Multicentre double-blind randomized controlled trial of perhexiline as a metabolic modulator to augment myocardial protection in patients with left ventricular hypertrophy undergoing cardiac surgery.

OBJECTIVES: Patients undergoing cardiac surgery require adequate myocardial protection. Manipulating myocardial metabolism may improve the extent of myocardial protection. Perhexiline has been shown to be an effective anti-anginal agent due to its metabolic modulation properties by inhibiting the uptake of free fatty acids into the mitochondrion, and thereby promoting a more efficient carbohydrate-driven myocardial metabolism. Metabolic modulation may augment myocardial protection, particularly in patients with left ventricular hypertrophy (LVH) known to have a deranged metabolic state and are at risk of poor postoperative outcomes. This study aimed to evaluate the role of perhexiline as an adjunct in myocardial protection in patients with LVH secondary to aortic stenosis (AS), undergoing an aortic valve replacement (AVR). METHODS: In a multicentre double-blind randomized controlled trial of patients with AS undergoing AVR ± coronary artery bypass graft surgery, patients were randomized to preoperative oral therapy with either perhexiline or placebo. The primary end point was incidence of inotrope use to improve haemodynamic performance due to a low cardiac output state during the first 6 h of reperfusion, judged by a blinded end points committee. Secondary outcome measures included haemodynamic measurements, electrocardiographic and biochemical markers of new myocardial injury and clinical safety outcome measures. RESULTS: The trial was halted early on the advice of the Data Safety and Monitoring Board. Sixty-two patients were randomized to perhexiline and 65 to placebo. Of these, 112 (54 perhexiline and 48 placebo) patients received the intervention, remained in the trial at the time of the operation and were analysed. Of 110 patients who achieved the primary end point, 30 patients (16 perhexiline and 14 placebo) had inotropes started appropriately; there was no difference in the incidence of inotrope usage OR of 1.65 [confidence interval (CI): 0.67-4.06] P = 0.28. There was no difference in myocardial injury as evidenced by electrocardiogram odds ratio (OR) of 0.36 (CI: 0.07-1.97) P = 0.24 or postoperative troponin release. Gross secondary outcome measures were comparable between the groups. CONCLUSIONS: Perhexiline as a metabolic modulator to enhance standard myocardial protection does not provide an additional benefit in haemodynamic performance or attenuate myocardial injury in the hypertrophied heart secondary to AS. The role of perhexiline in cardiac surgery is limited.

Clinical outcomes of Carbomedics Top Hat valve with a robust follow-up system.

AIM: Late failure of bioprosthetic valves may limit their use in patients < 60 years. The superior hemodynamic performance offered by the Carbomedics Top Hat supraannular valve enables greater effective orifice areas to be achieved. The aim of this study was to assess the clinical outcomes of this valve, using a robust follow-up system. METHODS: Patients who underwent aortic valve replacement with or without coronary artery bypass grafting between July 1997 and January 2010 with Carbomedics supraannular Top Hat valves were identified. Details of readmissions and late deaths were obtained from the National Hospital Episodes Statistics data and the Office of National Statistics, tracked by the Quality and Outcomes Research Unit. Late complications associated with this prosthesis were evaluated. RESULTS: Of 253 patients identified, 181 underwent isolated aortic valve replacement and 72 had aortic valve replacement with coronary artery bypass grafting. The 30-day mortality was 1.6%, and 5- and 10-year survival rates were 91.4% and 80.5%, respectively. Detailed readmission data were available after 2001 (n = 170). Two (1.2%) patients required reoperation for endocarditis and pannus formation. Of the 17 late deaths in this subset, 4 were attributable to cardiac causes. One patient was treated for heart failure, and 2 developed bleeding complications. CONCLUSIONS: Implantation of the Carbomedics Top Hat supraannular valve in our unit resulted in satisfactory in-hospital and midterm survival with low incidences of endocarditis and late heart failure.

The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics. RESULTS: Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56-1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07-0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34-0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis. CONCLUSIONS: Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery. CLINICALTRIALSGOV ID: NCT00845364.

Stab to the chest causing severe great vessel injury.

