Epidemiology of Clinically Relevant Bleeding in Critically Ill Adolescents* Objectives: The epidemiology of clinically relevant bleeding in critically ill adolescents, particularly those who are at high risk of venous thromboembolism, is unclear. In preparation for a randomized clinical trial of pharmacologic prophylaxis against venous thromboembolism, we characterized the epidemiology of clinically relevant bleeding in critically ill adolescents. Design: Post hoc analysis of data from a pediatric multicenter observational study of venous thromboembolism. Setting: Six PICUs. Patients: Adolescents 13–17 years old who received cardiac or pulmonary support for at least 48 hours were eligible. Those admitted with venous thromboembolism or receiving therapeutic anticoagulation were excluded. Interventions: None. Measurements and Main Results: Adolescents (n = 88) were followed daily for the development of any bleeding event. The severity of the event was categorized based on the definitions by the International Society on Thrombosis and Haemostasis. The frequency of clinically relevant bleeding was 29.5% (95% CI, 20.3–40.2%) or 3.7 events (95% CI, 2.5–5.4 events) per 100 patient-days. Adolescents with venous thromboembolism were more likely to develop clinically relevant bleeding (hazard ratio, 2.06; 95% CI, 1.08–3.94). Age was negatively associated with clinically relevant bleeding (hazard ratio for every 1-year increase in age: 0.68; 95% CI, 0.58–0.79). In contrast, predicted risk of mortality (hazard ratio for every 0.10 increase in risk: 1.35; 95% CI, 1.05–1.74) and admission for trauma or surgery (hazard ratio: 2.04; 95% CI, 1.21–3.44) were positively associated with clinically relevant bleeding. The association of clinically relevant bleeding with medications, interventions, or laboratory tests, including mechanical ventilation and pharmacologic prophylaxis with anticoagulation, did not reach statistical significance. Adolescents with clinically relevant bleeding stayed in the hospital longer than those without clinically relevant bleeding. Conclusions: Clinically relevant bleeding is common in critically ill adolescents who are at high risk of venous thromboembolism. Admission for trauma or surgery can be used to stratify the risk of clinically relevant bleeding in these adolescents.

Outcomes of Day 1 Multiple Organ Dysfunction Syndrome in the PICU* Objectives: We sought to describe current outcomes of Multiple Organ Dysfunction Syndrome present on day 1 of PICU admission. Design: Retrospective observational cohort study. Setting: Virtual Pediatric Systems, LLC, database admissions, January 2014 and December 2015. Patients: We analyzed 194,017 consecutive PICU admissions, (age 1 mo to 18 yr) from the 2014–2015 Virtual Pediatric Systems database. Interventions: We identified day 1 Multiple Organ Dysfunction Syndrome by International Pediatric Sepsis Consensus Conference criteria with day 1 laboratory and vital sign values. Functional status was evaluated by Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores from PICU admission and discharge. Measurements and Main Results: Overall, PICU mortality was 2.1%. We identified day 1 Multiple Organ Dysfunction Syndrome in 14.4% of admissions. Patients with Multiple Organ Dysfunction Syndrome had higher mortality than those without Multiple Organ Dysfunction Syndrome (10.3% vs 0.7%; p < 0.0001), and a higher percentage of survivors had greater than or equal to 2 category worsening in Pediatric Cerebral Performance Category score (3.6% vs 0.5%; p < 0.0001) or Pediatric Overall Performance Category score (6.0% vs 1.8%; p < 0.0001). The odds of death with day 1 Multiple Organ Dysfunction Syndrome was 14.3 (95% CI, 13–15.7), while the odds of death or discharge with Pediatric Overall Performance Category/Pediatric Cerebral Performance Category score greater than or equal to 3 (poor functional outcome) was 6.7 (95% CI, 6–7.4). In a subset of 148,188 patients from hospitals where limitation of support decisions were recorded, 5.8% patients with Multiple Organ Dysfunction Syndrome had limitation of support decisions in place, compared with 0.8% of patients without Multiple Organ Dysfunction Syndrome (p < 0.0001). Of day 1 Multiple Organ Dysfunction Syndrome patients who died, 43.1% had limitation of support decisions in place, and 41.6% had withdrawal of life-sustaining therapies (p < 0.0001). Conclusions: Multiple Organ Dysfunction Syndrome present on day 1 of admission continues to be a major source of morbidity and mortality in the PICU, but risk of poor neurologic outcome may be improved. Further research is needed to understand decisions regarding limitation of support and withdrawal of life-sustaining therapy decisions in patients admitted with day 1 Multiple Organ Dysfunction Syndrome.

