Joshua W. Salvin

Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis.

Deletions of chromosome 22q11 have been seen in association with DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). In the present study, we analysed samples from 76 patients referred with a diagnosis of either DGS or VCFS to determine the prevalence of 22q11 deletions in these disorders. Using probes and cosmids from the DiGeorge critical region (DGCR), deletions of 22q11 were detected in 83% of DGS and 68% of VCFS patients by DNA dosage analysis, fluorescence in situ hybridisation, or by both methods. Combined with our previously reported patients, deletions have been detected in 88% of DGS and 76% of VCFS patients. The results of prenatal testing for 22q11 deletions by FISH in two pregnancies are presented. We conclude that FISH is an efficient and direct method for the detection of 22q11 deletions in subjects with features of DGS and VCFS as well as in pregnancies at high risk for a deletion.

Neurological injury after extracorporeal membrane oxygenation use to aid pediatric cardiopulmonary resuscitation.

Objectives: Extracorporeal membrane oxygenation (ECMO) to aid failed cardiopulmonary resuscitation (CPR) in children is associated with a high incidence of neurologic injury. We sought to identify risk factors for acute neurologic injury in children undergoing ECMO to aid CPR (E-CPR). Design: Retrospective cohort study using data reported to the Extracorporeal Life Support Organization registry. Setting: Multi-institutional data. Patients: Patients <18 years of age undergoing E-CPR during 1992–2005. Interventions: None. Measurements and Results: We defined acute neurologic injury as the occurrence of brain death, brain infarction, or intracranial hemorrhage identified by ultrasound or computerized tomography imaging. Of 682 E-CPR patients, 147 (22%) patients had acute neurologic injury. Brain death occurred in 74 (11%), cerebral infarction in 45 (7%), and intracranial hemorrhage in 45 (7%). The in-hospital mortality rate in patients with acute neurologic injury was 89%. In a multivariable logistic regression model, pre-ECMO factors including cardiac disease (odds ratio [OR] 0.46 [95% confidence interval {CI} 0.28–0.76]) and pre-ECMO blood pH ≥6.865 (≥6.865–7.120; OR 0.49 [95% CI 0.25–0.94]; pH >7.120; OR 0.47 [95% CI 0.26–0.85]) compared with pH <6.865 were associated with decreased odds of neurologic injury. During ECMO, neurologic injury was associated with ECMO complications including pulmonary hemorrhage (OR 1.93, 95% CI 1.1–3.4), dialysis use (OR 2.36, 95% CI 1.4–4.0), and CPR during ECMO support (OR 2.08, 95% CI 1.6–3.8). Conclusions: Neurologic injury is a frequent complication in children undergoing E-CPR. Children with cardiac disease, less severe metabolic acidosis before ECMO, and an uncomplicated ECMO course have decreased odds of sustaining neurologic injury. Providing effective CPR and inclusion of brain protective therapies on ECMO should be considered in the future to improve neurologic outcomes for patients undergoing E-CPR.

Blood Transfusion After Pediatric Cardiac Surgery Is Associated With Prolonged Hospital Stay

BACKGROUND Red blood cell transfusion is associated with morbidity and mortality among adults undergoing cardiac surgery. We aimed to evaluate the association of transfusion with morbidity among pediatric cardiac surgical patients. METHODS Patients discharged after cardiac surgery in 2003 were retrospectively reviewed. The red blood cell volume administered during the first 48 postoperative hours was used to classify patients into nonexposure, low exposure (≤15 mL/kg), or high exposure (>15 mL/kg) groups. Cox proportional hazards modeling was used to evaluate the association of red blood cell exposure to length of hospital stay (LOS). RESULTS Of 802 discharges, 371 patients (46.2%) required blood transfusion. Demographic differences between the transfusion exposure groups included age, weight, prematurity, and noncardiac structural abnormalities (all p<0.001). Distribution of Risk Adjusted Classification for Congenital Heart Surgery, version 1 (RACHS-1) categories, intraoperative support times, and postoperative Pediatric Risk of Mortality Score, Version III (PRISM-III) scores varied among the exposure groups (p<0.001). Median duration of mechanical ventilation (34 hours [0 to 493] versus 27 hours [0 to 621] versus 16 hours [0 to 375]), incidence of infection (21 [14%] versus 29 [13%] versus 17 [4%]), and acute kidney injury (25 [17%] versus 29 [13%] versus 34 [8%]) were highest in the high transfusion exposure group when compared with the low or nontransfusion groups (all p<0.001). In a multivariable Cox proportional hazards model, both the low transfusion group (adjusted hazard ratio [HR] 0.80, 95% confidence interval [CI]: 0.66 to 0.97, p=0.02) and high transfusion group (adjusted HR 0.66, 95% CI: 0.53 to 0.82, p<0.001) were associated with increased LOS. In subgroup analyses, both low transfusion (adjusted HR 0.81, 95% CI: 0.65 to 1.00, p=0.05) and high transfusion (adjusted HR 0.65, 95% CI: 0.49 to 0.87, p=0.004) in the biventricular group but not in the single ventricle group was associated with increased LOS. CONCLUSIONS Blood transfusion is associated with prolonged hospitalization of children after cardiac surgery, with biventricular patients at highest risk for increased LOS. Future studies are necessary to explore this association and refine transfusion practices.

