Thorsten Wittwer

Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30 000 patients

AIMS To determine the strength of evidence for preoperative statin use for prevention of adverse postoperative outcomes in patients undergoing cardiac surgery. METHODS AND RESULTS After literature search in major databases, 19 studies were identified [three RCT (randomized prospective clinical trials), 16 observational] that reported outcomes of 31 725 cardiac surgery patients with (n = 17 201; 54%) or without (n = 14 524; 46%) preoperative statin therapy. Outcomes that were analysed included early all-cause mortality (30-day mortality), myocardial infarction (MI), atrial fibrillation (AF), stroke and renal failure. Odds ratio (OR) with 95% confidence intervals (95%CI) were reported using fixed or random effect models and publication bias was assessed. Preoperative statin therapy resulted in a 1.5% absolute risk reduction (2.2 vs. 3.7%; P < 0.0001) and 43% odds reduction for early all-cause mortality (OR 0.57; 95%CI: 0.49-0.67). A significant reduction (P < 0.01) in statin pretreated patients was also observed for AF (24.9 vs. 29.3%; OR 0.67, 95%CI: 0.51-0.88), stroke (2.1 vs. 2.9%, OR 0.74, 95%CI: 0.60-0.91), but not for MI (OR 1.11; 95%CI: 0.93-1.33) or renal failure (OR 0.78, 95%CI: 0.46-1.31). Funnel plot and Eggers regression analysis (P = 0.60) excluded relevant publication bias. CONCLUSION Our meta-analysis provides evidence that preoperative statin therapy exerts substantial clinical benefit on early postoperative adverse outcomes in cardiac surgery patients, but underscores the need for RCT trials.

Statins for prevention of atrial fibrillation after cardiac surgery: a systematic literature review

OBJECTIVE To determine the strength of evidence of preoperative statin therapy for prevention of atrial fibrillation after cardiac surgery. METHODS A meta-analysis was performed of randomized controlled trials and observational trials reporting the impact of preoperative statin therapy on the incidence of any type and new-onset atrial fibrillation after cardiac surgery. Unadjusted and adjusted treatment effects (odds ratio, 95% confidence intervals) were pooled using a random-effects model, and publication bias was assessed. RESULTS Thirteen studies were identified (3 randomized controlled trials, 10 observational trials) that reported the incidence of postoperative atrial fibrillation in 17,643 patients having cardiac surgery with (n = 10,304; 58%) or without (n = 7339; 42%) preoperative statin use. New-onset atrial fibrillation was reported in a total of 7855 patients. Postoperative incidence rates for any or new-onset atrial fibrillation were 24.6% and 29.9%, respectively. Preoperative statin use resulted in a 22% and 34% unadjusted odds reduction for any atrial fibrillation (odds ratio, 0.78; 95% confidence interval, 0.67-0.90) or new-onset atrial fibrillation (odds ratio, 0.66; 95% confidence interval, 0.51-0.84) after surgery (P < .001). Relevant publication bias and an unequal distribution of confounding variables favoring patients treated with statins were identified. Nevertheless, the beneficial actions of statins on atrial fibrillation persisted after pooled analysis of risk-adjusted treatment effects from randomized controlled trials and observational trials (any atrial fibrillation-odds ratio, 0.64; 95% confidence interval, 0.48-0.87; new-onset atrial fibrillation-odds ratio, 0.66; 95% confidence intervals, 0.48-0.89; P < .01). CONCLUSION Our meta-analysis provides evidence that preoperative statin therapy is associated with a reduction in the incidence of atrial fibrillation after cardiac surgery.

Marginal donor grafts in heart transplantation: lessons learned from 25 years of experience

Heart transplantation represents an established procedure in end‐stage heart failure patients and results in satisfying long‐term results. However, this surgical therapy is continuously limited by severe and progredient donor organ shortage in the last years. Therefore, adequate and optimal utilization of all suitable donor organs is mandatory to increase graft availability. Evidence exists that certain ‘standard’ donor criteria can be significantly liberalized to increase the available donor pool by accepting ‘Marginal Donors’ who would, under conventional transplant guidelines, be declined as potential organ donors. The aim of this study was to review the available literature with regard to definitions and experiences with ‘marginal’ donor hearts and to discuss critically the controversies of numerous entities of donor criteria, which might be successfully liberalized. This review is thought to give an up‐to‐date overview of a modern concept of cardiac allograft acceptance based on a 25‐year experience with heart transplantation.