Penetrating trauma has increased in developed and urban environments. Pulmonary artery injury is rare, but can be associated with significant morbidity. We report a case of delayed cardiac arrest following a stab injury to the chest. The patient had active great vessel bleeding and required extensive surgical intervention. Clinicians should have a high index of suspicion for life-threatening thoracic injuries following a stab injury to the chest, despite initial clinical stability or negative baseline radiological findings.

Subtle changes in renal function are associated with differences in late survival following adult cardiac surgery.

OBJECTIVES: To determine the predictors of post-operative renal function following adult cardiac surgery, and to assess the influence of this on late survival. METHODS: Prospectively collected data were analysed on 8032 patients who underwent coronary artery bypass grafting, valve surgery or combined procedures from 1 January 1998 until 31 December 2008, who did not require preoperative renal replacement therapy. The estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease formula accounting for ethnicity pre-operatively, post-operatively on the fourth post-operative day, and the post-operative nadir based upon the peak post-operative creatinine within 30 days of surgery. Late survival data were obtained from the UK Central Cardiac Audit Database (CCAD). Appropriate frailty analyses were conducted in R and model fit was compared using Aikaike's Information Criterion. Initial analysis intended to determine predictors of post-operative renal function including pre-operative eGFR, EuroSCORE and surgical procedure including the operative procedure and bypass time. Further analysis examined its influence on late survival. RESULTS: Median follow-up was 72 months (IQR 48-105) during which there were 904 late deaths. The most powerful predictor of the day 4 eGFR was the pre-operative eGFR but other factors contributed including increasing EuroSCORE and bypass time. The pre-operative eGFR was shown to be a strong and independent predictor of late outcome (P = 0.0001, HR 0.497 95%CI 0.434-564); however, model fit was significantly improved using the day 4 eGFR (P = 0.0001, HR 0.43 95%CI 0.385-0.482). No specific change in individual renal function was identified as a predictor of adverse late survival, and neither the pre-operative nor day 4 eGFR was predictive of the nadir of renal function. CONCLUSIONS: Subtle early changes in renal function at the time of surgery are powerful predictors of adverse late outcome and can be predicted by pre-operative renal function.

Which troponometric best predicts midterm outcome after coronary artery bypass graft surgery?

BACKGROUND: Various troponin I measurements (troponometrics) have been used as surrogate markers of patient outcome after coronary artery bypass grafting (CABG). Our aim was to define the postoperative troponometric best able to predict in-hospital and late mortality. METHODS: In 440 patients (seen from January 2000 to September 2004) undergoing isolated on-pump CABG with standardized anesthesia, perfusion, cardioplegia, and postoperative care, we followed all-cause mortality (census June 2009, 100% complete). Subjects underwent troponin I (cardiac troponin I [cTnI]) estimation at baseline and 6, 12, 24, 48, and 72 hours postoperatively, and individual time-point cTnI (T6, T12, T24, T48, T72), peak cTnI (Cmax), increase in cTnI between 6 and 12 hours (T↑6-12) and 6 and 24 hours (T↑6-24), cumulative area under the curve cTnI (CAUC24, CAUC48, and CAUC72), and cTnI≥13 ng·mL(-1) at any time point were each analyzed using univariate and multivariable Cox models to identify the probability of in-hospital and late death. Logistic EuroSCOREs and calculated creatinine clearance (CrCl) were also included. The Akaike information criterion (AIC) was used to determine goodness of fit. RESULTS: There were 62 of 440 deaths after a median (interquartile range) follow-up period of 7.0 (5.7 to 8.1) years. Univariate Cox analysis demonstrated T12, T24, T48, T72, T↑6-12, T↑6-24, standardized CAUC24, CAUC48, and CAUC72 each to be predictors of midterm mortality. On Cox multivariable analysis in models incorporating both logistic EuroSCOREs and CrCl, both T72 (hazard ratio [HR], 95% confidence interval [CI], 1.10 [1.06 to 1.14]; p<0.001) and CAUC72 (1.45 [1.26 to 1.62], p<0.001) were identified as independent predictors of mortality. Of these, CAUC72 was superior based on the lowest AIC. CONCLUSIONS: In myocardial protection studies, serial troponin I data should be collected until 72 hours postoperatively to calculate CAUC72, as this troponometric best predicts midterm mortality.

Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: results from the Hypertrophy, Insulin, Glucose, and Electrolytes (HINGE) trial.

BACKGROUND: Patients undergoing aortic valve replacement for critical aortic stenosis often have significant left ventricular hypertrophy. Left ventricular hypertrophy has been identified as an independent predictor of poor outcome after aortic valve replacement as a result of a combination of maladaptive myocardial changes and inadequate myocardial protection at the time of surgery. Glucose-insulin-potassium (GIK) is a potentially useful adjunct to myocardial protection. This study was designed to evaluate the effects of GIK infusion in patients undergoing aortic valve replacement surgery. METHODS AND RESULTS: Patients undergoing aortic valve replacement for aortic stenosis with evidence of left ventricular hypertrophy were randomly assigned to GIK or placebo. The trial was double-blind and conducted at a single center. The primary outcome was the incidence of low cardiac output syndrome. Left ventricular biopsies were analyzed to assess changes in 5' adenosine monophosphate-activated protein kinase (AMPK), Akt phosphorylation, and protein O-linked ß-N-acetylglucosamination (O-GlcNAcylation). Over a 4-year period, 217 patients were randomized (107 control, 110 GIK). GIK treatment was associated with a significant reduction in the incidence of low cardiac output state (odds ratio, 0.22; 95% confidence interval, 0.10 to 0.47; P=0.0001) and a significant reduction in inotrope use 6 to 12 hours postoperatively (odds ratio, 0.30; 95% confidence interval, 0.15 to 0.60; P=0.0007). These changes were associated with a substantial increase in AMPK and Akt phosphorylation and a significant increase in the O-GlcNAcylation of selected protein bands. CONCLUSIONS: Perioperative treatment with GIK was associated with a significant reduction in the incidence of low cardiac output state and the need for inotropic support. This benefit was associated with increased signaling protein phosphorylation and O-GlcNAcylation. Multicenter studies and late follow-up will determine whether routine use of GIK improves patient prognosis.

N-terminal pro-brain-type natriuretic peptide: a biochemical surrogate of cardiac function in the potential heart donor.

OBJECTIVES: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is elevated in subarachnoid haemorrhage, brainstem death (BSD) and heart failure. We examined the relationship between NT-proBNP and cardiac functional status after BSD and left ventricular (LV) BNP precursor gene expression. METHODS: We assayed NT-proBNP in the serum of potential heart donors investigated with pulmonary artery flotation catheters, transthoracic echocardiography and cardiac troponin (cTn) I and T. After 6.9 h of optimisation, haemodynamic studies were repeated to determine haemodynamic functional suitability for transplantation. Median (interquartile range (IQR)) NT-proBNP levels are reported according to initially measured dichotomised pulmonary capillary wedge pressure (PCWP), cardiac index (CI), indexed cardiac power output (CPOi), left ventricular ejection fraction (LVEF), wall motion score (WMS), extravascular lung water index (EVLWI), cTnT and cTnI and end-management functional suitability. LV biopsies were snap-frozen, mRNA extracted and reverse-transcribed, allowing performance of Taqman real-time polymerase chain reaction assays of mRNA-BNP precursor. RESULTS: There were 79 subjects. Median NT-proBNP was 121 pg ml(-1) (range 5-4139) and levels correlated with time from coning (p<0.01, r=-0.379). Higher NT-proBNP was found in donors with PCWP >14 mmHg; 504 (120-1544) versus 101 (38-285); p=0.01; CI <2.4 l min(-1) m(-2) 410 (123-1511) versus 95 (37-264); p=0.001; CPOi <0.5 Wm(-2) 256 (78-694) versus 105 (37-315); p=0.02; LVEF <50% 231 (75-499) versus 72 (36-177); p=0.04; WMS >2; 343 (80-673) versus 99 (37-236); p=0.01; cTnT >0.1 microg ml(-1) 499 (127-967) versus 80 (36-173); p<0.001 and cTnI >1 mg ml(-1) 410 (97-684) versus 88 (36-190); p<0.01 and in hearts functionally unsuitable at end-optimisation; 189 (74-522) versus 85 (39-243); p=0.02. Hearts functionally suitable for transplantation expressed significantly less mRNA encoding for BNP precursor (0.19-fold; p=0.01). CONCLUSION: During or after BSD, NT-proBNP is released and the heart is a likely source. Higher NT-proBNP levels are associated with donor heart dysfunction and a failure to achieve haemodynamic functional suitability criteria. This supports the hypothesis that biomarkers, including NT-proBNP, may be useful in donor heart assessment.

