 95% CI -149.8 to -49.3], and duration of ICU stay (WMD -0.23 days, 95% CI -0.40 to -0.07). Length of hospital stay was also reduced (WMD -0.59 days, 95% CI -1.17 to -0.02), but this result was less robust. A trend towards reduction in mortality was observed (RR 0.73, 95% CI 0.45 to 1.18). Randomized trials suggest that perioperative steroids have significant clinical benefit in CPB patients by decreasing the risk of new onset atrial fibrillation, while results are encouraging for reducing bleeding, length of stay, and mortality. These data do not raise major safety concerns, however, a sufficiently powered trial is warranted to confirm or refute these findings.

Very Long-Term Survival Implications of Heart Valve Replacement With Tissue Versus Mechanical Prostheses in Adults <60 Years of Age

Background— Several centers favor replacing a diseased native heart valve with a tissue rather than a mechanical prosthesis, even in younger adult patients. However, long-term data supporting this approach are lacking. We examined the survival implications of selecting a tissue versus a mechanical prosthesis at initial left-heart valve replacement in a cohort of adults <60 years of age who were followed for over 20 years. Methods and Results— Comorbid and procedural data were available from 6554 patients who underwent valve replacement at our institution over the last 35 years. Of these, 1512 patients contributed follow-up data beyond 20 years, of whom 567 were adults <60 years of age at first left-heart valve operation (mean survivor follow-up, 24.0±3.1 years). Late outcomes were examined with Cox regression. Valve reoperation, often for prostheses that are no longer commercially available, occurred in 89% and 84% of patients by 20 years after tissue aortic and mitral valve replacement, respectively, and was associated with a mortality of 4.3%. There was no survival difference between patients implanted with a tissue versus a mechanical prosthesis at initial aortic valve replacement (hazard ratio 0.95; 95% CI: 0.7, 1.3; P=0.7). For mitral valve replacement patients, long-term survival was poorer than after aortic valve replacement (hazard ratio 1.4; 95% CI: 1.1, 1.8; P=0.003), but again no detrimental effect was associated with use of a tissue versus a mechanical prosthesis (hazard ratio 0.9; 95% CI 0.5, 1.4; P=0.5). Conclusions— In our experience, selecting a tissue prosthesis at initial operation in younger adults does not negatively impact survival into the third decade of follow-up, despite the risk of reoperation.

The Cardiotomy Trial: A Randomized, Double-Blind Study to Assess the Effect of Processing of Shed Blood During Cardiopulmonary Bypass on Transfusion and Neurocognitive Function

Background— Reinfusion of unprocessed cardiotomy blood during cardiac surgery can introduce particulate material into the cardiopulmonary bypass circuit, which may contribute to postoperative cognitive dysfunction. On the other hand, processing of this blood by centrifugation and filtration removes coagulation factors and may potentially contribute to coagulopathy. We sought to evaluate the effects of cardiotomy blood processing on blood product use and neurocognitive functioning after cardiac surgery. Methods and Results— Patients undergoing coronary and/or aortic valve surgery using cardiopulmonary bypass were randomized to receive unprocessed blood (control, n=134) or cardiotomy blood that had been processed by centrifugal washing and lipid filtration (treatment, n=132). Patients and treating physicians were blinded to treatment assignment. A strict transfusion protocol was followed. Blood transfusion data were analyzed using Poisson regression models. The treatment group received more intraoperative red blood cell transfusions (0.23±0.69 U versus 0.08±0.34 U, P=0.004). Both red blood cell and nonred blood cell blood product use was greater in the treatment group and postoperative bleeding was greater in the treatment group. Patients were monitored intraoperatively by transcranial Doppler and they underwent neuropsychometric testing before surgery and at 5 days and 3 months after surgery. There was no difference in the incidence of postoperative cognitive dysfunction in the 2 groups (relative risk: 1.16, 95% CI: 0.86 to 1.57 at 5 days postoperatively; relative risk: 1.05, 95% CI: 0.58 to 1.90 at 3 months). There was no difference in the quality of life nor was there a difference in the number of emboli detected in the 2 groups. Conclusions— Contrary to expectations, processing of cardiotomy blood before reinfusion results in greater blood product use with greater postoperative bleeding in patients undergoing cardiac surgery. There is no clinical evidence of any neurologic benefit with this approach in terms of postoperative cognitive function.

Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery

Background— This observational study sought to identify the off-label use pattern of recombinant activated factor VII (rFVIIa) in cardiac surgery and to identify predictors of its effectiveness and risk. Methods and Results— At 18 Canadian centers, 522 nonhemophiliac cardiac surgical patients received rFVIIa during the period 2003 through 2006; data were available, and retrospectively collected, on 503 patients. The median (quartile 1, quartile 3) units of red blood cells transfused from surgery to therapy and in the 24 hours after therapy were 8 (5, 12) and 2 (1, 5), respectively (P<0.0001). Mortality rate was 32%, and mortality or major morbidity rate was 44%. These rates were within expected ranges (mortality, 27% to 35%; mortality or morbidity, 39% to 48%), which were calculated with a separate cohort of cardiac surgical patients who did not receive rFVIIa used as reference. Independent predictors of complications included instability before therapy (multiple inotropes or intra-aortic balloon pump) and increasing red blood cell units transfused before and after therapy. Variables independently associated with nonresponse included abnormal coagulation parameters and >15 red blood cell units transfused before therapy. Conclusions— In Canada, rFVIIa is used primarily when standard interventions have failed to control bleeding. In this setting, rFVIIa is associated with reduced blood product transfusions and, after risk adjustment, does not appear to be associated with increased or decreased complication rates. The effectiveness of the drug may be enhanced if it is given early in the course of refractory blood loss in the setting of adequate amounts of circulating coagulation factors.

Reoperation of Left Heart Valve Bioprostheses According to Age at Implantation

Background— Evidence supporting the use of bioprostheses for heart valve replacement in young adults is accumulating. However, reoperation data, which may help guide clinical decision making in young patients, remains poorly defined in the literature. Methods and Results— We examined the need for reoperation in 3975 patients who underwent first-time bioprosthetic aortic valve replacement (AVR) (n=3152) or mitral valve replacement (MVR) (n=823). There were 895 patients below the age of 60 years at bioprosthesis implant (AVR, n=636; MVR, n=259). The median interval to reoperation of contemporary, stented aortic bioprostheses was 7.74 years (95% CI 7.28 to 9.97 years) in patients less than 40 years, and 12.93 years (95% CI 11.10 to 15.76 years) in patients between 40 and 60 years of age. Multivariable risk factors associated with reoperation following bioprosthetic AVR include age (hazard ratio [HR] 0.94 per year, 95% CI 0.91 to 0.96, P<0.001) and concomitant coronary artery bypass grafting (HR 0.34, 95% CI 0.11 to 0.99, P=0.04). The median interval to reoperation of contemporary mitral bioprostheses was 8.11 years (95% CI 5.79 to 16.50 years) in patients less than 40 years, and 10.14 years (95% CI 8.64 to 11.14 years) in patients between 40 and 60 years of age. As for AVR, age (HR 0.96 per year, 95% CI 0.95 to 0.98, P<0.001) and concomitant coronary artery bypass grafting (HR 0.55, 95% CI 0.32 to 0.93, P=0.03) were associated with decreased reoperation risk following bioprosthetic MVR. Conclusions— These data constitute clinically relevant age-specific prognostic information regarding reoperation in young patients, who may wish to select a bioprosthesis at initial left heart valve replacement.

The inflammatory response to cardiopulmonary bypass: a therapeutic overview.

The demographic of cardiac surgery patients continues to evolve to include older, sicker candidates, all the while maintaining an expectation of excellent outcomes. These latter results can only be achieved by the parallel advancement and re-examination of the technology of cardiopulmonary bypass (CPB); the key tool used daily by surgical teams worldwide. In this review, we will provide an overview of integrated therapeutic strategies that can be utilized to minimize the complex and myriad changes related to inflammation after CPB with the understanding that this may abrogate the detrimental end-organ and systemic effects of blood activation. Therapeutic strategies specifically related to the technology can be classified into those targeting biomaterial dependent or independent processes. The former can be addressed by the utilization of currently available biocompatible surfaces such as with heparin-coated circuits, phosphorylcholine-coated circuits (‘biomembrane mimicry’) and circuits composed of copolymers containing surface-modifying additives. The most important strategies related to biomaterial independent activation include the modification of techniques related to cardiotomy blood management and blood filtration. Finally, all of these strategies must be integrated and tailored with complementary pharmacologic agents such as aprotinin and steroids to optimize anti-inflammatory synergism. Only if we are armed with a comprehensive knowledge of the molecular and cellular basis for these strategies will we be able to continue to evolve our treatment in parallel with our patients to achieve these goals.

