Yves d’Udekem

Redefining Expectations of Long-Term Survival After the Fontan Procedure Twenty-Five Years of Follow-Up From the Entire Population of Australia and New Zealand

Background— The life expectancy of patients undergoing a Fontan procedure is unknown. Methods and Results— Follow-up of all 1006 survivors of the 1089 patients who underwent a Fontan procedure in Australia and New Zealand was obtained from a binational population-based registry including all pediatric and adult cardiac centers. There were 203 atriopulmonary connections (AP; 1975–1995), 271 lateral tunnels (1988–2006), and 532 extracardiac conduits (1997–2010). The proportion with hypoplastic left heart syndrome increased from 1/173 (1%) before 1990 to 80/500 (16%) after 2000. Survival at 10 years was 89% (84%–93%) for AP and 97% (95% confidence interval [CI], 94%–99%) for lateral tunnels and extracardiac conduits. The longest survival estimate was 76% (95% CI, 67%–82%) at 25 years for AP. AP independently predicted worse survival compared with extracardiac conduits (hazard ratio, 6.2; P<0.001; 95% CI, 2.4–16.0). Freedom from failure (death, transplantation, takedown, conversion to extracardiac conduits, New York Heart Association III/IV, or protein-losing enteropathy/plastic bronchitis) 20 years after Fontan was 70% (95% CI, 63%–76%). Hypoplastic left heart syndrome was the primary predictor of Fontan failure (hazard ratio, 3.8; P<0.001; 95% CI, 2.0–7.1). Ten-year freedom from failure was 79% (95% CI, 61%–89%) for hypoplastic left heart syndrome versus 92% (95% CI, 87%–95%) for other morphologies. Conclusions— The long-term survival of the Australia and New Zealand Fontan population is excellent. Patients with an AP Fontan experience survival of 76% at 25 years. Technical modifications have further improved survival. Patients with hypoplastic left heart syndrome are at higher risk of failure. Large, comprehensive registries such as this will further improve our understanding of late outcomes after the Fontan procedure.

Remote Ischemic Preconditioning (RIPC) Modifies Plasma Proteome in Humans

Remote Ischemic Preconditioning (RIPC) induced by brief episodes of ischemia of the limb protects against multi-organ damage by ischemia-reperfusion (IR). Although it has been demonstrated that RIPC affects gene expression, the proteomic response to RIPC has not been determined. This study aimed to examine RIPC induced changes in the plasma proteome. Five healthy adult volunteers had 4 cycles of 5 min ischemia alternating with 5 min reperfusion of the forearm. Blood samples were taken from the ipsilateral arm prior to first ischaemia, immediately after each episode of ischemia as well as, at 15 min and 24 h after the last episode of ischemia. Plasma samples from five individuals were analysed using two complementary techniques. Individual samples were analysed using 2Dimensional Difference in gel electrophoresis (2D DIGE) and mass spectrometry (MS). Pooled samples for each of the time-points underwent trypsin digestion and peptides generated were analysed in triplicate using Liquid Chromatography and MS (LC-MS). Six proteins changed in response to RIPC using 2D DIGE analysis, while 48 proteins were found to be differentially regulated using LC-MS. The proteins of interest were involved in acute phase response signalling, and physiological molecular and cellular functions. The RIPC stimulus modifies the plasma protein content in blood taken from the ischemic arm in a cumulative fashion and evokes a proteomic response in peripheral blood.

Twenty-four-hour ambulatory blood pressure monitoring detects a high prevalence of hypertension late after coarctation repair in patients with hypoplastic arches.