Patient-prosthesis mismatch in patients with aortic stenosis undergoing isolated aortic valve replacement does not affect survival.

BACKGROUND: Data suggest that patient-prosthesis mismatch (PPM) adversely effects late survival after aortic valve replacement (AVR). This study examined the incidence and implications of PPM in patients undergoing isolated AVR. METHODS: Prospectively collected data on patients undergoing isolated AVR for aortic stenosis between January 1, 1997 and December 31, 2007 were analyzed. The projected effective valve orifice area from in vivo data was indexed to body surface area (EOAi). PPM was defined as moderate for EOAi of < or = 0.85 cm(2)/m(2) and severe if < or = 0.6 cm(2)/m(2). The reference group comprised patients with EOAi > 0.85 cm(2)/m(2). The effect of PPM on postoperative survival was assessed by multivariate analysis. RESULTS: Of 801 patients, PPM was severe in 48 (6.0%), moderate in 462 (57.8%), and nonexistent in 291 (36.4%). Mismatch was associated with increasing age and female gender, thus resulting in an increase in the EuroSCORE (reference group, 4.9 +/- 2.6; moderate PPM, 5.8 +/- 2.4; and severe PPM, 6.1+/-2.1; p < 0.001). PPM did not significantly increase hospital mortality. Four deaths occurred in the reference group (1.4%), 12 in the moderate PPM (2.6%), and none in the severe PPM group (p = 0.311). The 5-year survival estimates were 83% in reference, 86% in moderate PPM, and 89% in severe PPM (p = 0.25). By multivariate analysis, PPM was not an independent risk factor for reduced in-hospital or late survival. CONCLUSIONS: Moderate PPM is common in patients undergoing AVR for aortic stenosis, but severe mismatch is rare. Patients with PPM have similar early and late postoperative survival rate.

Echocardiography in the potential heart donor.

BACKGROUND: The relationship between echocardiographic left ventricular(LV) systolic function (E-function) and pulmonary artery catheter(PAC) assessment of hemodynamic function (H-function) in potential heart donors is ill defined. We investigated this and determined (a) whether optimization could improve abnormal E-function, (b) feasibility and usefulness of repeat transthoracic echocardiography (TTE), and (c) whether thyroid status and therapy affected E-function. MATERIALS AND METHODS: Transthoracic E-function imaging was performed at baseline and 4 hr in potential donors (enrolled in a randomized controlled trial of tri-iodothyronine+/-methylprednisolone [MP] therapy) undergoing PAC-guided algorithmic optimization. Images were analyzed post hoc for LV wall thickness, ejection fraction, and Tei index. RESULTS: The study comprised 66 donors. Both LV ejection fraction (LVEF) and LV-Tei correlated with cardiac index (CI; P<0.001), and LV Tei was most frequently measurable and repeatable(P=0.01). Normal LVEF independently predicted end-assessment H-functional suitability (odds ratio 1.05, 95% confidence interval 1.007-1.088 [P=0.021]) but had poor specificity. Initial subnormal E-function was identified in 29 of 66 of hearts, of which 58% (17/29) achieved H-function suitability criteria. In 52 hearts, repeat E-function assessment was possible. Nineteen of 52 had initially subnormal E-function, which improved in over half (53%). H-function could be manipulated to meet functional suitability criteria for transplant even without E-function change. Neither initial thyroid status nor hormonal therapy affected LV function. CONCLUSIONS: Echocardiography is possible in most potential heart donors. Normal E-function predicts hemodynamic suitability for transplantation but lacks specificity. More than 50% of hearts with subnormal E-function can attain hemodynamic transplantation criteria after donor management. Repeat echocardiography is feasible but has a limited role. Both initial echocardiography and PAC-guided management should be used routinely.

