BACKGROUND The Norwood procedure with a modified Blalock–Taussig (MBT) shunt, the first palliative stage for single-ventricle lesions with systemic outflow obstruction, is associated with high mortality. The right ventricle–pulmonary artery (RVPA) shunt may improve coronary flow but requires a ventriculotomy. We compared the two shunts in infants with hypoplastic heart syndrome or related anomalies. METHODS Infants undergoing the Norwood procedure were randomly assigned to the MBT shunt (275 infants) or the RVPA shunt (274 infants) at 15 North American centers. The primary outcome was death or cardiac transplantation 12 months after randomization. Secondary outcomes included unintended cardiovascular interventions and right ventricular size and function at 14 months and transplantation-free survival until the last subject reached 14 months of age. RESULTS Transplantation-free survival 12 months after randomization was higher with the RVPA shunt than with the MBT shunt (74% vs. 64%, P = 0.01). However, the RVPA shunt group had more unintended interventions (P = 0.003) and complications (P = 0.002). Right ventricular size and function at the age of 14 months and the rate of nonfatal serious adverse events at the age of 12 months were similar in the two groups. Data collected over a mean (±SD) follow-up period of 32±11 months showed a nonsignificant difference in transplantation-free survival between the two groups (P = 0.06). On nonproportional-hazards analysis, the size of the treatment effect differed before and after 12 months (P = 0.02). CONCLUSIONS In children undergoing the Norwood procedure, transplantation-free survival at 12 months was better with the RVPA shunt than with the MBT shunt. After 12 months, available data showed no significant difference in transplantation-free survival between the two groups. (ClinicalTrials.gov number, NCT00115934.)

Acute kidney injury (AKI) is a frequent complication of cardiac surgery and increases morbidity and mortality. The identification of reliable biomarkers that allow earlier diagnosis of AKI in the postoperative period may increase the success of therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 1219 adults undergoing cardiac surgery to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse patient outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. After multivariable adjustment, the highest quintiles of urine IL-18 and plasma NGAL associated with 6.8-fold and 5-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine and plasma NGAL levels associated with longer length of hospital stay, longer intensive care unit stay, and higher risk for dialysis or death. The clinical prediction model for AKI had an area under the receiver-operating characteristic curve (AUC) of 0.69. Urine IL-18 and plasma NGAL significantly improved the AUC to 0.76 and 0.75, respectively. Urine IL-18 and plasma NGAL significantly improved risk prediction over the clinical models alone as measured by net reclassification improvement (NRI) and integrated discrimination improvement (IDI). In conclusion, urine IL-18, urine NGAL, and plasma NGAL associate with subsequent AKI and poor outcomes among adults undergoing cardiac surgery. (Clinical Trials.gov number, NCT00774137).

Objective To determine the incidence, severity and risk-factors of AKI in children undergoing cardiac surgery for congenital heart defects. Design Prospective observational multicenter cohort study Setting Three pediatric intensive care units at academic centers. Patients 311 children between the ages of 1 month and 18 years undergoing pediatric cardiac surgery. Interventions None. Measurements and Main Results AKI was defined as a ≥ 50% increase in serum creatinine from the pre-operative value. Secondary outcomes were length of mechanical ventilation, length of ICU and hospital stays, acute dialysis, and in-hospital mortality. The cohort had an average age of 3.8 years with 45% females and was mostly white (82%). One third had prior cardiothoracic surgery, 91% of the surgeries were elective, and almost all patients required cardiopulmonary bypass (CPB). AKI occurred in 42% (130 patients) within 3 days after surgery. Children ≥ 2 years old and less than 13 years old had 72% lower likelihood of AKI (adjusted OR: 0.28, 95% CI: 0.16, 0.48), and patients 13 years and older had 70% lower likelihood of AKI (adjusted OR: 0.30, 95% CI: 0.10, 0.88) compared to patients less than 2 years old. Longer CPB time was linearly and independently associated with AKI. Development of AKI was independently associated with prolonged ventilation and with increased length of hospital stay. Conclusions AKI is common after pediatric cardiac surgery and is associated with prolonged mechanical ventilation and increased hospital stay. CPB time and age were independently associated with AKI risk. CPB time may be a marker for case complexity.