Off-bypass coronary bypass grafting via minithoracotomy using mechanical epicardial stabilization.

BACKGROUND Minimally or less invasive surgical coronary revascularization has gained increasing interest along with new techniques and devices designed for easier and safer procedures. Until recently, it appeared questionable whether grafting techniques with avoidance of cardiopulmonary bypass techniques would allow adequate results compared with conventional techniques using cardioplegic arrest. METHODS Since June 1996, minimally invasive direct coronary artery bypass grafting procedures without cardiopulmonary bypass were intended in 24 patients (19 male, 5 female; age, 60.5 +/- 10.5 years) applying a special system (CardioThoracic Systems, Inc) for internal mammary artery access and epicardial surface stabilization approaching through an anterolateral minithoracotomy. Neither video-assisted preparation nor additional pharmacologic stabilization was applied. Concomitant risk factors and associated comorbidity were frequent. RESULTS The procedure was completed in 23 patients, grafting the left anterior descending coronary artery (n = 21) or diagonal branches (n = 3, 1 sequential) as scheduled. In 1 case with internal mammary artery dissection, cardiopulmonary bypass and sternotomy became necessary. Simultaneous carotid endarterectomy was performed in 1 patient. There were two episodes of intraoperative ventricular fibrillation; no other major complications occurred. Postoperative evaluation was obtained in 16 patients (15 by angiography, 1 by Doppler echocardiography) so far and revealed adequate graft function and patency. CONCLUSIONS Using specially designed instruments for internal mammary artery access and epicardial surface stabilization, minimally invasive direct coronary artery bypass grafting procedures via a minithoracotomy avoiding cardiopulmonary bypass techniques may be applied safely and successfully, even in increased risk constellations.

Mycophenolate and sirolimus as calcineurin inhibitor-free immunosuppression improves renal function better than calcineurin inhibitor-reduction in late cardiac transplant recipients with chronic renal failure.

Background. Calcineurin-inhibitor-(CNI)-induced renal failure is one major cause of morbidity in cardiac transplantation (HTx). In this prospective, randomized, multicenter trial, the impact of immunosuppressive conversion toward CNI-free (mycophenolate mofetil [MMF] and sirolimus) or a CNI-reduced immunosuppressive regimen on renal function, efficacy, and safety was evaluated. Methods. Since 2004, 63 HTx-patients (0.5–18.4 years after HTx) with CNI-based immunosuppression and reduced creatinine clearance less than 60 mL/min (39±15 mL/min) were included in this trial. Patients in the CNI-free-Group (group 1) were converted to sirolimus that was started with 2 mg/day until target trough levels (8–14 ng/mL) were achieved. Subsequently, CNIs were withdrawn. In CNI-reduction-Group (group 2), CNI target trough levels were reduced by 40%. In both groups MMF was continued and trough level adjusted (1.5–4 &mgr;g/mL). Results. Patients demographics and survival (mean follow-up time: 16.7±9 months) was equal (100%). Renal function improved significantly after complete CNI withdrawal while remaining unchanged with CNI-reduction (Creatinine clearance after 12 months: 53±24 mg/dL [group 1] vs. 38±20 mg/dL [group 2], P=0.01). End-stage renal failure (hemodialysis) was avoided by CNI-withdrawal and occurred only after CNI reduction (n=6; P=0.01). Acute rejection episodes were more common in group 2 (4 vs. 2). Graft function remained stable (echocardiography) within both groups. Adverse events were more common in group 1 (65%) than in group 2 (n=40%) and were responsible for discontinuation in 4 and 0 cases, respectively. Conclusions. Conversion toward a CNI-free immunosuppression (Mycophenolate, sirolimus) is superior to CNI-reduced immunosuppression in improving renal failure in late HTx-recipients. However, this benefit is relativized by the increased incidence and severity of sirolimus/MMF-associated side effects.