The proinflammatory environment in potential heart and lung donors: prevalence and impact of donor management and hormonal therapy.

BACKGROUND: Brain stem death can elicit a potentially manipulable cardiotoxic proinflammatory cytokine response. We investigated the prevalence of this response, the impact of donor management with tri-iodothyronine (T3) and methylprednisolone (MP) administration, and the relationship of biomarkers to organ function and transplant suitability. METHODS: In a prospective randomized double-blinded factorially designed study of T3 and MP therapy, we measured serum levels of interleukin-1 and -6 (IL-1 and IL-6), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein, and procalcitonin (PCT) levels in 79 potential heart or lung donors. Measurements were performed before and after 4 hr of algorithm-based donor management to optimize cardiorespiratory function and +/-hormone treatment. Donors were assigned to receive T3, MP, both drugs, or placebo. RESULTS: Initial IL-1 was elevated in 16% donors, IL-6 in 100%, TNF-alpha in 28%, CRP in 98%, and PCT in 87%. Overall biomarker concentrations did not change between initial and later measurements and neither T3 nor MP effected any change. Both PCT (P =0.02) and TNF-alpha (P =0.044) levels were higher in donor hearts with marginal hemodynamics at initial assessment. Higher PCT levels were related to worse cardiac index and right and left ventricular ejection fractions and a PCT level more than 2 ng x mL(-1) may attenuate any improvement in cardiac index gained by donor management. No differences were observed between initially marginal and nonmarginal donor lungs. A PCT level less than or equal to 2 ng x mL(-1) but not other biomarkers predicted transplant suitability following management. CONCLUSIONS: There is high prevalence of a proinflammatory environment in the organ donor that is not affected by tri-iodothyronine or MP therapy. High PCT and TNF-alpha levels are associated with donor heart dysfunction.

Donor cardiac troponin-I: a biochemical surrogate of heart function.

OBJECTIVE: Cardiac troponin-I (cTnI) levels in the potential heart transplant donor may be a marker of heart dysfunction and predictive of recipient outcome. We studied the prevalence of cTnI elevation, its association with heart function and usability and its relationship with the time duration from coning. METHODS: In a prospective study, cTnI measurement, Swan-Ganz catheterisation and transthoracic echocardiography were performed at initial assessment in 79 potential heart donors (mean age 43 +/- 13.1 years). All donors were then managed according to a strict algorithm to optimise cardiac function, some receiving hormonal therapy as part of a randomised trial. Donor heart suitability for transplantation was assessed after 7 h of management. The association of cTnI with initial functional indices was assessed and outcome compared for donors categorised according to cTnI level < or = 1 microg l(-1) or >1 microg l(-1). RESULTS: Serum cTnI levels negatively correlated with initial cardiac index (CI) (p = 0.003), right (p < 0.001) and left ventricular ejection fraction (p = 0.001) and positively with LV Tei index (p = 0.003). Serum cTnI was >1 microg l(-1) in 29/79 donors. Higher CVP (10 +/- 5.1 vs 7.9 +/- 2.9; p = 0.026) and PAWP (12 +/- 5.4 vs 8.1 +/- 3.1; p = 0.002), lower cardiac index (2.7 +/- 1.1 vs 3.6 +/- 0.9; p = 0.001) and fractional shortening (p < 0.01) and worse wall motion score index (p < 0.01) were observed in the cTnI >1 microg l(-1) group. CTnI and functional markers correlated with the time duration from coning. CONCLUSION: The donor cTnI level represents a biochemical surrogate of functional donor heart assessment. High cTnI is associated with worse donor heart function and may act as a prompt for detailed assessment and optimisation.

The haemodynamic effects of adjunctive hormone therapy in potential heart donors: a prospective randomized double-blind factorially designed controlled trial.

