T. Charles Casper

Pediatric and neonatal extracorporeal membrane oxygenation: does center volume impact mortality?*.

Objective:Extracorporeal membrane oxygenation, an accepted rescue therapy for refractory cardiopulmonary failure, requires a complex multidisciplinary approach and advanced technology. Little is known about the relationship between a center’s case volume and patient mortality. The purpose of this study was to analyze the relationship between hospital extracorporeal membrane oxygenation annual volume and in-hospital mortality and assess if a minimum hospital volume could be recommended. Design:Retrospective cohort study. Setting:A retrospective cohort admitted to children’s hospitals in the Pediatric Health Information System database from 2004 to 2011 supported with extracorporeal membrane oxygenation was identified. Indications were assigned based on patient age (neonatal vs pediatric), diagnosis, and procedure codes. Average hospital annual volume was defined as 0–19, 20–49, or greater than or equal to 50 cases per year. Maximum likelihood estimates were used to assess minimum annual case volume. Patients:A total of 7,322 pediatric patients aged 0–18 were supported with extracorporeal membrane oxygenation and had an indication assigned. Interventions:None. Measurements and Main Results:Average hospital extracorporeal membrane oxygenation volume ranged from 1 to 58 cases per year. Overall mortality was 43% but differed significantly by indication. After adjustment for case-mix, complexity of cardiac surgery, and year of treatment, patients treated at medium-volume centers (odds ratio, 0.86; 95% CI, 0.75–0.98) and high-volume centers (odds ratio, 0.75; 95% CI, 0.63–0.89) had significantly lower odds of death compared with those treated at low-volume centers. The minimum annual case load most significantly associated with lower mortality was 22 (95% CI, 22–28). Conclusions:Pediatric centers with low extracorporeal membrane oxygenation average annual case volume had significantly higher mortality and a minimum volume of 22 cases per year was associated with improved mortality. We suggest that this threshold should be evaluated by additional study.

VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock

BACKGROUND Prospective studies on the incidence of VTE during severe sepsis and septic shock remain absent, hindering efficacy assessments regarding VTE prevention strategies in sepsis. METHODS We prospectively studied 113 consecutively enrolled patients in the ICU with severe sepsis and septic shock at three hospitals. All patients provided informed consent. VTE thromboprophylaxis was recorded for all patients. Patients underwent ultrasonography and were followed for VTE prior to ICU discharge. All-cause 28-day mortality was recorded. Variables from univariate analyses that were associated with VTE (including central venous catheter [CVC] insertion, age, length of stay, and mechanical ventilation) were included in a multivariable logistic regression analysis using backward stepwise elimination to determine VTE predictors. RESULTS Mean APACHE (Acute Physiology and Chronic Health Evaluation) II score was 18.2 ± 7.0, and age was 50 ± 18 years. Despite all patients receiving guideline-recommended thromboprophylaxis, the incidence of VTE was 37.2% (95% CI, 28.3-46.8). Most VTE events were clinically significant (defined as pulmonary embolism, proximal DVT, and/or symptomatic distal DVT) and associated with an increased length of stay (18.2 ± 9.9 days vs 13.4 ± 11.5 days, P < .05). Mortality was higher in patients with acute VTE but did not reach statistical significance. Insertion of a CVC and longer mechanical ventilation duration were significant VTE risk factors. VTE incidence did not differ by thromboprophylaxis type. CONCLUSIONS To our knowledge this is the first multicenter prospective study to identify a high incidence of VTE in patients with severe sepsis and septic shock, despite the use of universal, guideline-recommended thromboprophylaxis. Our findings suggest that the systemic inflammatory milieu of sepsis may uniquely predispose patients with sepsis to VTE. More effective VTE prevention strategies are necessary in patients with sepsis. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT02353910; URL: www.clinicaltrials.gov.

Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis

OBJECTIVE To describe patient demographics, interventions, and outcomes in hospitalized children with macrophage activation syndrome (MAS) complicating systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA). METHODS We performed a retrospective cohort study using data recorded in the Pediatric Health Information System (PHIS) database from October 1, 2006 to September 30, 2010. Participants had International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for MAS and either SLE or JIA. The primary outcome was hospital mortality (for the index admission). Secondary outcomes included intensive care unit (ICU) admission, critical care interventions, and medication use. RESULTS A total of 121 children at 28 childrens hospitals met the inclusion criteria, including 19 children with SLE and 102 children with JIA. The index admission mortality rate was 7% (8 of 121 patients). ICU admission (33%), mechanical ventilation (26%), and inotrope/vasopressor therapy (26%) were common. Compared to children with JIA, those with SLE had a similar mortality rate (6% versus 11%, respectively; exact P = 0.6). More patients with SLE than those with JIA received ICU care (63% versus 27%; P = 0.002), received mechanical ventilation (53% versus 21%; P = 0.003), and had cardiovascular dysfunction (47% versus 23% received inotrope/vasopressor therapy; P = 0.02). Children with SLE and those with JIA received cyclosporine at similar rates, but more children with SLE received cyclophosphamide and mycophenolate mofetil, and more children with JIA received interleukin-1 antagonists. CONCLUSION Organ system dysfunction is common in children with rheumatic diseases complicated by MAS, and more organ system support is required in children with underlying SLE than in children with JIA. Current treatment of pediatric MAS varies based on the underlying rheumatic disease.

Pediatric diabetic ketoacidosis, fluid therapy, and cerebral injury: the design of a factorial randomized controlled trial

Treatment protocols for pediatric diabetic ketoacidosis (DKA) vary considerably among centers in the USA and worldwide. The optimal protocol for intravenous (IV) fluid administration is an area of particular controversy, mainly in regard to possible associations between rates of IV fluid infusion and the development of cerebral edema (CE), the most common and the most feared complication of DKA in children. Theoretical concerns about associations between osmotic fluid shifts and CE have prompted recommendations for conservative fluid infusion during DKA. However, recent data suggest that cerebral hypoperfusion may play a role in cerebral injury associated with DKA. Currently, there are no existing data from prospective clinical trials to determine the optimal fluid treatment protocol for pediatric DKA. The Pediatric Emergency Care Applied Research Network FLUID (FLuid therapies Under Investigation in DKA) study is the first prospective randomized trial to evaluate fluid regimens for pediatric DKA. This 13‐center nationwide factorial design study will evaluate the effects of rehydration rate and fluid sodium content on neurological status during DKA treatment, the frequency of clinically overt CE and long‐term neurocognitive outcomes following DKA.

Regional myocardial dysfunction following Norwood with right ventricle to pulmonary artery conduit in patients with hypoplastic left heart syndrome.

BACKGROUND Improved early survival has led many centers to use the right ventricle-to-pulmonary artery (RVPA) conduit instead of the modified Blalock-Taussig shunt for Norwood palliation of hypoplastic left-heart syndrome. However, there is concern regarding the potential deleterious effects of the required right ventriculotomy for placement of the RVPA conduit on global and regional right ventricular (RV) function. The purpose of this study was to investigate global and regional RV wall motion abnormalities after Norwood palliation with RVPA conduit using Velocity Vector Imaging (VVI). METHODS Thirty consecutive patients with hypoplastic left-heart syndrome who underwent stage 2 palliation between January 2007 and December 2009 were identified from the surgical database. VVI was performed on two-dimensional echocardiographic images obtained before second-stage palliation. Peak systolic circumferential and radial velocity, strain, and strain rate were measured from parasternal short-axis and apical four-chamber views. RV ejection fraction was measured using the biplane modified Simpsons rule. Regional RV systolic deformations were compared between different RV segments. VVI measures were also compared with RV systolic function. In a subgroup (n = 14), VVI was repeated on follow-up after stage 2 palliation to evaluate changes in regional and global RV deformation. RESULTS A total of 30 patients (20 males) were studied. The median age at the time of interstage echocardiography was 12 weeks (range, 8-18 weeks). In the short axis, average peak systolic circumferential strain values for the anterior, posterior, septal, and RV free wall segments were 3.79 ± 2.52%, 11.4 ± 5.2%, 13.3 ± 6.5%, and 11.1 ± 5.0%, respectively. From the short-axis view, the anterior RV segment (ventriculotomy site) exhibited significantly reduced circumferential velocity, peak systolic strain, and strain rate (P < .0001). Mean global VVI measurements were correlated with RV ejection fraction. On follow-up after stage 2 palliation, the ventriculotomy region showed persistently reduced velocity, peak systolic strain, and strain rate compared with all other segments. CONCLUSIONS In patients with hypoplastic left-heart syndrome after Norwood palliation with RVPA conduit, RV myocardial deformation was significantly reduced at the ventriculotomy site, which persisted after stage 2 palliation. VVI-derived measures demonstrating impairment of global systolic myocardial deformation were correlated with RV systolic function. Long-term multicenter studies to evaluate the effects of ventriculotomy scar on single systemic right ventricle are required.