Application of ECMO in Multitrauma Patients With ARDS as Rescue Therapy

Abstract  Background: Despite recent advances in critical care management, the mortality of acute respiratory distress syndrome (ARDS) remains high. The final rescue therapy for patients with severe hypoxia refractory to conventional therapy modalities is the extracorporeal gas exchange. Methods: We report the management of three polytraumatized patients with life‐threatening injuries, severe blunt thoracic trauma, and consecutive ARDS treating by extracorporeal membrane oxygenation (ECMO). Two patients suffered a car accident with severe lung contusion and parenychmal bleeding. Bronchial rupture and mediastinal emphysema was found in one of them. Another patient developed ARDS after attempted suicide with multiple fractures together with blunt abdominal and thoracic trauma. Results: All patients were placed on ECMO and could be rapidly stabilized. They were weaned from ECMO after a mean of 114 ± 27 hours of support without complications, respectively. Mean duration of ICU stay was 37 ± 23 days. Conclusions: Quick encouragement of ECMO for the temporary management of gas exchange may increase survival rates in trauma patients with ARDS.

Caspofungin as First-Line Therapy for the Treatment of Invasive Aspergillosis After Thoracic Organ Transplantation

INTRODUCTION Although amphotericin was the gold standard in the treatment of invasive aspergillosis in transplant recipients, nephrotoxicity and lack of efficacy often limits its use. Itraconazole is better tolerated but less efficacious and influences immunosuppressant trough levels significantly. We report our first clinical experience with the use of caspofungin as first-line therapy in heart and lung transplant recipients with invasive aspergillosis. METHODS Caspofungin was administered at 50 to 70 mg/day in heart and lung transplant recipients with renal impairment while invasive aspergillosis was diagnosed and classified. Aspergillus serology, serologic inflammatory markers, and X-rays were taken to monitor infectious activity. Creatinine and immunosuppressant trough levels were monitored closely. RESULTS Invasive aspergillosis was diagnosed by chest X-ray, serology, and positive sputum in 1 heart-lung, 7 heart, and 4 single-lung transplant recipients, and caspofungin was administered for a mean time of 21 +/- 9 days. Basic immunosuppressants were tacrolimus in 9 patients or cyclosporine in 3. Complete remission was achieved in 10 patients (83%). Adverse effects of caspofungin were fever in 6, diarrhea in 3, and neutropenia in 1. Renal function remained stable (3.2 +/- 1 mg/dl before vs 2.3 +/- 0.9 mg/dl after, p = 0.07). Trough levels of all immunosuppressants did not change significantly during caspofungin treatment (10.9 +/- 4.1 ng/ml before vs 9.9 +/- 4.0 ng/ml after [p = 0.31] for tacrolimus; 214 +/- 98 ng/ml before vs 229 +/- 88 ng/ml after [p = 0.41] for cyclosporin A), while the administered dosage remained stable. CONCLUSION In heart and lung transplant recipients with invasive aspergillosis, caspofungin seemed to be an effective anti-fungal agent with a promising safety profile. Further prospective randomized trials are needed to investigate an advantageous role of caspofungin in the treatment of invasive aspergillosis.

Minimally invasive coronary artery revascularization on the beating heart

BACKGROUND The quality of surgical beating heart revascularization is frequently questioned, especially when the surgical access is limited. Nevertheless, the number of off-pump coronary procedures is expanding worldwide. METHODS Since getting started with minimally invasive direct coronary artery bypass to anterior myocardial vessels in June 1996, 306 patients received left internal mammary artery grafting through an anterior minithoracotomy. Risk increasing comorbidities were present in 168 of them. Particular attention was paid to early postoperative angiographic results and complications. RESULTS The 30-day mortality summed up at 1.0% and was limited to patients with additional risks for conventional bypass grafting. Early postoperative control angiographies in 232 patients confirmed a global patency rate of 97.8%, revealing in addition four unexpected malinsertions to diagonal branches. In surviving patients major complications like myocardial infarction, stroke, or multiorgan failure were completely absent. CONCLUSIONS Minimally invasive direct coronary artery bypass grafting appears to allow for a safe and effective revascularization of the left anterior descending artery by use of the left internal mammary artery. Especially patients with risk increasing comorbidities should benefit from this approach, provided the surgical indication based on a dominating left anterior descending artery lesion. Angiographic minimally invasive direct coronary artery bypass results seem to fulfill the expectations generated by results obtained in conventional left internal mammary artery grafting and appear to be superior to interventional means.