OBJECTIVES To determine by 24-hour blood pressure monitoring the risk of hypertension late after coarctation repair in patients with arch hypoplasia. METHODS Sixty-two of 116 consecutive patients (age, ≥10 years) who had coarctation repair and were quoted subjectively by the surgeon or the cardiologist to have arch hypoplasia at the time of the repair underwent a transthoracic echocardiogram and 24-hour blood pressure monitoring. Median age at repair was 11 days (range, 6-48 days). Mean preoperative z score of the proximal transverse arch was -2.43 ± 0.46. Eight patients had a repair via sternotomy (6 end-to-side anastomoses, 2 patch repairs) and 54 had a conventional repair via thoracotomy. RESULTS After a follow-up of 18 ± 5 years, 27% of the patients (17/62) had resting hypertension and 60% (37/62) had abnormal ambulatory blood pressure. Sensitivity of high resting blood pressure in detecting an abnormal 24-hour ambulatory blood pressure was 41%. Twenty patients had arch obstruction at last follow-up. Eighteen of them (90%) had abnormal ambulatory blood pressure. None of the patients operated on with end-to-side repair via sternotomy had reobstruction compared with 33% (18/54) of those repaired via thoracotomy. CONCLUSIONS Patients with a hypoplastic arch operated via thoracotomy have an alarming prevalence of hypertension. Regular follow-up with 24-hour ambulatory blood pressure monitoring is warranted, especially in patients who have had a smaller aortic arch at the time of the initial operation.

Remote ischemic preconditioning in cyanosed neonates undergoing cardiopulmonary bypass: A randomized controlled trial

OBJECTIVE The myocardial protective effect of remote ischemic preconditioning has been demonstrated in heterogeneous groups of patients undergoing cardiac surgery. No studies have examined this technique in neonates. The present study was performed to examine the remote ischemic preconditioning efficacy in this high-risk patient group. METHODS A preliminary, randomized, controlled trial was conducted to investigate whether remote ischemic preconditioning in cyanosed neonates undergoing cardiac surgery confers protection against cardiopulmonary bypass. Two groups of neonates undergoing cardiac surgery were recruited for the present study: patients with transposition of the great arteries undergoing the arterial switch procedure and patients with hypoplastic left heart syndrome undergoing the Norwood procedure. The subjects were randomized to the remote ischemic preconditioning or sham control groups. Remote ischemic preconditioning was induced by four 5-minute cycles of lower limb ischemia and reperfusion using a blood pressure cuff. Troponin I and the biomarkers for renal and cerebral injury were measured pre- and postoperatively. RESULTS A total of 39 neonates were recruited-20 with transposition of the great arteries and 19 with hypoplastic left heart syndrome. Of the 39 neonates, 20 were randomized to remote ischemic preconditioning and 19 to the sham control group. The baseline demographics appeared similar between the randomized groups. The cardiopulmonary bypass and crossclamp times were not significantly different between the 2 groups. The troponin I levels were not significantly different at 6 hours after cardiopulmonary bypass nor were the postoperative inotrope requirements. Markers of renal (neutrophil gelatinase-associated lipocalin) and cerebral injury (S100b, neuron-specific enolase) were not significantly different between the 2 groups. CONCLUSIONS Our data suggest that remote ischemic preconditioning in hypoxic neonates undergoing cardiopulmonary bypass surgery does not provide myocardial, renal, or neuronal protection. Additional studies are needed to examine the relationships among developmental age, hypoxia, and the molecular mechanisms of ischemic preconditioning.

Should We Recommend Exercise after the Fontan Procedure

BACKGROUND The Fontan procedure, the last of a series of operations performed in patients with congenital heart defects, offers improved exercise capacity compared to baseline function but is still reduced compared to healthy peers. Exercise training may improve exercise tolerance but there is no consensus on the safety of this practice or the optimal training regimen. We performed a systematic literature review on the effects of exercise training in patients with a Fontan circulation. METHODS Medline and Embase databases were systematically searched for articles regarding Fontan Procedure and cardiac rehabilitation. RESULTS A total of 23 articles met all inclusion criteria; in total, 201 Fontan subjects were included. Characteristics of the exercise training programs varied significantly. There were no adverse effects related to training programs reported in the literature. Most studies reported benefit across various exercise parameters related to exercise tolerance. CONCLUSIONS Exercise training is safe and beneficial in patients with a Fontan circulation. Exercise training should become a standard of care within this population. Physiological adaptation following exercise training needs to be investigated more extensively.

