Douglas F. Willson

Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children

OBJECTIVE: After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. PATIENTS AND METHODS: Relevant manuscripts published in the English language were searched in Medline by using search terms “opioid,” “opiate,” “sedation,” “analgesia,” “child,” “infant-newborn,” “tolerance,” “dependency,” “withdrawal,” “analgesic,” “receptor,” and “individual opioid drugs.” Clinical and preclinical studies were reviewed for data synthesis. RESULTS: Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. CONCLUSIONS: Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal.

Pediatric Acute Respiratory Distress Syndrome: Consensus Recommendations From the Pediatric Acute Lung Injury Consensus Conference

OBJECTIVE To describe the final recommendations of the Pediatric Acute Lung Injury Consensus Conference. DESIGN Consensus conference of experts in pediatric acute lung injury. SETTING Not applicable. SUBJECTS PICU patients with evidence of acute lung injury or acute respiratory distress syndrome. INTERVENTIONS None. METHODS A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published, data were lacking a modified Delphi approach emphasizing strong professional agreement was used. MEASUREMENTS AND MAIN RESULTS A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published data were lacking a modified Delphi approach emphasizing strong professional agreement was used. The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the following topics related to pediatric acute respiratory distress syndrome: 1) Definition, prevalence, and epidemiology; 2) Pathophysiology, comorbidities, and severity; 3) Ventilatory support; 4) Pulmonary-specific ancillary treatment; 5) Nonpulmonary treatment; 6) Monitoring; 7) Noninvasive support and ventilation; 8) Extracorporeal support; and 9) Morbidity and long-term outcomes. There were 132 recommendations with strong agreement and 19 recommendations with weak agreement. Once restated, the final iteration of the recommendations had none with equipoise or disagreement. CONCLUSIONS The Consensus Conference developed pediatric-specific definitions for acute respiratory distress syndrome and recommendations regarding treatment and future research priorities. These are intended to promote optimization and consistency of care for children with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation.

Weaning and extubation readiness in pediatric patients.

Objective: A systematic review of weaning and extubation for pediatric patients on mechanical ventilation. Data Selection: Pediatric and adult literature, English language. Study Selection: Invited review. Data Sources: Literature review using National Library of Medicine PubMed from January 1972 until April 2008, earlier cross-referenced article citations, the Cochrane Database of Systematic Reviews, and the Internet. Conclusions: Despite the importance of minimizing time on mechanical ventilation, only limited guidance on weaning and extubation is available from the pediatric literature. A significant proportion of patients being evaluated for weaning are actually ready for extubation, suggesting that weaning is often not considered early enough in the course of ventilation. Indications for extubation are even less clear, although a trial of spontaneous breathing would seem a prerequisite. Several indices have been developed in an attempt to predict weaning and extubation success but the available literature would suggest they offer no improvement over clinical judgment. Extubation failure rates range from 2% to 20% and bear little relationship to the duration of mechanical ventilation. Upper airway obstruction is the single most common cause of extubation failure. A reliable method of assessing readiness for weaning and predicting extubation success is not evident from the pediatric literature.

Complications in infants hospitalized for bronchiolitis or respiratory syncytial virus pneumonia.

OBJECTIVE To characterize complications among infants hospitalized for bronchiolitis or respiratory syncytial virus (RSV). STUDY DESIGN Retrospective data from 684 infants with bronchiolitis or RSV pneumonia, < or =1 year old, admitted to 10 childrens hospitals from April 1995 to September 1996. Outcomes included complication rates and effects on hospital and pediatric intensive care unit (PICU) length of stay (LOS) and hospital costs. RESULTS Most infants (79%) had one or more complication, with serious complications in 24%. Even minor complications were associated with significantly longer PICU and hospital LOS and higher costs (P<.001). Respiratory complications were most frequent (60%), but infectious (41%), cardiovascular (9%), electrolyte imbalance (19%), and other complications (9%) were common. Complication rates were higher in former premature infants (87%), infants with congenital heart disease (93%), and infants with other congenital abnormalities (90%) relative to infants without risk factors (76%). Infants 33 to 35 weeks gestational age (GA) had the highest complication rates (93%), longer hospital LOS, and higher costs (P<.004) than other former premature infants. CONCLUSIONS Complications were common in infants hospitalized for bronchiolitis or RSV pneumonia and were associated with longer LOS and higher costs. Former premature infants and infants with congenital abnormalities are at significantly greater risk for complications. Broader use of RSV prevention should be considered for these higher-risk infants.