A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children

Magnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health-related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sβ(0) thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P = .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P = .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www.clinicaltrials.gov as #NCT01197417.

A case-control study of dietary salt intake in pediatric-onset multiple sclerosis.

BACKGROUND High salt intake may be associated with pro-inflammatory changes in the immune response, and increased clinical and MRI activity in adults with relapsing-remitting multiple sclerosis. OBJECTIVE We sought to determine if dietary salt intake is associated with pediatric-onset MS risk in a multicenter, case-control study. METHODS Pediatric-onset CIS/MS cases within four years of onset and controls less than 22 years old recruited from 14 pediatric-MS centers were studied. Dietary sodium intake was assessed using the validated Block Kids Food Screener (NutritionQuest). Sodium intake, excess sodium, and sodium terciles were compared between cases and controls. Logistic regression models were adjusted for age, gender, ethnicity, body mass index, and socioeconomic status. RESULTS Among 170 cases (mean age=15.2±3.5) and 331 controls (mean age=14.0±3.7), no significant difference in unadjusted mean sodium intake was found between cases (2044mg/d) and controls (2030mg/d, p=0.99). The proportion of subjects consuming excess sodium, based on the adequate intake for age and gender, was similar between cases and controls (65% versus 69%, p=0.34). There were no increased odds of higher sodium intake among cases as compared to controls (for each 100mg/d increase in sodium, OR=1.00, 95% CI 0.98, 1.02; p=0.93, for excess sodium intake, OR=1.05, 95% CI 0.67, 1.64; p=0.84). CONCLUSIONS Our results show no strong association between dietary salt intake and pediatric-onset MS risk, suggesting that salt intake may not play a prominent role in susceptibility to MS in children.

Early Lactate Elevations Following Resuscitation From Pediatric Cardiac Arrest Are Associated With Increased Mortality

Objective: To describe the association of lactate levels within the first 12 hours after successful resuscitation from pediatric cardiopulmonary arrest with hospital mortality. Design: Retrospective cohort study. Setting: Fifteen children’s hospital associated with the Pediatric Emergency Care Applied Research Network. Patients: Patients between 1 day and 18 years old who had a cardiopulmonary arrest, received chest compressions more than 1 minute, had a return of spontaneous circulation more than 20 minutes, and had lactate measurements within 6 hours of arrest. Interventions: None. Measurements and Main Results: Two hundred sixty-four patients had a lactate sampled between 0 and 6 hours (lactate0–6) and were evaluable. Of those, 153 patients had a lactate sampled between 7 and 12 hours (lactate7–12). One hundred thirty-eight patients (52%) died. After controlling for arrest location, total number of epinephrine doses, initial rhythm, and other potential confounders, the odds of death per 1 mmol/L increase in lactate0–6 was 1.14 (1.08, 1.19) (p < 0.001) and the odds of death per 1 mmol/L increase in lactate7–12 was 1.20 (1.11, 1.30) (p < 0.0001). Area under the curve for in-hospital arrest mortality for lactate0–6 was 0.72 and for lactate7–12 was 0.76. Area under the curve for out-of-hospital arrest mortality for lactate0–6 was 0.8 and for lactate7–12 was 0.75. Conclusions: Elevated lactate levels in the first 12 hours after successful resuscitation from pediatric cardiac arrest are associated with increased mortality. Lactate levels alone are not able to predict outcomes accurately enough for definitive prognostication but may approximate mortality observed in this large cohort of children’s hospitals.

