Frank W. Moler

Initial experience with partial liquid ventilation in pediatric patients with the acute respiratory distress syndrome

OBJECTIVE Liquid ventilation with perfluorocarbon previously has not been reported in pediatric patients with respiratory failure beyond the neonatal period. We evaluated the technique of partial liquid ventilation in six pediatric patients with the acute respiratory distress syndrome of sufficient severity to require extracorporeal life support (ECLS). DESIGN This study was a noncontrolled, phase I/II experimental study with a single group pretest/posttest design. SETTING All studies were performed at a tertiary, pediatric referral hospital at the University of Michigan Medical School. PATIENTS Six pediatric patients, from 8 wks to 5 1/2 yrs of age, with severe respiratory failure requiring ECLS to support gas exchange. INTERVENTIONS After 2 to 9 days on ECLS, perfluorocarbon was administered into the trachea until the dependent zone of each lung was filled. The initial administered was 12.9 +/- 2.3 mL/kg (range 5 to 20). Gas ventilation of the perfluorocarbon-filled lungs (partial liquid ventilation) was then performed. The perfluorocarbon dose was repeated daily for a total of 3 to 7 days, with a cumulative dose of 45.2 +/- 6.1 mL/kg (range 30 to 72.5). MEASUREMENTS AND MAIN RESULTS All measurements of native gas exchange were made during brief periods of discontinuation of ECLS and include PaO2 and the alveolar-arterial oxygen gradient, P(A-a)O2. Static pulmonary compliance, corrected for weight, was also measured directly. The mean PaO2 increased from 39 +/- 6 to 92 +/- 29 torr (5.2 +/- 0.8 to 12.2 +/- 3.9 kPa) over the 96 hrs after the initial dose (p = .021 by repeated-measures analysis of variance). The average P(A-a)O2 decreased from 635 +/- 10 to 499 +/- 77 torr (84.7 +/- 1.3 to 66.5 +/- 10.3 kPa) over the same time period (p = .059), while the mean static pulmonary compliance (normalized for patient weight) increased from 0.12 +/- 0.02 to 0.28 +/- 0.08 mL/cm H2O/kg (p = .01). All six patients survived. Complications potentially associated with partial liquid ventilation were limited to pneumothoraces in two of six patients. CONCLUSIONS Perfluorocarbon may be safely administered into the lungs of pediatric patients with severe respiratory failure on ECLS and may be associated with improvement in gas exchange and pulmonary compliance.

Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children

BACKGROUND Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS We conducted this trial of two targeted temperature interventions at 38 childrens hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644.).

Multicenter cohort study of in-hospital pediatric cardiac arrest.

Objectives: 1) To describe clinical characteristics, hospital courses, and outcomes of a cohort of children cared for within the Pediatric Emergency Care Applied Research Network who experienced in-hospital cardiac arrest with sustained return of circulation between July 1, 2003 and December 31, 2004, and 2) to identify factors associated with hospital mortality in this population. These data are required to prepare a randomized trial of therapeutic hypothermia on neurobehavioral outcomes in children after in-hospital cardiac arrest. Design: Retrospective cohort study. Setting: Fifteen children’s hospitals associated with Pediatric Emergency Care Applied Research Network. Patients: Patients between 1 day and 18 years of age who had cardiopulmonary resuscitation and received chest compressions for >1 min, and had a return of circulation for >20 mins. Interventions: None. Measurements and Main Results: A total of 353 patients met entry criteria; 172 (48.7%) survived to hospital discharge. Among survivors, 132 (76.7%) had good neurologic outcome documented by Pediatric Cerebral Performance Category scores. After adjustment for age, gender, and first documented cardiac arrest rhythm, variables available before and during the arrest that were independently associated with increased mortality included pre-existing hematologic, oncologic, or immunologic disorders, genetic or metabolic disorders, presence of an endotracheal tube before the arrest, and use of sodium bicarbonate during the arrest. Variables associated with decreased mortality included postoperative cardiopulmonary resuscitation. Extending the time frame to include variables available before, during, and within 12 hours following arrest, variables independently associated with increased mortality included the use of calcium during the arrest. Variables associated with decreased mortality included higher minimum blood pH and pupillary responsiveness. Conclusions: Many factors are associated with hospital mortality among children after in-hospital cardiac arrest and return of circulation. Such factors must be considered when designing a trial of therapeutic hypothermia after cardiac arrest in pediatric patients.