Effects of Mild Hypothermia and Rewarming on Renal Function After Coronary Artery Bypass Grafting

BACKGROUND Hypothermia is a potential strategy for visceral organ protection during cardiopulmonary bypass (CPB). We report data from two randomized studies evaluating mild hypothermia and rewarming on postoperative renal function in cardiac surgical patients. METHODS Patients undergoing nonemergency, isolated coronary artery bypass grafting were enrolled into two studies. In the first, 223 patients were cooled to 32 degrees C during CPB and randomly assigned to rewarming to 37 degrees C (RW-37 degrees) or 34 degrees C (RW-34 degrees). The second study randomized 267 patients to sustained mild hypothermia at 34 degrees C (S-34 degrees) or normothermia (S-37 degrees) without rewarming. Serum creatinine levels were measured. Creatinine clearance was calculated. Significant renal dysfunction was defined as a 25% increase in serum creatinine or a 25% decrease in creatinine clearance postoperatively. RESULTS Postoperative serum creatinine levels were persistently higher in the RW-37 degrees patients than in the RW-34 degrees group (p < 0.01). RW-37 degrees patients had a higher incidence of renal dysfunction (17%) than RW-34 degrees patients (9%, p = 0.07). Sustained mild hypothermia had no beneficial effect on postoperative serum creatinine levels (p = 0.44) or significant renal dysfunction: S-34 degrees, 20% vs S-37 degrees, 15% (p = 0.28). Diabetes (odds ratio [OR], 1.6; 95% confidence interval [CI] 1.3 to 2.1), prolonged CPB time (OR, 1.1; 95% CI, 1.0 to 1.2), and rewarming (OR, 1.4; 95% CI, 1.0 to 1.9) were independent risk factors for significant renal dysfunction. Renal dysfunction was associated with longer hospital stay (8.4 +/- 0.8 vs 6.8 +/- 04 days, p < 0.001). CONCLUSIONS Sustained mild hypothermia does not improve renal outcome. However, rewarming on CPB is associated with increased renal injury and should be avoided.

Relationship Between Preventability of Death After Coronary Artery Bypass Graft Surgery and All-Cause Risk-Adjusted Mortality Rates

Background— The goal of this study was to determine the relationship between all-cause, risk-adjusted, in-hospital mortality after coronary artery bypass graft surgery and the proportion of preventable in-hospital deaths as a measure of quality of care at an institution level. Methods and Results— We conducted a retrospective analysis of 347 randomly selected in-hospital deaths after isolated coronary artery bypass graft surgery at 9 institutions in Ontario over the period of 1998 to 2003. Nurse-abstracted chart summaries were reviewed by 2 experienced cardiac surgeons who were blinded to patient, surgeon, and hospital and used a standardized implicit tool to identify preventable death. A third reviewer reassessed all cases in which the first 2 reviewers disagreed. Rates of preventable deaths were estimated for each hospital and compared with all-cause mortality rates. A structured adverse event audit completed by each surgeon-reviewer was used to identify quality improvement opportunities for the preventable deaths. A total of 111 of 347 deaths (32%) were judged preventable despite a low risk-adjusted mortality range (1.3% to 3.1%) across hospitals. No significant correlation was found between all-cause, risk-adjusted in-hospital mortality rates and the proportion of preventable deaths at the hospital level (Spearman coefficient, −0.42; P=0.26). A large proportion of preventable deaths were related to problems in the operating room (86%) and intensive care unit (61%). Many deaths were associated with deviations in perioperative care (32% based on concurrence of 2 reviewers, and another 42% in cases in which 1 reviewer reached that opinion). Conclusions— Approximately one third of in-hospital coronary artery bypass graft deaths were judged preventable by surgeon reviewers. All-cause risk-adjusted mortality rates are convenient measures of institutional quality of care but were not correlated with preventable mortality in our jurisdiction. Providers should conduct detailed adverse event audits to drive meaningful improvements in quality.