AIMS: The aim of this study was to assess the haemodynamic effects of tri-iodothyronine (T3) and methylprednisolone in potential heart donors. METHODS AND RESULTS: In a prospective randomized double-blind trial, 80 potential cardiac donors were allocated to receive T3 (0.8 microg kg(-1) bolus; 0.113 microg kg(-1) h(-1) infusion) (n = 20), methylprednisolone (1000 mg bolus) (n = 19), both drugs (n = 20), or placebo (n = 21) following initial haemodynamic assessment. After hormone or placebo administration, cardiac output-guided optimization was initiated, using vasopressin as a pressor and weaning norepinephrine and inotropes. Treatment was administered for 5.9 +/- 1.3 h until retrieval or end-assessment. Cardiac index increased significantly (P < 0.001) but administration of T3 and methylprednisolone alone or in combination did not affect this change or the heart retrieval rate. Thirty-five per cent (14/40) of initially marginal or dysfunctional hearts were suitable for transplant at end-assessment. At end-assessment, 50% of donor hearts fulfilled criteria for transplant suitability. CONCLUSION: Cardiac output-directed donor optimization improves donor circulatory status and has potential to increase the retrieval rate of donor hearts. Tri-iodothyronine and methylprednisolone therapy do not appear to acutely affect cardiovascular function or yield.

Mild renal dysfunction predicts in-hospital mortality and post-discharge survival following cardiac surgery.

OBJECTIVES: To assess the impact of preoperative renal dysfunction on in-hospital mortality and late survival outcome following adult cardiac surgery. METHODS: Prospectively collected data were analysed on 7621 consecutive patients not requiring preoperative renal-replacement therapy, who underwent CABG, valve surgery or combined procedures from 1/1/98 to 1/12/06. Preoperative estimated glomerular filtration rate was calculated using Cockcroft-Gault formula. Patients were classified in the four chronic kidney disease (CKD) stage classes defined by the National Kidney Foundation Disease Outcome Quality Initiative Advisory Board. Late survival data were obtained from the UK Central Cardiac Audit Database. RESULTS: There were 243 in-hospital deaths (3.2%). There was a stepwise increase in operative mortality with each CKD class independent of the type of surgery. Multivariate analysis confirmed CKD class to be an independent predictor of in-hospital mortality (class 2 OR 1.45, 95% CI 1.1-2.35, p=0.001; class 3 OR 2.8, 95% CI 1.68-4.46, p=0.0001; class 4 OR 7.5, 95% CI 3.76-15.2, p=0.0001). The median follow-up after surgery was 42 months (IQR 18-74) and there were 728 late deaths. Survival analysis using a Cox regression model confirmed CKD class to be an independent predictor of late survival (class 2 HR 1.2, 95% CI 1.1-1.6, p=0.0001; class 3 HR 1.95, 95% CI 1.6-2.4, p=0.0001; and class 4 HR 3.2, 95% CI 2.2-4.6, p=0.0001). Ninety-eight percent (7517/7621) of patients had a preoperative creatinine <200 micromol/l, which is not included as a risk factor in most risk stratification systems. CONCLUSIONS: Mild renal dysfunction is an important independent predictor of in-hospital and late mortality in adult patients undergoing cardiac surgery.

Bleeding in cardiac surgery: the use of aprotinin does not affect survival.

OBJECTIVE: The antifibrinolytic drug aprotinin has been the most widely used agent to reduce bleeding and its complications in cardiac surgery. Several randomized trials and meta-analyses have demonstrated it to be effective and safe. However, 2 recent reports from a single database have implicated the use of aprotinin as a risk for postoperative complications and reduced long-term survival. METHODS: In this single-institution observational study involving 7836 consecutive patients (1998-2006), we assessed the safety of using aprotinin in risk reduction strategy for postoperative bleeding. RESULTS: Aprotinin was used in 44% of patients. Multivariate analysis identified aprotinin use in risk reduction for reoperation for bleeding (odds ratio, 0.51; 95% confidence interval, 0.36-0.72; P = .001) and need for blood transfusion postoperatively (odds ratio, 0.67; 95% confidence interval, 0.57-0.79; P = .0002). The use of aprotinin did not affect in-hospital mortality (odds ratio, 1.03; 95% confidence interval, 0.71-1.49; P = 0.73), intermediate-term survival (median follow-up, 3.4 years; range, 0-8.9 years; hazard ratio, 1.09; 95% confidence interval, 0.93-1.28; P = .30), incidence of postoperative hemodialysis (odds ratio, 1.16; 95% confidence interval, 0.73-1.85; P = .49), and incidence of postoperative renal dysfunction (odds ratio, 0.78; 95% confidence interval, 0.59-1.03; P = .07). CONCLUSION: This study demonstrates that aprotinin is effective in reducing bleeding after cardiac surgery, is safe, and does not affect short- or medium-term survival.