Outcome of pediatric patients treated with extracorporeal life support after cardiac surgery

BACKGROUND Extracorporeal life support (ECLS) has been used for over two decades in select patients after cardiac surgery. We previously described factors associated with death in this population. We now review our recent experience to reassess factors related to mortality. METHODS All pediatric patients who received ECLS support within 7 days after surgery between July 1995 and June 2001 were examined to describe clinical features associated with survival. We compared the results with our prior report to assess changes in practice and outcome. RESULTS Seventy-four patients were followed. Fifty percent survived to discharge. Hospital survival was not significantly related to patient age, cannulation site, or indication. Thirty-five percent of patients required hemofiltration while on ECLS and were significantly less likely to survive (23% vs 65%). A multivariate analysis combining all children from our prior report with the present cohort revealed that patients who received hemofiltration were five times more likely to die (odds ratio 5.01, 95% confidence interval 2.11-11.88). Children with an adequate two-ventricular repair had lower risk of death (odds ratio 0.42, 95% confidence interval 0.19-0.91) after adjusting for patient age, study period, and hours elapsed before initiation of ECLS after surgery. CONCLUSIONS Patients with an adequate two-ventricle repair have significantly higher hospital survival, whereas those with single ventricle physiology or need for dialysis have decreased survival.

The impact of extracorporeal membrane oxygenation on survival in pediatric patients with acute respiratory failure

OBJECTIVE Extracorporeal membrane oxygenation (ECMO) has been used with increasing frequency in the treatment of acute respiratory failure in pediatric patients. Our objective in this study was to test the hypothesis that ECMO improves outcome in pediatric patients with acute respiratory failure. DESIGN Multicenter, retrospective cohort analysis. SETTING Forty one pediatric intensive care units participated in the study under the auspices of the Pediatric Critical Care Study Group. PATIENTS All pediatric patients admitted to the participating institutions with acute respiratory failure during 1991 were included. Patients with congenital heart disease, contraindications to ECMO, or incomplete data were excluded, yielding a data set of 331 patients from 32 hospitals. INTERVENTIONS Conventional mechanical ventilation, high-frequency ventilation, and extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS Multivariate logistic regression analysis was used to identify factors associated with survival. In a second analysis, pairs of ECMO and non-ECMO patients, matched by severity of disease and respiratory diagnosis, were compared. The use of ECMO (p = .0082), but not the use of high-frequency ventilation, was associated with a reduction in mortality. Other factors independently associated with mortality included oxygenation index (p < .0001), Pediatric Risk of Mortality score (PRISM) (p < .0001) and the Paco2 (p = .045). In 53 diagnosis- and risk-matched pairs, there was a significantly lower mortality rate (26.4% vs. 47.2%; p < .01) in the ECMO-treated patients. When all patients were stratified into mortality risk quartiles on the basis of oxygenation index and PRISM score, the proportion of deaths among ECMO-treated patients in the 50% to 75% mortality risk quartile was less than half the proportion in the non-ECMO treated patients (28.6% vs. 71.4% p < .05)> No effect was seen in the other quartiles. CONCLUSIONS The use of ECMO was associated with an improved survival in pediatric patients with respiratory failure. The lack of association of outcome with treatment in the ECMO-capable hospital or with another tertiary technology (i.e. high-frequency ventilation) suggests that ECMO itself was responsible for the improved outcome. Further studies of this procedure are warranted but require broad-based multi-institutional participation to provide sufficient statistical power and sensitivity to demonstrate efficacy.

Multicenter cohort study of out-of-hospital pediatric cardiac arrest*

Objectives:To describe a large cohort of children with out-of-hospital cardiac arrest with return of circulation and to identify factors in the early postarrest period associated with survival. These objectives were for planning an interventional trial of therapeutic hypothermia after pediatric cardiac arrest. Methods:A retrospective cohort study was conducted at 15 Pediatric Emergency Care Applied Research Network clinical sites over an 18-month study period. All children from 1 day (24 hrs) to 18 yrs of age with out-of-hospital cardiac arrest and a history of at least 1 min of chest compressions with return of circulation for at least 20 mins were eligible. Measurements and Main Results:One hundred thirty-eight cases met study entry criteria; the overall mortality was 62% (85 of 138 cases). The event characteristics associated with increased survival were as follows: weekend arrests, cardiopulmonary resuscitation not ongoing at hospital arrival, arrest rhythm not asystole, no atropine or NaHCO3, fewer epinephrine doses, shorter duration of cardiopulmonary resuscitation, and drowning or asphyxial arrest event. For the 0- to 12-hr postarrest return-of-circulation period, absence of any vasopressor or inotropic agent (dopamine, epinephrine) use, higher lowest temperature recorded, greater lowest pH, lower lactate, lower maximum glucose, and normal pupillary responses were all associated with survival. A multivariate logistic model of variables available at the time of arrest, which controlled for gender, age, race, and asystole or ventricular fibrillation/ventricular tachycardia anytime during the arrest, found the administration of atropine and epinephrine to be associated with mortality. A second model using additional information available up to 12 hrs after return of circulation found 1) preexisting lung or airway disease; 2) an etiology of arrest drowning or asphyxia; 3) higher pH, and 4) bilateral reactive pupils to be associated with lower mortality. Receiving more than three doses of epinephrine was associated with poor outcome in 96% (44 of 46) of cases. Conclusions:Multiple factors were identified as associated with survival after out-of-hospital pediatric cardiac arrest with the return of circulation. Additional information available within a few hours after the return of circulation may diminish outcome associations of factors available at earlier times in regression models. These factors should be considered in the design of future interventional trials aimed to improve outcome after pediatric cardiac arrest.