Effect of ABO-Incompatible Listing on Infant Heart Transplant Waitlist Outcomes: Analysis of the United Network for Organ Sharing (UNOS) Database

BACKGROUND Midterm heart transplant outcomes of ABO-incompatible (ABO-I) organ use in infants are favorable. ABO-I transplantation has resulted in reduced waitlist mortality in some countries. This study assessed the effect of an ABO-I listing strategy on pre-transplant outcomes in the United States. METHODS The Organ Procurement and Transplantation Network (OPTN)/United Network of Organ Sharing (UNOS) database was used to identify infants aged younger than 1 year listed as status 1 for heart transplantation between January 1, 2001, and May 20, 2008. The cohort was divided into 2 groups: eligible for ABO-compatible (ABO-C) transplant and eligible for ABO-I transplant. Baseline characteristics, waitlist times, and outcomes were compared in univariate analysis. Competing risks analysis evaluated differences in time to transplant in the presence of other outcomes. RESULTS Of 1,029 infants listed for transplant, 277 (27%) were listed for an ABO-I transplant. Overall, 92% of transplant recipients received an ABO-C organ regardless of listing type. Among recipients eligible for ABO-I, only 27% received an ABO-I organ. The percentage that underwent transplant in each group did not differ. Although infants listed for an ABO-I organ had a shorter wait time for transplant, waitlist mortality was similar. CONCLUSIONS Despite the intended merits of ABO-I heart transplantation, ABO-I listing and organ acceptance have not yielded lower waitlist mortality in the United States under the current UNOS allocation algorithm. Consideration should be given to altering the allocation system to one that gives less preference toward blood group compatibility in hopes of improving organ use and reducing waitlist mortality.

Clinical features of neuromyelitis optica in children US Network of Pediatric MS Centers report

Objective: To compare clinical features of pediatric neuromyelitis optica (NMO) to other pediatric demyelinating diseases. Methods: Review of a prospective multicenter database on children with demyelinating diseases. Case summaries documenting clinical and laboratory features were reviewed by an adjudication panel. Diagnoses were assigned in the following categories: multiple sclerosis (MS), acute disseminated encephalomyelitis, NMO, and recurrent demyelinating disease not otherwise specified. Results: Thirty-eight cases of NMO were identified by review panel, 97% of which met the revised International Panel on NMO Diagnosis NMO-SD 2014 criteria, but only 49% met 2006 Wingerchuk criteria. Serum or CSF NMO immunoglobulin G (IgG) was positive in 65% of NMO cases that were tested; however, some patients became seropositive more than 3 years after onset despite serial testing. No patient had positive CSF NMO IgG and negative serum NMO IgG in contemporaneous samples. Other than race (p = 0.02) and borderline findings for sex (p = 0.07), NMO IgG seropositive patients did not differ in demographic, clinical, or laboratory features from seronegatives. Visual, motor, and constitutional symptoms (including vomiting, fever, and seizures) were the most common presenting features of NMO. Initiation of disease-modifying treatment was delayed in NMO vs MS. Two years after onset, patients with NMO had higher attack rates, greater disability accrual measured by overall Expanded Disability Status Scale score, and visual scores than did patients with MS. Conclusion: The new criteria for NMO spectrum disorders apply well to the pediatric setting, and given significant delay in treatment of NMO compared to pediatric MS and worse short-term outcomes, it is imperative to apply these to improve access to treatment.