Perioperative Assessment of Cerebral Oxygen Metabolism in Infants With Functionally Univentricular Hearts Undergoing the Bidirectional Cavopulmonary Connection Objectives: The transition from single-ventricle lesions with surgically placed systemic-to-pulmonary artery shunt to the circulation following a bidirectional cavopulmonary connection results in higher pressure in the superior vena cava when compared with the preceding circulation. The aim of this study was to evaluate the impact of this transition on the perioperative cerebral oxygen metabolism. Design: Prospective observational cohort study. Setting: Pediatric critical care unit of a tertiary referral center. Patients: Sixteen infants after bidirectional cavopulmonary connection. Intervention: Cardiac surgery (bidirectional cavopulmonary connection). Measurements and Main Results: We measured regional cerebral oxygen saturation, amount of hemoglobin, blood flow velocity, and microperfusion immediately before, 12–24 hours, and 36–48 hours following bidirectional cavopulmonary connection. Based on these measurements, we calculated cerebral fractional tissue oxygen extraction and approximated cerebral metabolic rate of oxygen. Mean pressure in the superior vena cava increased significantly (8 vs 17 mm Hg; p < 0.001) following bidirectional cavopulmonary connection. Mean cerebral oxygen saturation increased from 49.0% (27.4–61.0) to 56.9% (39.5–64.0) (p = 0.008), whereas mean cerebral blood flow velocity decreased from 80.0 arbitrary units (61.9–93.0) to 67.3 arbitrary units (59.0–83.3) (p < 0.001). No change was found in the cerebral amount of hemoglobin and in the cerebral microperfusion. Mean cerebral fractional tissue oxygen extraction (0.48 [0.17–0.63] vs 0.30 [0.19–0.56]; p = 0.006) and approximated cerebral metabolic rate of oxygen (5.82 arbitrary units [2.70–8.78] vs 2.27 arbitrary units [1.19–7.35]; p < 0.001) decreased significantly. Conclusions: Establishment of bidirectional cavopulmonary connection is associated with postoperative improvement in cerebral oxygen metabolism. Cerebral amount of hemoglobin did not increase, although creation of the bidirectional cavopulmonary connection results in significant elevation in superior vena cava pressure. Improvement in cerebral oxygen metabolism was due to lower cerebral blood flow velocity and stable microperfusion, which may indicate intact cerebral autoregulation.

Changes in Anesthetic and Postoperative Sedation–Analgesia Practice Associated With Early Extubation Following Infant Cardiac Surgery: Experience From the Pediatric Heart Network Collaborative Learning Study* Objectives: The Pediatric Heart Network sponsored the multicenter Collaborative Learning Study that implemented a clinical practice guideline to facilitate early extubation in infants after repair of isolated coarctation of the aorta and tetralogy of Fallot. We sought to compare the anesthetic practice in the operating room and sedation-analgesia management in the ICU before and after the implementation of the guideline that resulted in early extubation. Design: Secondary analysis of data from a multicenter study from January 2013 to April 2015. Predefined variables of anesthetic, sedative, and analgesia exposure were compared before and after guideline implementation. Propensity score weighted logistic regression analysis was used to determine the independent effect of intraoperative dexmedetomidine administration on early extubation. Setting: Five children’s hospitals. Patients: A total of 240 study subjects who underwent repair of coarctation of the aorta or tetralogy of Fallot (119 preguideline implementation and 121 postguideline implementation). Interventions: None. Measurements and Main Results: Clinical practice guideline implementation was accompanied by a decrease in the median total intraoperative dose of opioids (49.7 vs 24.0 µg/kg of fentanyl equivalents, p < 0.001) and benzodiazepines (1.0 vs 0.4 mg/kg of midazolam equivalents, p < 0.001), but no change in median volatile anesthetic agent exposure (1.3 vs 1.5 minimum alveolar concentration hr, p = 0.25). Intraoperative dexmedetomidine administration was associated with early extubation (odds ratio 2.5, 95% CI, 1.02–5.99, p = 0.04) when adjusted for other covariates. In the ICU, more patients received dexmedetomidine (43% vs 75%), but concomitant benzodiazepine exposure decreased in both the frequency (66% vs 57%, p < 0.001) and cumulative median dose (0.5 vs 0.3 mg/kg of ME, p = 0.003) postguideline implementation. Conclusions: The implementation of an early extubation clinical practice guideline resulted in a reduction in the dose of opioids and benzodiazepines without a change in volatile anesthetic agent used in the operating room. Intraoperative dexmedetomidine administration was independently associated with early extubation. The total benzodiazepine exposure decreased in the early postoperative period.