In-hospital versus out-of-hospital pediatric cardiac arrest: A multicenter cohort study

Objectives: To describe a large multicenter cohort of pediatric cardiac arrest (CA) with return of circulation (ROC) from either the in-hospital (IH) or the out-of-hospital (OH) setting and to determine whether significant differences related to pre-event, arrest event, early postarrest event characteristics, and outcomes exist that would be critical in planning a clinical trial of therapeutic hypothermia (TH). Design: Retrospective cohort study. Setting: Fifteen Pediatric Emergency Care Applied Research Network sites. Patients: Patients aged 24 hours to 18 years with either IH or OH CA who had a history of at least 1 minute of chest compressions and ROC for at least 20 minutes were eligible. Interventions: None. Measurements and Main Results: A total of 491 patients met study entry criteria with 353 IH cases and 138 OH cases. Major differences between the IH and OH cohorts were observed for patient prearrest characteristics, arrest event initial rhythm described, and arrest medication use. Several postarrest interventions were used differently, however, the use of TH was similar (<5%) in both cohorts. During the 0–12-hour interval following ROC, OH cases had lower minimum temperature and pH, and higher maximum serum glucose recorded. Mortality was greater in the OH cohort (62% vs. 51%, p = 0.04) with the cause attributed to a neurologic indication much more frequent in the OH than in the IH cohort (69% vs. 20%; p < 0.01). Conclusions: For pediatric CA with ROC, several major differences exist between IH and OH cohorts. The finding that the etiology of death was attributed to neurologic indications much more frequently in OH arrests has important implications for future research. Investigators planning to evaluate the efficacy of new interventions, such as TH, should be aware that the IH and OH populations differ greatly and require independent clinical trials.

Respiratory syncytial virus morbidity and mortality estimates in congenital heart disease patients: a recent experience.

ObjectiveTo determine recent morbidity and mortality rates from respiratory syncytial virus infection in a pediatric congenital heart disease population. DesignRetrospective cohort study design. SettingThe C. S. Mott Childrens Hospital, University of Michigan Medical Center. PatientsA total of 740 pediatric patients hospitalized at the University of Michigan Medical Center for symptomatic respiratory syncytial virus infection, of whom, 79 patients had clinically important congenital heart disease. InterventionsNone. Measurements and Main ResultsWe retrospectively examined the charts of 740 patients hospitalized at our childrens hospital from July 1, 1983 to June 30, 1990 with symptomatic respiratory syncytial virus infection to assess morbidity and mortality outcomes. Seventy-nine patients had congenital heart disease and 40 of these patients had pulmonary hypertension. For the entire cohort and a subset of patients with community-acquired infection, those patients with congenital heart disease had longer durations of hospitalization and greater need for, and days of, both intensive care and mechanical ventilation than patients without congenital heart disease. Mortality risk for respiratory syncytial virus community-acquired infection was not different for congenital heart disease vs. noncongenital heart disease patients (0.0% vs. 0.2%; p = 1.00). When examining only patients with congenital heart disease, those patients with pulmonary hypertension had increased hospital days and greater intensive care and mechanical ventilation durations compared with patients without this diagnosis. The overall mortality rate was low and was equally low for congenital heart disease groups with or without pulmonary hypertension (2.5 vs. 2.6). For community-acquired illness, no mortality was found in either congenital heart disease group. When the cohort of congenital heart disease patients was divided into pre- and postribavirin administration eras, no differences in mean hospital duration, ICU days, and mechanical ventilation days were noted. Of the 79 congenital heart disease patients, only two died during their hospitalization in which respiratory syncytial virus infection occurred. Both patients had nosocomial-acquired respiratory syncytial virus and both were from the postribavirin administration cohort. One of these two patients had received antiviral therapy. Neither death was secondary to respiratory syncytial virus respiratory failure (based on pathologic examination). ConclusionsWe conclude that respiratory syncytial virus mortality risk in pediatric patients with congenital heart disease is less than the risk reported a decade ago. Respiratory syncytial virus infection in congenital heart disease patients with pulmonary hypertension is associated with increased morbidity but not increased mortality rates. The markedly decreased respiratory syncytial virus mortality risk in patients with congenital heart disease currently experienced is likely secondary to improvements in intensive care management and advances in the surgical correction in this population rather than antiviral therapy.