Fetal tricuspid valve size and growth as predictors of outcome in pulmonary atresia with intact ventricular septum.

OBJECTIVE. Pulmonary atresia with intact ventricular septum is a complex congenital cardiovascular anomaly that frequently requires single ventricle palliation. Fetal diagnosis of pulmonary atresia with intact ventricular septum is common, but the natural history of pulmonary atresia with intact ventricular septum diagnosed in midgestation, predictors of neonatal anatomy, and predictors of biventricular repair have not been determined. The objective of this study was to determine whether the size and rate of growth of the fetal tricuspid valve predict neonatal anatomy and biventricular repair. DESIGN AND RESULTS. Twenty-three fetuses diagnosed with pulmonary atresia with intact ventricular septum between 1990 and 2004 were studied. Of 13 fetuses with a midgestation fetal tricuspid valve z score ≤−3, 1 achieved biventricular repair, compared with 5 of 5 with a tricuspid valve z score >−3. Of 13 fetuses with a midgestation fetal tricuspid valve z score ≤−3, 8 were diagnosed postnatally with a right ventricular dependent coronary circulation, compared with none with a tricuspid valve z score >−3. Midgestation and late gestation fetal tricuspid valve z scores correlated with neonatal tricuspid valve z score. The average rate of tricuspid valve growth between mid- and late fetal echocardiograms was significantly lower in patients who did not achieve biventricular repair than in those who did (0.012 ± 0.008 cm per week vs 0.028 ± 0.014 cm per week). CONCLUSIONS. Fetal tricuspid valve z score and rate of growth predict postnatal outcome in pulmonary atresia with intact ventricular septum. These findings may have important implications for prenatal counseling and selection of patients for fetal pulmonary valve dilation.

Extracorporeal membrane oxygenation after stage 1 palliation for hypoplastic left heart syndrome

OBJECTIVE To report the outcomes from a large multicenter cohort of neonates requiring extracorporeal membrane oxygenation (ECMO) after stage 1 palliation for hypoplastic left heart syndrome. METHODS Using data from the Extracorporeal Life Support Organization (2000-2009), we computed the survival to hospital discharge for neonates (age ≤30 days) supported with ECMO after stage 1 palliation for hypoplastic left heart syndrome. The factors associated with mortality were evaluated using multivariate logistic regression analysis. RESULTS Among 738 neonates, the survival rate was 31%. The median age at cannulation was 7 days (interquartile range, 4-11). Black race (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.6), mechanical ventilation before ECMO (>15-131 hours: OR, 1.6; 95% CI, 1.1-2.4; >131 hours: OR, 1.9; 95% CI, 1.3-2.9), use of positive end expiratory pressure (>6-8 cm H(2)O: OR, 1.7; 95% CI, 1.1-2.7; >8 cm H(2)O: OR, 1.9; 95% CI, 1.2-3.1), and longer ECMO duration (per day, OR, 1.2; 95% CI, 1.1-1.3) increased mortality. ECMO support for failure to wean from cardiopulmonary bypass (OR, 1.6; 95% CI, 1.02-2.4) also decreased survival. ECMO complications, including renal failure (OR, 1.9; 95% CI, 1.2-3.1), inotrope requirement (OR, 1.5; 95% CI, 1.1-2.1), myocardial stun (OR, 3.2; 95% CI, 1.3-7.7), metabolic acidosis (OR, 2.9; 95% CI, 1.3-6.7), and neurologic injury (OR, 1.7; 95% CI, 1.1-2.6), during support also increased mortality. CONCLUSIONS Mortality for neonates with hypoplastic left heart syndrome supported with ECMO after stage 1 palliation is high. Longer ventilation before cannulation, longer support duration, and ECMO complications increased mortality.

