Eric M. Graham

Cause, timing, and location of death in the Single Ventricle Reconstruction trial

OBJECTIVES The Single Ventricle Reconstruction trial randomized 555 subjects with a single right ventricle undergoing the Norwood procedure at 15 North American centers to receive either a modified Blalock-Taussig shunt or right ventricle-to-pulmonary artery shunt. Results demonstrated a rate of death or cardiac transplantation by 12 months postrandomization of 36% for the modified Blalock-Taussig shunt and 26% for the right ventricle-to-pulmonary artery shunt, consistent with other publications. Despite this high mortality rate, little is known about the circumstances surrounding these deaths. METHODS There were 164 deaths within 12 months postrandomization. A committee adjudicated all deaths for cause and recorded the timing, location, and other factors for each event. RESULTS The most common cause of death was cardiovascular (42%), followed by unknown cause (24%) and multisystem organ failure (7%). The median age at death for subjects dying during the 12 months was 1.6 months (interquartile range, 0.6 to 3.7 months), with the highest number of deaths occurring during hospitalization related to the Norwood procedure. The most common location of death was at a Single Ventricle Reconstruction trial hospital (74%), followed by home (13%). There were 29 sudden, unexpected deaths (18%), although in retrospect, 12 were preceded by a prodrome. CONCLUSIONS In infants with a single right ventricle undergoing staged repair, the majority of deaths within 12 months of the procedure are due to cardiovascular causes, occur in a hospital, and within the first few months of life. Increased understanding of the circumstances surrounding the deaths of these single ventricle patients may reduce the high mortality rate.

Does a ventriculotomy have deleterious effects following palliation in the Norwood procedure using a shunt placed from the right ventricle to the pulmonary arteries

INTRODUCTION A recent modification to the Norwood procedure involving a shunt placed directly from the right ventricle to the pulmonary arteries may improve postoperative haemodynamics. Concerns remain, however, about the potential problems produced by the required ventriculotomy. METHODS We compared 76 patients with hypoplastic left heart syndrome who underwent the Norwood procedure, 35 receiving a modified Blalock-Taussig shunt and the remaining 41 a shunt placed directly from the right ventricle to the pulmonary arteries. We reviewed their subsequent progress through the second stage of palliation. A single observer graded right ventricular function, and the severity of tricuspid regurgitation, based on blinded review of the most recent echocardiograms prior to the second stage of palliation. RESULTS At the time of catheterization prior to the second stage, patients with a shunt placed from the right ventricle to the pulmonary arteries, rather than a modified Blalock-Taussig shunt, had higher arterial diastolic blood pressure, at 44 versus 40 millimetres of mercury, p equal to 0.02, lower ventricular end diastolic pressures, at 8 versus 11 millimetres of mercury, p equal to 0.0002, and larger pulmonary arteries as judged using the Nakata index, at 270 versus 188 millimetres squared per metres squared, p equal to 0.009. There was no difference in qualitative ventricular systolic function or tricuspid regurgitation between groups. No differences were found between groups during the hospitalization following the second stage of palliation. A trend towards improved survival to the second stage was seen following the construction of a shunt from the right ventricle to the pulmonary arteries. CONCLUSIONS Construction of a shunt from the right ventricle to the pulmonary arteries is associated with lower right ventricular end diastolic pressures, larger pulmonary arterial size, and higher systemic arterial diastolic pressures. No apparent deleterious effects of the right ventriculotomy were observed in terms of qualitative ventricular systolic function or tricuspid regurgitation.

Renin-Angiotensin-Aldosterone Genotype Influences Ventricular Remodeling in Infants With Single Ventricle

Background— We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle. Methods and Results— Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with <2 homozygous risk genotypes (low risk) at 2 time points: before the superior cavopulmonary connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: Thirty-eight were high risk, and 116 were low risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and estimated glomerular filtration rate increased after SCPC in the low-risk (P<0.05), but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline, and height remained lower in the high-risk group at 14 months, especially in those receiving enalapril (P<0.05). Conclusions— Renin-angiotensin-aldosterone system–upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume-unloading surgery. Follow-up is warranted to assess long-term impact. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00113087.