Use of extracorporeal life support as a bridge to pediatric cardiac transplantation

BACKGROUND Extracorporeal life support (ECLS) has been used for post-cardiotomy rescue, but its use as a bridge to heart transplantation (OHT) in patients with post-surgical or end-stage ventricular failure remains controversial. METHODS Records were reviewed for patients receiving ECLS for ventricular failure from January 1991 to August 2001. Patients listed for OHT were analyzed separately. Listing for OHT requirements were improbable myocardial recovery, absence of contraindications (central nervous system damage, high pulmonary resistance, ongoing infection, etc.), and parental consent. Outcome variables included patient demographics, diagnosis, days from ECLS initiation to United Network for Organ Sharing (UNOS) listing (latency), list time, renal function, and survival to discharge. RESULTS Of 145 patients with ventricular failure who received ECLS, 21 pediatric patients were UNOS listed. Of 124 non-listed patients, 57 (46%) survived to discharge. All but 3 survivors were separated from ECLS in </=7 days. Twelve underwent OHT and 10 survived to discharge (list time, 6 days; median ECLS time, 14 days). Five had ECLS discontinued without undergoing OHT (1 later underwent OHT, 2 survived to discharge). Five experienced complications while receiving ECLS and died without undergoing OHT. Six of 9 patients who required dialysis for renal failure died. Of 11 infants listed, 4 were weaned from ECLS without undergoing OHT (2 survived to discharge), 5 had OHT (ECLS support, 4 days; 4 survived to discharge) and 2 died (ECLS support, 16 and 47 days). CONCLUSIONS (1) Extracorporeal life support can be used as a bridge to OHT (even among the infant population) for at least 2 weeks with acceptable survival and hospital discharge rates, and (2) renal insufficiency with the concomitant requirement for dialysis decreases the likelihood of survival before and after OHT.

Extracorporeal life support outcome for 128 pediatric patients with respiratory failure.

PURPOSE The aim of this study was to describe a single-center experience with pediatric extracorporeal life support (ECLS) and to determine variables predictive of outcome in pediatric patients, both before the institution of ECLS and while on support. METHODS From October 1985 to September 1998 the authors supported 128 children with severe acute hypoxemic respiratory failure(n = 121, Pao2/FIo2 ratio = 58+/-29) or acute hypercarbic respiratory failure (n = 7, Paco2 = 128+/-37), despite maximal conventional ventilation. Mode of access included venoarterial bypass (VA, n = 64), venovenous bypass (VV, n = 53), and VV to VA bypass (n = 11). The techniques used included lung rest, pulmonary physiotherapy, diuresis to dry weight using hemofiltration if needed, minimal anticoagulation, and optimal systemic oxygen delivery. RESULTS The median age was 1.4 years (range, 2 weeks to 17 years). The mean duration of ECLS was 288+/-240 hours (range, 4 to 1148 hours or 0.2 to 47.8 days). Lung compliance increased from 0.32+/-0.02 mL/cm H2O/kg to 0.59+/-0.03 mL/cm H2O/kg in survivors, but only increased from 0.34+/-0.02 mL/cm H2O/kg to 0.35+/-0.02 mL/cm H2O/kg in nonsurvivors (P<.002 comparing change between survivors and nonsurvivors). Mean body weight decreased from 9%+/-2% over dry weight to 4%+/-2% in survivors, whereas in nonsurvivors the mean body weight increased from 25%+/-5% over dry weight to 35%+/-7% (P<.001). Outcome results by diagnosis were pneumonia, 73%; acute respiratory distress syndrome, 67%; and airway support, 60%, with overall lung recovery occurring in 77%, and hospital survival in 71%. Multivariate logistic regression modelling of patients with hypoxemic respiratory failure found the only pre-ECLS variable significantly associated with outcome to be pH (P<.05). Variables during the course of ECLS significantly associated with decreased survival were the presence of creatinine greater than 3.0 (P<.01), the need for inotropes (P<.04), failure to return the patient to dry weight (P<.04), and lung compliance that did not improve significantly. (P<.01). CONCLUSIONS ECLS provides life support in severe respiratory failure in children, allowing time for injured lungs to recover. Pre-ECLS predictors, such as pH and variables during ECLS, such as presence of renal failure, improvement in compliance, return to dry weight, and the need for inotropes on ECLS, may be useful for predicting outcome.