Deep sternal wound infection requiring revision surgery: impact on mid-term survival following cardiac surgery.

OBJECTIVE: To assess the impact of deep sternal wound infection on in-hospital mortality and mid-term survival following adult cardiac surgery. METHODS: Prospectively collected data on 4586 consecutive patients who underwent a cardiac surgical procedure via a median sternotomy from 1st January 2001 to 31st December 2005 were analysed. Patients with a deep sternal wound infection (DSWI) were identified in accordance with the Centres for Disease Control and Prevention guidelines. Nineteen variables (patient-related, operative and postoperative) were analysed. Logistic regression analysis was used to calculate a propensity score for each patient. Late survival data were obtained from the UK Central Cardiac Audit Database. Mean follow-up of DSWI patients was 2.28 years. RESULTS: DSWI requiring revision surgery developed in 1.65% (76/4586) patients. Stepwise multivariable logistic regression analysis identified age, diabetes, a smoking history and ventilation time as independent predictors of a DSWI. DSWI patients were more likely to develop renal failure, require reventilation and a tracheostomy postoperatively. Treatment included vacuum assisted closure therapy in 81.5% (62/76) patients and sternectomy with musculocutaneous flap reconstruction in 35.5% (27/76) patients. In-hospital mortality was 9.2% (7/76) in DSWI patients and 3.7% (167/4510) in non-DSWI patients (OR 1.300 (0.434-3.894) p=0.639). Survival with Cox regression analysis with mean propensity score (co-variate) showed freedom from all-cause mortality in DSWI at 1, 2, 3 and 4 years was 91%, 89%, 84% and 79%, respectively compared with 95%, 93%, 90% and 86%, respectively for patients without DSWI ((p=0.082) HR 1.59 95% CI (0.94-2.68)). CONCLUSION: DSWI is not an independent predictor of a higher in-hospital mortality or reduced mid-term survival following cardiac surgery in this population.

Early donor management increases the retrieval rate of lungs for transplantation.

BACKGROUND: Lung transplantation activity is frustrated by donor lung availability. We sought to examine the effect of active donor management and hormone administration on pulmonary function and yield in cadaveric heart-beating potential lung donors. METHODS: We studied 182 potential lung donors (arterial oxygen tension [PaO2]/fractional inspired oxygen [FIO2] ratio > or = 230). From this group, 60 patients (120 lungs) were allocated, within a randomized trial, to receive methylprednisolone (1 g), triiodothyronine (0.8 microg/kg bolus and 0.113 microg/kg/h infusion), both methylprednisolone and triiodothyronine, or placebo as soon as feasible after consent and initial assessment. Trial donors underwent protocol-guided optimization of ventilation and hemodynamics, lung water assessment, and bronchoscopy. Function was assessed by PaO2/FIO2 ratio, extravascular lung water index (EVLWI), and pulmonary vascular resistance (PVR). A nontrial group of 122 donors (244 lungs) received similar management without bronchoscopy, pulmonary artery flotation catheter monitoring, or lung water assessment. RESULTS: Within the trial, management commenced within a median of 2 hours (interquartile range, 0.5 to 3.5 hours) of consent and continued for an average of 6.9 +/- 1.2 hours. The PaO2/FIO2 ratio deteriorated (p = 0.028) from 397 +/- 78 (95% CL, 376 to 417) to 359 +/- 126 (95% CL, 328 to 390) and EVLWI from 9.7 +/- 4.5 mL/kg (95% CL, 8.6 to 10.9 mL/kg) to 10.8 +/- 5.2 mL/kg (95% CL, 9.4 to 12.2 mL/kg; p = 0.009). PVR remained unchanged (p = 0.28). At end management, 48 of 120 trial lungs (40%) were transplanted versus 66 of 244 nontrial lungs (27%; p = 0.016). Neither methylprednisolone and triiodothyronine nor T3 increased lung yield or affected PaO2/FIO2 or EVLWI; however, methylprednisolone attenuated the increase in EVLWI (p = 0.009). CONCLUSIONS: Early active management of lung donors increases yield. Steroid administration reduces progressive lung water accumulation.

Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.

BACKGROUND: Both glucose-insulin-potassium (GIK) and tri-iodothyronine (T3) may improve cardiovascular performance after coronary artery surgery (CABG) but their effects have not been directly compared and the effects of combined treatment are unknown. METHODS AND RESULTS: In 2 consecutive randomized double-blind placebo-controlled trials, in patients undergoing first time isolated on-pump CABG between January 2000 and September 2004, 440 patients were recruited and randomized to either placebo (5% dextrose) (n=160), GIK (40% dextrose, K+ 100 mmol.L(-1), insulin 70 u.L(-1)) (0.75 mL.kg(-1) h(-1)) (n=157), T3 (0.8 microg.kg(-1) followed by 0.113 microg.kg(-1) h(-1)) (n=63) or GIK+T3 (n=60). GIK/placebo therapy was administered from start of operation until 6 hours after removal of aortic cross-clamp (AXC) and T3/placebo was administered for a 6-hour period from removal of AXC. Serial hemodynamic measurements were taken up to 12 hours after removal of AXC and troponin I (cTnI) levels were assayed to 72 hours. Cardiac index (CI) was significantly increased in both the GIK and GIK/T3 group in the first 6 hours compared with placebo (P<0.001 for both) and T3 therapy (P=0.009 and 0.029, respectively). T3 therapy increased CI versus placebo between 6 and 12 hours after AXC removal (P=0.01) but combination therapy did not. Release of cTnI was lower in all treatment groups at 6 and 12 hours after removal of AXC. CONCLUSIONS: Treatment with GIK, T3, and GIK/T3 improves hemodynamic performance and results in reduced cTnI release in patients undergoing on-pump CABG surgery. Combination therapy does not provide added hemodynamic effect.

Patient-prosthesis mismatch does not affect survival following aortic valve replacement.

OBJECTIVE: Patient-prosthesis mismatch (PPM) has been reported to increase perioperative mortality and reduce postoperative survival in patients undergoing aortic valve replacement (AVR). We analysed the effect of PPM at values predicting severe mismatch on survival following AVR in our unit. METHODS: Prospectively collected data on 1481 consecutive patients who had undergone AVR with or without coronary artery revascularisation between 1997 and 2005 were analysed. Projected in vitro valve effective orifice area (EOA) and geometric prosthesis internal orifice area (GOA) were evaluated and values were indexed to body surface area (cm(2)m(-2)). PPM was defined as EOAi<0.6 and/or GOAi<1.1. Long-term survival data were obtained from the National Institute of Statistics. RESULTS: One thousand four hundred and eighteen patients were identified. 67/1418 (4.7%) patients had GOAi<1.1; 122/1418 (8.6%) had EOAi<0.6 and 38 (2.6%) patients exhibited both forms of mismatch. One thousand two hundred and sixty-seven patients (89%) demonstrated no mismatch (reference group). There were 75 in-hospital deaths (overall mortality 5.3%) with no significant difference between the mismatch and the reference groups. Survival data were available for up to 8 years (median 36 months, IQR 6-60 months). There were 160 late deaths (13/143 PPM group vs 147/1198 reference group). The 5-year survival estimate was similar for both groups (83% PPM group; 81% reference group; p=0.47). Cox-hazard analysis identified advanced age as the only predictor of reduced survival (age>80, RR 2.13, 95% CI 1.38-4.586, p=0.004). CONCLUSIONS: Severe patient-prosthesis mismatch was predicted in 4-10% of patients undergoing AVR but this did not affect in-hospital mortality or mid-term survival.