Factors Associated With Prolonged Recovery After the Fontan Operation

Background— Mortality and major morbidity after the Fontan operation is low in the current era. However, factors contributing to prolonged postoperative recovery are not clearly understood. Methods and Results— Data on all patients admitted to the cardiac intensive care unit (CICU) after a Fontan operation between June 2001 and December 2005 were retrospectively analyzed. We excluded all patients who died, required Fontan takedown, or required ECMO. The study cohort was further divided into a prolonged recovery group that included patients with >75%ile for duration of mechanical ventilation or pleural drainage, and a standard recovery group which included all other patients. A multivariable logistic regression model was used to compare demographic, anatomic, and physiological variables between the prolonged and standard recovery groups. There were 226 Fontan operations performed. Of the study population (n=218), the median age was 2.61 years (1.0 to 31.9 years) and weight was 12.45 kg (8.4 to 77.5 kg). The most common diagnosis was hypoplastic left heart syndrome (n=80, 36.7%). A systemic right atrioventricular valve was present in 139 (63.7%). The lateral tunnel fenestrated Fontan was the most common surgery (n=195, 89.4%). Within the study population, 81 (38%) patients meet criteria for prolonged recovery. Univariate risk factors for prolonged recovery included higher preoperative PVR (P=0.033), longer bypass times (P=0.009), higher postbypass lactate level (P=0.017), higher postoperative central venous (P<0.001) common atrial pressure (P=0.042), inotropic score (P<0.001), and need for greater volume resuscitation during the 24 postoperative hours (>75% for the entire group; P<0.001). In a multivariable model, need for greater volume resuscitation (OR 2.81, 95% CI 1.30, 6.05) was the only independent risk factor for prolonged outcome after the Fontan operation. Conclusions— High volume expansion in the early postoperative period is an independent risk factor for prolonged recovery. The need for high volume expansion may represent the compound effects of multiple risk factors including preoperative hemodynamics and a marked systemic inflammatory response to surgery and cardiopulmonary bypass, which in turn may mediate prolonged recovery.

Perioperative factors associated with prolonged mechanical ventilation after complex congenital heart surgery.

Objective: To evaluate perioperative factors associated with prolonged mechanical ventilation in children undergoing complex cardiac surgery for congenital heart disease. Design: Retrospective chart review. Setting: A tertiary care pediatric cardiac intensive care. Interventions: None. Measurements and Main Results: This retrospective cohort study included all patients undergoing complex cardiac surgical procedures (Risk Adjustment in Congenital Heart Surgery-1 category ≥3) at our institution during 2003. We defined prolonged mechanical ventilation as need for mechanical ventilation for ≥7 days (90th percentile of duration of mechanical ventilation for the whole cohort). Multivariate logistic regression analyses were used to determine independent relationships between perioperative factors and prolonged mechanical ventilation. A total of 362 patients were admitted to the cardiac intensive care unit after a cardiac surgical procedure of Risk Adjustment in Congenital Heart Surgery-1 ≥3 level of complexity and survived to hospital discharge. Median age was 242 days (range, 4 days−14.4 yrs), the median duration of mechanical ventilation was 1.5 days (range, 0–7 days), and 41 patients (11%) were ventilated for ≥7 days. Age of <30 days at surgery, higher Pediatric Risk of Mortality III score at the time of cardiac intensive care unit admission, the presence of major noncardiac structural anomalies, healthcare-associated infections, noninfectious pulmonary complications (pleural effusions and pneumothorax), and the need for reintervention were all independently associated with prolonged mechanical ventilation. Conclusions: Younger age, greater severity of illness at postoperative admission, healthcare-associated infections, noninfectious pulmonary complications, and the need for reintervention are associated with prolonged mechanical ventilation after complex cardiac surgery. Future studies and quality improvement initiatives should focus on those risk factors that are modifiable to promote early extubation in children recovering from complex congenital heart surgery.