Spontaneous Breathing Trial for Prediction of Extubation Success in Pediatric Patients Following Congenital Heart Surgery: A Randomized Controlled Trial* Objectives: To evaluate the usefulness of a spontaneous breathing trial for predicting extubation success in pediatric patients in the postoperative period after cardiac surgery compared with a physician-led weaning. Study Design: Randomized, controlled trial. Setting: PICU of a tertiary-care university hospital. Patients: A population of pediatric patients following cardiac surgery for congenital heart disease. Interventions: Patients on mechanical ventilation for more than 12 hours after surgery who were considered ready for weaning were randomized to the spontaneous breathing trial group or the control group. The spontaneous breathing trial was performed on continuous positive airway pressure with the pressure support of 10 cmH2O, the positive end-expiratory pressure of 5 cmH2O, and the fraction of inspired oxygen less than or equal to 0.5 for 2 hours. Patients in the control group underwent ventilator weaning according to clinical judgment. Measurements and Main Results: The primary endpoint was extubation success defined as no need for reintubation within 48 hours after extubation. Secondary outcomes were PICU length of stay, hospital length of stay, occurrence rate of ventilator-associated pneumonia, and mortality. One hundred and ten patients with the median age of 8 months were included in the study: 56 were assigned to the spontaneous breathing trial group and 54 were assigned to the control group. Demographic and clinical data and Risk Adjustment for Congenital Heart Surgery-1 classification were similar in both groups. Patients undergoing the spontaneous breathing trial had greater extubation success (83% vs 68%, p = 0.02) and shorter PICU length of stay (median 85 vs 367 hr, p < 0.0001) compared with the control group, respectively. There was no significant difference between groups in hospital length of stay, occurrence rate of ventilator-associated pneumonia, and mortality. Conclusions: Pediatric patients with congenital heart disease undergoing the spontaneous breathing trial postoperatively had greater extubation success and shorter PICU length of stay compared with those weaned according to clinical judgment.

The Effect of Levosimendan Versus Milrinone on the Occurrence Rate of Acute Kidney Injury Following Congenital Heart Surgery in Infants: A Randomized Clinical Trial* Objectives: It has been shown that, in contrast to other inotropic agents, levosimendan improves glomerular filtration rate after adult cardiac surgery. The aim of this study was to investigate the efficacy of levosimendan, compared with milrinone, in preventing acute kidney dysfunction in infants after open-heart surgery with cardiopulmonary bypass. Design: Two-center, double-blinded, prospective, randomized clinical trial. Setting: The study was performed in two tertiary pediatric centers, one in Sweden (Gothenburg) and one in Finland (Helsinki). Patients: Infants between 1 and 12 months old, diagnosed with Tetralogy of Fallot, complete atrioventricular septal defect or nonrestrictive ventricular septal defect, undergoing total corrective cardiac surgery with cardiopulmonary bypass. Interventions: Seventy-two infants were randomized to receive a perioperative infusion of levosimendan (0.1 µg/kg/min) or milrinone (0.4 µg/kg/min). The infusion was initiated at the start of cardiopulmonary bypass and continued for 26 hours. Measurements and Main Results: The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1. Secondary outcomes included the following: 1) acute kidney injury according to the serum creatinine criteria of the Kidney Diseases: Improving Global Outcomes; 2) acute kidney injury with serum creatinine corrected for fluid balance; 3) plasma neutrophil gelatinase-associated lipocalin; 4) cystatin C; 5) urea; 6) lactate; 7) hemodynamic variables; 8) use of diuretics in the PICU; 9) need of dialysis; 10) length of ventilator therapy; and 11) length of PICU stays. There was no significant difference in postoperative serum creatinine between the treatment groups over time (p = 0.65). The occurrence rate of acute kidney injury within 48 hours was 46.9% in the levosimendan group and 39.5% in the milrinone group (p = 0.70). There were no significant differences in other secondary outcome variables between the groups. Conclusions: Levosimendan compared with milrinone did not reduce the occurrence rate of acute kidney injury in infants after total corrective heart surgery for atrioventricular septal defect, ventricular septal defect, or Tetralogy of Fallot.