Objectives To test the hypothesis that, without diagnostic changes in serum creatinine, increased NGAL levels identify patients with subclinical acute kidney injury (AKI) and, therefore, worse prognosis. Background Neutrophil gelatinase-associated lipocalin (NGAL) detects subclinical AKI hours to days before increases in serum creatinine indicate manifest loss of renal function. Methods We analyzed pooled data from 2,322 patients with cardiorenal syndrome type 1 from ten prospective observational studies of NGAL. We used the terms NGAL(−) or NGAL(+) according to study-specific NGAL cut-off for optimal AKI prediction and the terms sCREA(−) or sCREA(+) to consensus diagnostic increases in serum creatinine defining AKI. A-priori-defined outcomes included need for renal replacement therapy (primary endpoint), hospital mortality, their combination and duration of stay in intensive care and in-hospital. Results Of study patients, 1,296 (55.8%) were NGAL(−)/sCREA(−), 445 (19.2%) NGAL(+)/sCREA(−), 107 (4.6%) NGAL(−)/sCREA(+) and 474 (20.4%) NGAL(+)/sCREA(+). According to the four study groups, there was a stepwise increase in subsequent renal replacement therapy initiation, (NGAL(−)/sCREA(−): 0.0015% vs. NGAL(+)/sCREA(−): 2.5% [odds ratio 16.4, 95% CI 3.6–76.9, P<0.001], NGAL(−)/sCREA(+): 7.5% and NGAL(−)/sCREA(−): 8.0%, respectively), hospital mortality (4.8%, 12.4%, 8.4%, 14.7%, respectively) and their combination (four-group comparisons: all P<0.001). There was a similar and consistent progressive increase in median number of intensive care and in-hospital days with increasing biomarker positivity: NGAL(−)/sCREA(−): 4.2 and 8.8 days; NGAL(+)/sCREA(−): 7.1 and 17.0 days; NGAL(−)/sCREA(+): 6.5 and 17.8 days; NGAL(+)/sCREA(+): 9.0 and 21.9 days; four-group comparisons: P=0.003 and P=0.040, respectively. Urine and plasma NGAL indicated a similar outcome pattern. Conclusions In the absence of diagnostic increases in serum creatinine, NGAL detects patients with subclinical AKI who have an increased risk of adverse outcomes. The concept and definition of AKI may need re-assessment.

Acute kidney injury (AKI) occurs commonly after pediatric cardiac surgery and associates with poor outcomes. Biomarkers may help the prediction or early identification of AKI, potentially increasing opportunities for therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 311 children undergoing surgery for congenital cardiac lesions to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. Severe AKI, defined by dialysis or doubling in serum creatinine during hospital stay, occurred in 53 participants at a median of 2 days after surgery. The first postoperative urine IL-18 and urine NGAL levels strongly associated with severe AKI. After multivariable adjustment, the highest quintiles of urine IL-18 and urine NGAL associated with 6.9-and 4.1-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation. The accuracy of urine IL-18 and urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.72 and 0.71, respectively. The addition of these urine biomarkers improved risk prediction over clinical models alone as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, urine IL-18 and urine NGAL, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.