Extracorporeal membrane oxygenation support after the Fontan operation

OBJECTIVE Extracorporeal membrane oxygenation has been used to support children with cardiac failure after the Fontan operation. Mortality is high, and causes of mortality remain unclear. We evaluated the in-hospital mortality and factors associated with mortality in these patients. METHODS Extracorporeal Life Support Organization registry data on patients requiring extracorporeal membrane oxygenation after the Fontan operation from 1987 to 2009 were retrospectively analyzed. Demographics and extracorporeal membrane oxygenation data were compared for survivors and nonsurvivors. A multivariable logistic regression model was used to identify factors associated with mortality. RESULTS Of 230 patients, 81 (35%) survived to hospital discharge. Cardiopulmonary resuscitation was more frequent (34% vs 17%, P = .04), and median fraction of inspired oxygen concentration was higher (1 [confidence interval, 0.9-1.0] vs 0.9 [confidence interval, 0.8-1.0], P = .03) before extracorporeal membrane oxygenation in nonsurvivors compared with survivors. Extracorporeal membrane oxygenation duration and incidence of complications, including surgical bleeding, neurologic injury, renal failure, inotrope use on extracorporeal membrane oxygenation, and bloodstream infection, were higher in nonsurvivors compared with survivors (P < .05 for all). In a multivariable model, neurologic injury (odds ratio, 5.18; 95% confidence interval, 1.97-13.61), surgical bleeding (odds ratio, 2.36; 95% confidence interval, 1.22-4.56), and renal failure (odds ratio, 2.81; 95% confidence interval, 1.41-5.59) increased mortality. Extracorporeal membrane oxygenation duration of more than 65 hours to 119 hours (odds ratio, 0.33; 95% confidence interval, 0.14-0.76) was associated with decreased mortality. CONCLUSIONS Cardiac failure requiring extracorporeal membrane oxygenation after the Fontan operation is associated with high mortality. Complications during extracorporeal membrane oxygenation support increase mortality odds. Prompt correction of surgical bleeding when possible may improve survival.

The association of carotid artery cannulation and neurologic injury in pediatric patients supported with venoarterial extracorporeal membrane oxygenation

Objectives: To describe the prevalence of neurologic injury in a recent cohort of patients 18 years old or younger cannulated for venoarterial extracorporeal membrane oxygenation. To evaluate the association of carotid artery cannulation with neurologic injury when compared with other cannulation sites. To determine if age impacts the association of carotid artery cannulation with neurologic injury. Design: Retrospective analysis of data from the Extracorporeal Life Support Organization registry. Setting: Neonatal and pediatric medical/surgical and cardiac ICUs of 118 international tertiary care centers worldwide. Patients: Pediatric patients 18 years old or younger cannulated for venoarterial extracorporeal membrane oxygenation and reported to the Extracorporeal Life Support Organization registry during 2007 and 2008. Interventions: None. Measurements and Main Results: Two thousand nine hundred seventy-seven patients underwent venoarterial extracorporeal membrane oxygenation during the study period. Indications for extracorporeal membrane oxygenation included pulmonary (n = 1,390, 47%), cardiac (n = 1,168, 39%), extracorporeal membrane oxygenation during cardiopulmonary resuscitation (n = 418, 14%), and unknown (n = 1). Arterial cannulation sites were aorta (n = 938, 32%), femoral artery (n = 118, 4%), and carotid artery (n = 1,921, 64%). Overall, 611 patients (21%) had evidence of neurologic injury defined as seizures, infarction, and/or hemorrhage. The occurrence of neurologic injury varied significantly by cannulation site: femoral artery (n = 18, 15%), aorta (n = 160, 17%), and carotid artery (n = 433, 23%); p equals 0.001. Neonates represented the largest group of patients cannulated for venoarterial extracorporeal membrane oxygenation (n = 1,807, 61%), the majority of patients cannulated via the carotid artery (n = 1,276, 66%), and had the highest burden of neurologic injury (n = 398, 22%). Age, preextracorporeal membrane oxygenation high-frequency oscillatory ventilation use, preextracorporeal membrane oxygenation arterial pH and serum bicarbonate level, and preextracorporeal membrane oxygenation cardiac arrest were independently associated with neurologic injury in a covariate model. Carotid artery cannulation site was added to this adjusted model and found to independently increase odds of neurologic injury (odds ratio, 1.4 [95% CI, 1.01–1.69]). An interaction term containing age and cannulation site was not associated with neurologic injury (odds ratio, 1.06 [95% CI, 0.84–1.34]). Conclusions: Carotid artery cannulation for venoarterial extracorporeal membrane oxygenation in patients 18 years old or younger is associated with statistically significant increased odds of neurologic injury. These increased odds are present across all age groups.

Extracorporeal membrane oxygenation for postcardiotomy mechanical cardiovascular support in children with congenital heart disease

Extracorporeal membrane oxygenation (ECMO) is increasingly used to support postcardiotomy cardiorespiratory failure in children with congenital heart disease. We report on survival outcomes and factors associated with survival for postcardiotomy ECMO patients.