Conversion to sirolimus and mycophenolate can attenuate the progression of bronchiolitis obliterans syndrome and improves renal function after lung transplantation.

Background. Bronchiolitis obliterans syndrome (BOS) is the major problem after lung and heart-lung transplantation (LTx/HLTx). Sirolimus (Sir) and Mycophenolate (MMF) showed a promising efficacy in the treatment of BOS in animal models. The first clinical experience in converting LTx/HLTx-recipients with BOS from calcineurin inhibitor-(CNI)-based immunosuppression to a Sir-MMF based immunosuppression is reported herein. Methods. Six LTx- and five HLTx-recipients (eight men; 0.9 to 8 years after transplantation) with CNI-based immunosuppression (plus MMF) in whom BOS was diagnosed were included in the study. Mean patient age was 37±13 years (range 17–62 years). Sir was started with 6 mg and continued adjusted to according target trough levels (8-14 ng/ml). Subsequently, the CNIs were tapered down and finally stopped. Follow up included self determined pulmonary function tests, microbiological screening, chest radiographs, and laboratory studies Results. Two acute rejection episodes occurred during the study period. The incidence of infection was 2.2±1.3 infections/patient-year after conversion. Mean FEV1 decreased after a mean follow up of 14.8±1.4months: from 2.1±0.7l prior conversion to 1.3±0.6l after conversion (P=0.03). However, graft function remained stable in three patients and progression of BOS slowed down in three patients. Overall, 2 of 10 patients died due to ongoing BOS while awaiting retransplantation Conclusions. After BOS was diagnosed, conversion to MMF and Sir stabilized graft function only in some of the converted patients. Therefore, earlier administration of Sir-based immunosuppression might be a more promising approach. Whether conversion to CNI-free immunosuppression can actually ameliorate the extent or progression of BOS has to be investigated in randomized trials.

Impact of PAF antagonist BN 52021 (Ginkolide B) on post-ischemic graft function in clinical lung transplantation

BACKGROUND Platelet activating factor (PAF) is associated with ischemia/reperfusion injury (I/R) after lung transplantation. Following promising experimental results, this prospective trial investigated the potential effect of PAF antagonist BN 52021 (ginkolide B) on clinical Euro-Collins (EC)-based lung preservation. METHODS We analyzed 8 double-lung transplant patients in each of 3 groups. In the low-dose group (LDG), donor lungs were perfused with EC containing 2 mg/kg BN 52021, whereas we used 10 mg/kg in the high-dose group (HDG) and placebo in the control group (CG). Before reperfusing the first lung, we administered intravenously 120 mg BN 52021 (LDG), 600 mg BN 52021 (HDG), or placebo (CG). Hemodynamics in terms of pulmonary arterial pressure, pulmonary vascular resistance and serial determinations of the alveolo-arterial oxygen difference (AaDO(2)) were recorded. We measured blood levels of PAF pre-operatively and post-operatively, after 10 minutes and after 3, 8, 24, 48, and 144 hours. RESULTS Within 32 hours, we noted a tendency toward better AaDO(2) in the LDG and the HDG compared with the CG (p > 0.05). We observed a significant improvement of AaDO(2) after 3 hours (HDG, p = 0.033) and 8 hours (LDG, p = 0.024), with poorest values in the CG. The PAF concentrations were lowest in the HDG, with significant deterioration 10 minutes after reperfusion. In contrast, placebo led to higher PAF levels. We measured significantly lower PAF concentrations (HDG vs CG) at 10 minutes and at 6 days post-operatively. CONCLUSIONS Use of high-dose PAF antagonist BN 52021 can easily be combined with clinical preservation methods and may help optimize pulmonary function with reduced PAF levels, in the early post-ischemic period.