Practice variability and outcomes of coil embolization of aortopulmonary collaterals before fontan completion: A report from the Pediatric Heart Network Fontan Cross-Sectional Study

BACKGROUND The practice of coiling aortopulmonary collaterals (APCs) before Fontan completion is controversial, and published data are limited. We sought to compare outcomes in subjects with and without pre-Fontan coil embolization of APCs using the Pediatric Heart Network Fontan Cross-Sectional Study database which enrolled survivors of prior Fontan palliation. METHODS We compared hospital length of stay after Fontan in 80 subjects who underwent APC coiling with 459 subjects who did not. Secondary outcomes included post-Fontan complications and assessment of health status and ventricular performance at cross-sectional evaluation (mean 8.6 ± 3.4 years after Fontan). RESULTS Centers varied markedly in frequency of pre-Fontan APC coiling (range 0%-30% of subjects, P < .001). The coil group was older at Fontan (P = .004) and more likely to have single right ventricular morphology (P = .054) and pre-Fontan atrioventricular valve regurgitation (P = .03). The coil group underwent Fontan surgery more recently (P < .001), was more likely to have a prior superior cavopulmonary anastomosis (P < .001), and more likely to undergo extracardiac Fontan connection (P < .001) and surgical fenestration (P < .001). In multivariable analyses, APC coiling was not associated with length of stay (hazard ratio for remaining in-hospital 0.91, 95% CI 0.70-1.18, P = .48) or postoperative complications, except more post-Fontan catheter interventions (hazard ratio 1.74, 95% CI 1.04-2.91, P = .03), primarily additional APC coils. The groups had similar outcomes at cross-sectional evaluation. CONCLUSION Management of APCs before Fontan shows marked practice variation. We did not find an association between pre-Fontan coiling of APCs and shorter postoperative hospital stay or with better late outcomes. Prospective studies of this practice are needed.

Factors associated with neurodevelopment for children with single ventricle lesions.

OBJECTIVE To measure neurodevelopment at 3 years of age in children with single right-ventricle anomalies and to assess its relationship to Norwood shunt type, neurodevelopment at 14 months of age, and patient and medical factors. STUDY DESIGN All subjects in the Single Ventricle Reconstruction Trial who were alive without cardiac transplant were eligible for inclusion. The Ages and Stages Questionnaire (ASQ, n = 203) and other measures of behavior and quality of life were completed at age 3 years. Medical history, including measures of growth, feeding, and complications, was assessed through annual review of the records and phone interviews. The Bayley Scales of Infant Development, Second Edition (BSID-II) scores from age 14 months were also evaluated as predictors. RESULTS Scores on each ASQ domain were significantly lower than normal (P < .001). ASQ domain scores at 3 years of age varied nonlinearly with 14-month BSID-II. More complications, abnormal growth, and evidence of feeding, vision, or hearing problems were independently associated with lower ASQ scores, although models explained <30% of variation. Type of shunt was not associated with any ASQ domain score or with behavior or quality-of-life measures. CONCLUSION Children with single right-ventricle anomalies have impaired neurodevelopment at 3 years of age. Lower ASQ scores are associated with medical morbidity, and lower BSID-II scores but not with shunt type. Because only a modest percentage of variation in 3-year neurodevelopmental outcome could be predicted from early measures, however, all children with single right-ventricle anomalies should be followed longitudinally to improve recognition of delays.

Comparison of Norwood Shunt Types: Do the Outcomes Differ 6 Years Later?

BACKGROUND A modification to the Norwood procedure involving a right ventricle-to-pulmonary artery (RV-PA) shunt may improve early postoperative outcomes. Concerns remain about the effect of the right ventriculotomy required with this shunt on long-term ventricular function. METHODS Between January 2000 and April 2005, 76 patients underwent the Norwood procedure, 35 with a modified Blalock-Taussig shunt (mBTS) and 41 with a RV-PA shunt. Patients were monitored until death or September 1, 2009, with an average follow-up of 6.8 years. Cardiac catheterization, echocardiograms, perioperative Fontan courses, and need for cardiac transplantation were compared between groups. RESULTS Cumulative survival was 63% (22 of 35) in the mBTS group vs 78% (32 of 41) in the RV-PA group (p = 0.14). Pre-Fontan echocardiography revealed poorer ventricular function in RV-PA patients (p = 0.03). Cardiac transplantation was required in 6 of 32 (19%) patients with a prior RV-PA shunt vs 1 of 23 (4%) in the mBTS group (p = 0.06). This results in an almost identical cumulative transplant-free survival between groups; 60% (21 of 35) in the mBTS group and 63% (26 of 41) in the RV-PA group (p = 0.95). CONCLUSIONS Neither shunt offers a clear survival advantage through an average follow-up of 6.8 years. The RV-PA shunt results in impaired late ventricular function that may result in an increased need for cardiac transplantation.

Initial Experience With a Miniaturized Multiplane Transesophageal Probe in Small Infants Undergoing Cardiac Operations

PURPOSE There has been reluctance to use intraoperative transesophageal echocardiography (TEE) in small infants. We assessed the utility and safety of a new miniaturized multiplane micro-TEE probe in small infants undergoing cardiac operations. DESCRIPTION Hemodynamic and ventilation variables were prospectively recorded before and after micro-TEE insertion and removal in infants weighing 5 kg or less undergoing cardiac operations. EVALUATION The study included 42 patients with a mean weight of 3.6 +/- 0.9 kg (range, 1.7 to 5 kg). All probe insertions were successful. There were no complications or clinically significant changes in hemodynamic or ventilation variables. Information provided by TEE resulted in surgical revision in 6 of the 42 patients. CONCLUSIONS The micro-TEE provides high quality, useful diagnostic images without hemodynamic or ventilation compromise in small infants undergoing cardiac operations. This advance is important with the growing trend towards complete repair of complex structural heart disease in small infants.