Plasma Neutrophil Gelatinase-Associated Lipocalin Is Associated With Acute Kidney Injury and Clinical Outcomes in Neonates Undergoing Cardiopulmonary Bypass Objectives: Acute kidney injury is a frequent complication following neonatal cardiac surgery and is associated with significant morbidity and mortality. The objectives of this study were to determine if plasma neutrophil gelatinase-associated lipocalin levels were associated with acute kidney injury and clinical outcomes in neonates with congenital heart disease undergoing cardiopulmonary bypass. Design: Retrospective single-center observational study. Setting: A pediatric cardiac ICU within a tertiary-care academic hospital. Patients: Patients age less than 30 days undergoing cardiac surgery requiring cardiopulmonary bypass. Interventions: None. Measurements and Main Results: Plasma neutrophil gelatinase-associated lipocalin peaked at 12 hours postcardiopulmonary bypass and more than doubled compared with preoperative levels. Higher preoperative and 24-hour postoperative neutrophil gelatinase-associated lipocalin levels were associated with acute kidney injury (r = 0.30, r = 0.49), longer duration of mechanical ventilation (r = 0.40, r = 0.51), ICU (r = 0.32, r = 0.33) and hospital lengths of stay (r = 0.28, r = 0.32), and total hospital charges (r = 0.35, r = 0.30; all p values < 0.05). Conclusions: Both preoperative and 24-hour postoperative plasma neutrophil gelatinase-associated lipocalin levels are associated with acute kidney injury and worse clinical outcomes in neonates undergoing cardiac surgery. Plasma neutrophil gelatinase-associated lipocalin levels may have a role in risk stratification for predicting postoperative renal dysfunction as well as providing a potential clinical trajectory in the postoperative period.

Short- and Long-Term Outcomes of Extremely Preterm Infants in Japan According to Outborn/Inborn Birth Status* Objectives: Outborn (born outside tertiary centers) infants, especially extremely preterm infants, are at an increased risk of mortality and morbidity in comparison to inborn (born in tertiary centers) infants. Extremely preterm infants require not only skilled neonatal healthcare providers but also highly specialized equipment and environment surroundings. Maternal transport at an appropriate timing must be done to avoid the delivery of extremely preterm infants in a facility without the necessary capabilities. Cases of unexpected deliveries at birth centers or level I maternity hospitals need to be attended emergently. We compared the differences in short- and long-term outcomes between outborn and inborn infants to improve our regional perinatal system. Design: Retrospective cohort study. Setting: Neonatal Research Network of Japan database. Patients: Extremely preterm infants (gestational age between 22 + 0 and 27 + 6 wk) in the Neonatal Research Network of Japan database between 2003 and 2011. Interventions: None. Measurements and Main Results: A total of 12,164 extremely preterm infants, who were divided into outborn (n = 785, 6.5%) and inborn (n = 11,379, 93.5%) groups, were analyzed. Significant differences were observed in demographic and clinical factors between the two groups. Outborn infants had higher short-term odds of severe intraventricular hemorrhage (adjusted odds ratio, 1.49; 95% CI, 1.11–2.00; p < 0.01), necrotizing enterocolitis (adjusted odds ratio, 1.49; 95% CI, 1.11–2.00; p < 0.01), and focal intestinal perforation (adjusted odds ratio, 1.58; 95% CI, 1.09–2.30; p = 0.02). There were no significant differences in long-term outcomes between the two groups, except in the rate of cognitive impairment (adjusted odds ratio, 1.49; 95% CI, 1.01–2.20; p = 0.04). Conclusions: The frequency of severe intraventricular hemorrhage, necrotizing enterocolitis or focal intestinal perforation, and cognitive impairment was significantly higher in outborn infants. Thus, outborn/inborn birth status may play a role in short- and long-term outcomes of extremely preterm infants. However, more data and evaluation of improvement in the current perinatal environment are needed.