Current Therapy for Hypoplastic Left Heart Syndrome and Related Single Ventricle Lesions

Universally fatal only 4 decades ago, the progress in the 3-stage palliation of hypoplastic left heart syndrome and related single right ventricular lesions has drastically improved the outlook for these patients. Although the stage II operation (hemi-Fontan or bidirectional Glenn) and stage III Fontan procedure have evolved into relatively low-risk operations, the stage I Norwood procedure remains one of the highest-risk and costliest common operations performed in congenital heart surgery. Yet, despite this fact, experienced centers now report hospital survivals of >90% for the Norwood procedure. This traditional 3-stage surgical palliation has seen several innovations in the past decade aimed at improving outcomes, particularly for the Norwood procedure. One significant change is a renewed interest in the right ventricle-to-pulmonary artery shunt as the source of pulmonary blood flow, rather than the modified Blalock-Taussig shunt for the Norwood. The multi-institutional Single Ventricle Reconstruction trial randomly assigned 555 patients to one or the other shunt, and these subjects continue to be followed closely as they now approach 10 years postrandomization. In addition to modifications to the Norwood procedure, the hybrid procedure, a combined catheter-based and surgical approach, avoids the Norwood procedure in the newborn period entirely. The initial hybrid procedure is then followed by a comprehensive stage II, which combines components of both the Norwood and the traditional stage II, and later completion of the Fontan. Proponents of this approach hope to improve not only short-term survival, but also potentially longer-term outcomes, such as neurodevelopment, as well. Regardless of the approach, traditional surgical staged palliation or the hybrid procedure, survivals have vastly improved, and large numbers of these patients are surviving not only through their Fontan in early childhood, but also into adolescence and young adulthood. As this population grows, it becomes increasingly important to understand the longer-term outcomes of these Fontan patients, not only in terms of survival, but also in terms of the burden of disease, neurodevelopmental outcomes, psychosocial development, and quality of life.

The influence of bypass temperature on the systemic inflammatory response and organ injury after pediatric open surgery: A randomized trial

OBJECTIVE Systemic cooling for cardiopulmonary bypass is widely used to attenuate the systemic inflammatory response syndrome and organ injury in children after open surgery. We compared the effects of moderate (24 °C) and mild (34 °C) hypothermia during bypass on markers of the systemic inflammatory response syndrome and organ injury, and on clinical outcome after corrective surgery for congenital heart disease. METHODS Sixty-six children (mean age, 6.8 ± 5.7 months; mean weight, 6.2 ± 2.3 kg) were randomized to 24 °C or 34 °C bypass temperature during cardiac surgery. Perfusion strategies were otherwise strictly identical. Clinical data and blood samples were collected before bypass, 5 minutes after aortic crossclamp release, and 4, 24, and 48 hours after bypass. Patients were followed up until discharge from the hospital. RESULTS In the 54 children with outcome data, bypass temperature did not influence the duration of mechanical ventilation between the 24 °C group and the 34 °C group (median [interquartile range] 22 [13-40] hours vs 14 [8-40] hours, P = .14), intensive care unit stay (43 [24-49] hours vs 29 [23-47] hours, P = .79), blood loss (29 [20-38] mL/kg vs 23 [13-38] mL/kg, P = .36), or incidence of postoperative infection (9% vs 11%, P = 1.0). There was no evidence of an influence of bypass temperature on the markers of acute inflammation, innate immune response, organ injury, coagulation, or hemodynamics. CONCLUSIONS There is no evidence that the systemic inflammatory response syndrome and organ injury after pediatric open surgery are influenced by bypass temperature. The routine use of hypothermic bypass may not be warranted in the pediatric population.