Differential effects of aprotinin and tranexamic acid on outcomes and cytokine profiles in neonates undergoing cardiac surgery

OBJECTIVE Factors contributing to postoperative complications include blood loss and a heightened inflammatory response. The objective of this study was to test the hypothesis that aprotinin would decrease perioperative blood product use, reduce biomarkers of inflammation, and result in improved clinical outcome parameters in neonates undergoing cardiac operations. METHODS This was a secondary retrospective analysis of a clinical trial whereby neonates undergoing cardiac surgery received either aprotinin (n = 34; before May 2008) or tranexamic acid (n = 42; after May 2008). Perioperative blood product use, clinical course, and measurements of cytokines were compared. RESULTS Use of perioperative red blood cells, cryoprecipitate, and platelets was reduced in neonates receiving aprotinin compared with tranexamic acid (P < .05). Recombinant activated factor VII use (2/34 [6%] vs 18/42 [43%]; P < .001), delayed sternal closure (12/34 [35%] vs 26/42 [62%]; P = .02), and inotropic requirements at 24 and 36 hours (P < .05) were also reduced in the aprotinin group. Median duration of mechanical ventilation was reduced compared with tranexamic acid: 2.9 days (interquartile range: 1.7-5.1 days) versus 4.2 days (2.9-5.2 days), P = .04. Production of tumor necrosis factor and interleukin-2 activation were attenuated in the aprotinin group at 24 hours postoperatively. No differential effects on renal function were seen between agents. CONCLUSIONS Aprotinin, compared with tranexamic acid, was associated with reduced perioperative blood product use, improved early indices of postoperative recovery, and attenuated indices of cytokine activation, without early adverse effects. These findings suggest that aprotinin may have unique effects in the context of neonatal cardiac surgery and challenge contentions that antifibrinolytics are equivalent with respect to early postoperative outcomes.

Preoperative management of hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) is the most common functional single ventricle congenital cardiac defect. This syndrome is characterised by a functional single right ventricle and systemic outflow obstruction. The systemic and pulmonary circulations compete for cardiac output with a resultant pr-ecarious balance among systemic, pulmonary and coronary blood flows. A once fatal diagnosis, advances in operative and perioperative care have resulted in a dramatic improvement in survival. The preoperative management of neonates with HLHS is based predominately on clinical experience and extrapolated data from the postoperative literature. Management focuses on maintaining patency of the systemic outflow, balancing the p-ulmonary and systemic blood flows, and preserving the function of a single right ventricle to maximise oxygen delivery to the tissues. This paper reviews the available therapies for the preoperative management of HLHS.

Intraoperative Steroid Use and Outcomes Following the Norwood Procedure: An Analysis of the Pediatric Heart Network's Public Database.

Objective: Data supporting the use of perioperative steroids during cardiac surgery are conflicting, and most pediatric studies have been limited by small sample sizes and/or diverse cardiac diagnoses. The objective of this study was to determine if intraoperative steroid administration improved outcomes following the Norwood procedure. Design: A retrospective analysis was performed on the 549 neonates who underwent a Norwood procedure in the publicly available datasets from the Pediatric Heart Network’s Single Ventricle Reconstruction trial. Groups were compared to determine if outcomes differed between intraoperative steroid recipients (n = 498, 91%) and nonrecipients (n = 51, 9%). Setting: Fifteen North American centers. Subjects: Infants enrolled in the Single Ventricle Reconstruction trial. Interventions: None. Measurements and Main Results: Baseline characteristics and intraoperative variables were similar between groups with the exception of a shorter duration of cross clamp and cardiopulmonary bypass time in the group that received steroids. Subjects who did not receive intraoperative steroids had improved hospital survival (94% vs 83%, p = 0.03) but longer ICU stays (16 d; interquartile range, 12–33 vs 14 d; interquartile range, 9–28; p = 0.04) and hospital stays (29 d; interquartile range, 21–50 vs 23 d; interquartile range, 15–40; p = 0.01) than steroid recipients. In multivariate analysis, lengths of stay associations were no longer significant, but hospital survival trended toward favoring the nonsteroid group with an odds ratio of 3.52 (95% CI, 0.98–12.64; p = 0.054). Conclusions: In the large multicentered Single Ventricle Reconstruction trial, there was widespread use of intraoperative steroids. Intraoperative steroid administration was not associated with an improvement in outcomes and may be associated with a reduction in hospital survival in neonates undergoing the Norwood procedure. This study highlights the need for a randomized control trial.