The Base Deficit, International Normalized Ratio, and Glasgow Coma Scale (BIG) Score, and Functional Outcome at Hospital Discharge in Children With Traumatic Brain Injury* Objectives: To examine the association of the base deficit, international normalized ratio, and Glasgow Coma Scale (BIG) score on emergency department arrival with functional dependence at hospital discharge (Pediatric Cerebral Performance Category ≥ 4) in pediatric multiple trauma patients with traumatic brain injury. Design: A retrospective cohort study of a pediatric trauma database from 2001 to 2018. Setting: Level 1 trauma program at a university-affiliated pediatric institution. Patients: Two to 17 years old children sustaining major blunt trauma including a traumatic brain injury and meeting trauma team activation criteria. Interventions: None. Measurements and Main Results: Two investigators, blinded to the BIG score, determined discharge Pediatric Cerebral Performance Category scores. The BIG score was measured on emergency department arrival. The 609 study patients were 9.7 ± 4.4 years old with a median Injury Severity Score 22 (interquartile range, 12). One-hundred seventy-one of 609 (28%) had Pediatric Cerebral Performance Category greater than or equal to 4 (primary outcome). The BIG constituted a multivariable predictor of Pediatric Cerebral Performance Category greater than or equal to 4 (odds ratio, 2.39; 95% CI, 1.81–3.15) after adjustment for neurosurgery requirement (odds ratio, 2.83; 95% CI, 1.69–4.74), pupils fixed and dilated (odds ratio, 3.1; 95% CI, 1.49–6.38), and intubation at the scene or referral hospital (odds ratio, 2.82; 95% CI, 1.35–5.87) and other postulated predictors of poor outcome. The area under the BIG receiver operating characteristic curve was 0.87 (0.84–0.90). Using an optimal BIG cutoff less than or equal to 8, sensitivity and negative predictive value for functional dependence at discharge were 93% and 96%, respectively, compared with a sensitivity of 79% and negative predictive value of 91% with Glasgow Coma Scale less than or equal to 8. In children with Glasgow Coma Scale 3, the BIG score was associated with brain death (odds ratio, 2.13; 95% CI, 1.58–2.36). The BIG also predicted disposition to inpatient rehabilitation (odds ratio, 2.26; 95% CI, 2.17–2.35). Conclusions: The BIG score is a simple, rapidly obtainable severity of illness score that constitutes an independent predictor of functional dependence at hospital discharge in pediatric trauma patients with traumatic brain injury. The BIG score may benefit Trauma and Neurocritical care programs in identifying ideal candidates for traumatic brain injury trials within the therapeutic window of treatment.

Acquired von Willebrand Syndrome in Pediatric Extracorporeal Membrane Oxygenation Patients: A Single Institution’s Experience* Objectives: 1) Describe the prevalence of acquired von Willebrand syndrome in pediatric patients undergoing extracorporeal membrane oxygenation deemed to be at increased risk for the disease in our institution, 2) discuss the challenges of testing for acquired von Willebrand syndrome diagnosis, 3) describe the characteristics of the patient population found to have acquired von Willebrand syndrome and their outcomes, and 4) discuss the potential implications of acquired von Willebrand syndrome on bleeding complications. Design: Retrospective chart review. Setting: PICU and cardiovascular ICU in a single institution. Patients: All PICU and cardiovascular ICU extracorporeal membrane oxygenation patients 0–18 years old who underwent screening for acquired von Willebrand syndrome between January 2014 and December 2016. Interventions: Humate P administration to a small subset of acquired von Willebrand syndrome positive subjects. Measurements and Main Results: Laboratory data of identified patients were analyzed. The diagnosis of acquired von Willebrand syndrome was made based on decreased ristocetin cofactor activity to von Willebrand factor antigen ratio and/or abnormal multimer analysis. Clinical data were extracted from the chart and through the Pediatric Extracorporeal Membrane Oxygenation Outcome Registry to describe the demographics, comorbidities, and outcomes of this patient population. In the 2 years, 29 patients had laboratory testing performed for surveillance and in cases of clinical bleeding. Of these, 23 (79%) were positive by criteria. No significant difference in mortality rate was found between patients with acquired von Willebrand syndrome versus without. We also did not find a significant difference in the blood product utilization or bleeding complications between patients with acquired von Willebrand syndrome versus without. Humate P was administered in 39% of patients (9/23) who were positive for acquired von Willebrand syndrome, but no significant difference was seen in blood product utilization or bleeding complications between acquired von Willebrand syndrome patients receiving Humate P versus those who did not. Conclusions: Acquired von Willebrand syndrome is a common but under recognized disorder in pediatric extracorporeal membrane oxygenation patients. The clinical implications of this disorder on bleeding and its potential treatments are still unclear.