Objectives We investigated the temporal pattern and predictive value (alone and in combination) of four urinary biomarkers [neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), liver fatty-acid binding protein (L-FABP) and kidney injury molecule-1 (KIM-1)] for cardiac surgery-associated acute kidney injury (AKI). Background Serum creatinine (SCr) is a delayed marker for AKI after cardiopulmonary bypass (CPB). Rapidly detectable AKI biomarkers could allow early intervention and improve outcomes. Methods Data from 220 pediatric patients were analyzed. Urine samples were obtained before and at intervals after CPB initiation. AKI was defined as a ≥50% increase in SCr from baseline within 48h after CPB. The temporal pattern of biomarker elevation was established and biomarker elevations were correlated with AKI severity and clinical outcomes. Biomarker predictive abilities were evaluated by AUC, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results AKI occurred in 27% of patients. Urine NGAL significantly increased in AKI patients at 2h after CPB initiation. IL-18 and L-FABP increased at 6h and KIM-1 increased at 12h. Biomarker elevations correlated with AKI severity and clinical outcomes, and improved AKI prediction above a clinical model. At 2h, addition of NGAL increased the AUC from 0.74 to 0.85 (p<0.0001). At 6h, NGAL, IL-18 and L-FABP each improved the AUC from 0.72 to 0.91, 0.84 and 0.77, respectively (all p<0.05). The added predictive ability of the biomarkers was supported by NRI and IDI. Biomarker combinations further improved AKI prediction. Conclusion Urine NGAL, IL-18, L-FABP, and KIM-1 are sequential predictive biomarkers for AKI and correlate with disease severity and clinical outcomes after pediatric CPB. These biomarkers, particularly in combination, may help establish the timing of injury and allow earlier intervention in AKI.

Background Survivors of the Norwood procedure may suffer neurodevelopmental impairment. Clinical trials to improve outcomes have focused primarily on methods of vital organ support during cardiopulmonary bypass. Methods In the Single Ventricle Reconstruction trial of the Norwood procedure with modified Blalock-Taussig shunt vs. right-ventricle-to-pulmonary-artery shunt, 14-month neurodevelopmental outcome was assessed using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development®-II. We used multivariable regression to identify risk factors for adverse outcome. Results Among 373 transplant-free survivors, 321 (86%) returned at age 14.3±1.1 (mean±SD) months. Mean PDI (74±19) and MDI (89±18) scores were lower than normative means (each P<.001). Neither PDI or MDI score was associated with type of Norwood shunt. Independent predictors of lower PDI score (R2= 26%) were clinical center (P=.003), birth weight<2.5 kg (P=.023), longer Norwood hospitalization (P<.001), and more complications between Norwood procedure discharge and age 12 months (P<.001). Independent risk factors for lower MDI score (R2= 34%) included center (P<.001), birth weight<2.5 kg (P=.04), genetic syndrome/anomalies (P=.04), lower maternal education (P=.04), longer mechanical ventilation after the Norwood procedure (P<.001), and more complications after Norwood discharge to age 12 months (P<.001). We found no significant relationship of PDI or MDI score to, perfusion type, other aspects of vital organ support (e.g. hematocrit, pH strategy), or cardiac anatomy. Conclusion Neurodevelopmental impairment in Norwood survivors is more highly associated with innate patient factors and overall morbidity in the first year than with intraoperative management strategies. Improved outcomes are likely to require interventions that occur outside the operating room.

Objectives We sought to identify risk factors for mortality and morbidity during the Norwood hospitalization in newborn infants with hypoplastic left heart syndrome and other single right ventricle anomalies enrolled in the Single Ventricle Reconstruction trial. Methods Potential predictors for outcome included patient- and procedure-related variables and center volume and surgeon volume. Outcome variables occurring during the Norwood procedure and before hospital discharge or stage II procedure included mortality, end-organ complications, length of ventilation, and hospital length of stay. Univariate and multivariable Cox regression analyses were performed with bootstrapping to estimate reliability for mortality. Results Analysis included 549 subjects prospectively enrolled from 15 centers; 30-day and hospital mortality were 11.5% (63/549) and 16.0% (88/549), respectively. Independent risk factors for both 30-day and hospital mortality included lower birth weight, genetic abnormality, extracorporeal membrane oxygenation (ECMO) and open sternum on the day of the Norwood procedure. In addition, longer duration of deep hypothermic circulatory arrest was a risk factor for 30-day mortality. Shunt type at the end of the Norwood procedure was not a significant risk factor for 30-day or hospital mortality. Independent risk factors for postoperative renal failure (n = 46), sepsis (n = 93), increased length of ventilation, and hospital length of stay among survivors included genetic abnormality, lower center/surgeon volume, open sternum, and post-Norwood operations. Conclusions Innate patient factors, ECMO, open sternum, and lower center/surgeon volume are important risk factors for postoperative mortality and/or morbidity during the Norwood hospitalization.