Outcomes of Atrioventricular Valve Operation in Patients With Fontan Circulation

BACKGROUND Data on outcomes of atrioventricular (AV) valve surgical procedures in patients with Fontan circulation are limited. METHODS We conducted a retrospective review of all children with Fontan circulation who underwent AV valve operations. RESULTS From 1981 to 2014, 581 patients underwent Fontan operations, and 9.3% (54/581) of them required AV valve operations. The first AV valve operation was performed before (n = 32), during (n = 15), or after (n = 7) the Fontan operation. The mean follow-up time was 9.8 ± 7.1 years (range, 6 months to 32 years). Operative mortality for the initial AV valve operation was 1.9% (1/54) and occurred in a patient who had the initial valve operation concomitantly with the Fontan. Late mortality was 5.7% (3/53). Heart transplantation was performed in 13.0% (7/54) of patients. Freedom from death or transplantation after the first AV valve operation was 89.8 ± 4.4% at 5 years (95% confidence interval [CI], 77.1 to 95.6) and 81.0 ± 6.2% at 10 years (95% CI, 65.0 to 90.2). Reoperation on the AV valve was performed in 44.4% (24/54) of patients. The median time to initial valve reoperation was 3.1 years (interquartile range, 0.8 to 7.4 years). Freedom from reoperation or transplantation was 63.4 ± 7.0% at 5 years (95% CI, 48.2 to 75.3) and 48.9 ± 7.9% at 10 years (95% CI, 32.8 to 63.2). Freedom from moderate or more regurgitation in patients who had not undergone reoperation or transplantation was 74.0 ± 6.9% (95% CI, 57.5 to 84.8) at 5 years and 67.5 ± 7.7% (95% CI:,50.0 to 80.0) at 10 years. After initial valve operation, thromboembolic events occurred in 13.0% (7/54) of patients, stroke occurred in 24.1% (13/54) of patients, pacemaker insertion was required in 16.7% (9/54) of patients, and protein-losing enteropathy was diagnosed in 7.4% (4/54) of patients. Of the 43 surviving transplant-free patients, 62.8% (27/43) were in New York Heart Association (NYHA) class I, 34.9% (15/43) were in NYHA class II, and 1 patient was in NYHA class III. CONCLUSIONS The AV valve operation done before, during, or after the Fontan operation is associated with low operative mortality but a high reoperation rate with significant risk of late death, transplantation, and persistent AV valve regurgitation.

Changing trends in the management of pulmonary atresia with intact ventricular septum: the Melbourne experience

OBJECTIVE Management of pulmonary atresia with intact ventricular septum (PAIVS) can be directed to either biventricular repair or univentricular palliation. The optimal management strategy has yet to be defined. METHODS All patients operated at the Royal Childrens Hospital, Melbourne for PAIVS between 1990 and 2006 (n = 81) were reviewed. Patients were retrospectively stratified into a simple three-tiered classification based on right ventricle (RV) size. Multivariate logistic regression analysis was performed to identify risk factors of mortality. RESULTS The distribution of RV sizes was normal in 11 (14%), moderate hypoplasia in 45 (56%), and severe hypoplasia in 25 (31%) patients. RV-to-coronary-artery connections were present in 33 (41%) and RV coronary dependence in six patients (7%). Sixteen patients died (20%). The end-status of the remaining patients was biventricular repair in 31/81 (38%), 1½-ventricle repair in 10/81 (12%), Fontan circulation in 14/81 (17%), transplantation in 1/81 (1%), and still awaiting repair in 9/81 (11%). Ten-year survival was 80% (95% confidence interval (CI): 71-87%). Independent predictors of mortality were lower tricuspid valve (TV) annulus size Z-score and the presence of RV-to-coronary-artery connections. CONCLUSIONS A simple three-tiered classification based on RV size may allow initial stratification into biventricular or univentricular repair for patients with normal RV size and severe RV hypoplasia. In patients with moderate RV hypoplasia, the presence of RV-to-coronary-artery connections or a TV Z-score<-2 should caution one against attempting biventricular repair.

A technique of fenestration for extracardiac Fontan with long-term patency

A technique for extracardiac conduit fenestration specifically devised to achieve long-term patency is presented. From 2001 to 2007, 65 patients underwent a fenestrated extracardiac Fontan procedure using this technique where the atrial orifice of the divided inferior vena cava was sutured in an end to side fashion to the leftward aspect of the conduit. The circumferential suture line was centred by the fenestration but remained away from the edge of the latter. All patients receive oral anticoagulation. Clinical and echocardiographic follow-up were obtained. Concurrent follow-up was 100%. There was one early death (mortality 1.5%). Two patients had Fontan failure requiring takedown and another two were transplanted. The fenestration was found to be patent in the rest of patients of the series (n=60) at a median follow-up of 11 months (range 1-91). The mean velocity across the fenestration was 1.6+/-0.55 m/s. No patient required reintervention related to the fenestration. All patients remained in sinus rhythm. This technique is easily reproducible, consistently provides long-term patency and low incidence of complications. The use of inferior vena cava orifice of the right atrium explains the absence of supra ventricular arrhythmias.