Parents' perspectives on physician-parent communication near the time of a child's death in the pediatric intensive care unit

Objective: Communicating bad news about a child’s illness is a difficult task commonly faced by intensive care physicians. Greater understanding of parents’ scope of experiences with bad news during their child’s hospitalization will help physicians communicate more effectively. Our objective is to describe parents’ perceptions of their conversations with physicians regarding their child’s terminal illness and death in the pediatric intensive care unit (PICU). Design: A secondary analysis of a qualitative interview study. Setting: Six children’s hospitals in the National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Participants: Fifty-six parents of 48 children who died in the PICU 3–12 months before the study. Interventions: Parents participated in audio recorded semistructured telephone interviews. Interviews were analyzed using established qualitative methods. Measurements and Main Results: Of the 56 parents interviewed, 40 (71%) wanted to provide feedback on the way information about their child’s terminal illness and death was communicated by PICU physicians. The most common communication issue identified by parents was the physicians’ availability and attentiveness to their informational needs. Other communication issues included honesty and comprehensiveness of information, affect with which information was provided, withholding of information, provision of false hope, complexity of vocabulary, pace of providing information, contradictory information, and physicians’ body language. Conclusions: The way bad news is discussed by physicians is extremely important to most parents. Parents want physicians to be accessible and to provide honest and complete information with a caring affect, using lay language, and at a pace in accordance with their ability to comprehend. Withholding prognostic information from parents often leads to false hopes and feelings of anger, betrayal, and distrust. Future research is needed to investigate whether the way bad news is discussed influences psychological adjustment and family functioning among bereaved parents.

Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure

OBJECTIVE Prospective study of the efficacy of calf lung surfactant extract in pediatric respiratory failure. DESIGN Multi-institutional, prospective, randomized, controlled, unblinded trial. SETTING Eight pediatric intensive care units (ICU) of tertiary medical centers. PATIENTS Forty-two children with acute hypoxemic respiratory failure characterized by diffuse, bilateral pulmonary infiltrates, need for ventilatory support, and an oxygenation index of >7. INTERVENTION Instillation of intratracheal surfactant (80 mL/m2). MEASUREMENTS AND MAIN RESULTS Ventilator parameters, arterial blood gases, and derived oxygenation and ventilation indices were recorded before and at intervals after surfactant administration. Complications and outcome measures, including mortality, duration of mechanical ventilation, and length of pediatric ICU and hospital stay, were also examined. Patients who received surfactant demonstrated rapid improvement in oxygenation and, on average, were extubated 4.2 days (32%) sooner and spent 5 fewer days (30%) in pediatric intensive care than control patients. There was no difference in mortality or overall hospital stay. Surfactant administration was associated with no serious adverse effects. CONCLUSIONS Administration of calf lung surfactant extract, calfactant, appears to be safe and is associated with rapid improvement in oxygenation, earlier extubation, and decreased requirement for intensive care in children with acute hypoxemic respiratory failure. Further study is needed, however, before widespread use in pediatric respiratory failure can be recommended.

Identification of pediatric septic shock subclasses based on genome-wide expression profiling

BackgroundSeptic shock is a heterogeneous syndrome within which probably exist several biological subclasses. Discovery and identification of septic shock subclasses could provide the foundation for the design of more specifically targeted therapies. Herein we tested the hypothesis that pediatric septic shock subclasses can be discovered through genome-wide expression profiling.MethodsGenome-wide expression profiling was conducted using whole blood-derived RNA from 98 children with septic shock, followed by a series of bioinformatic approaches targeted at subclass discovery and characterization.ResultsThree putative subclasses (subclasses A, B, and C) were initially identified based on an empiric, discovery-oriented expression filter and unsupervised hierarchical clustering. Statistical comparison of the three putative subclasses (analysis of variance, Bonferonni correction, P < 0.05) identified 6,934 differentially regulated genes. K-means clustering of these 6,934 genes generated 10 coordinately regulated gene clusters corresponding to multiple signaling and metabolic pathways, all of which were differentially regulated across the three subclasses. Leave one out cross-validation procedures indentified 100 genes having the strongest predictive values for subclass identification. Forty-four of these 100 genes corresponded to signaling pathways relevant to the adaptive immune system and glucocorticoid receptor signaling, the majority of which were repressed in subclass A patients. Subclass A patients were also characterized by repression of genes corresponding to zinc-related biology. Phenotypic analyses revealed that subclass A patients were younger, had a higher illness severity, and a higher mortality rate than patients in subclasses B and C.ConclusionGenome-wide expression profiling can identify pediatric septic shock subclasses having clinically relevant phenotypes.

Calf's lung surfactant extract in acute hypoxemic respiratory failure in children

OBJECTIVE Open-label trial of the safety and short-term efficacy of calfs lung surfactant in pediatric respiratory failure. DESIGN Multi-institutional, uncontrolled, observational trial. SETTING Six pediatric intensive care units of tertiary medical centers. PATIENTS Twenty-nine children with acute hypoxemic respiratory failure, characterized by diffuse, bilateral, pulmonary infiltrates, need for ventilator support, and an oxygenation index of > or = 7. INTERVENTIONS Up to four doses of intratracheal surfactant (80 mL/m2). MEASUREMENTS AND MAIN RESULTS Ventilator parameters, arterial blood gases, and derived oxygenation and ventilation indices were recorded before, and at intervals after, surfactant administration. Complications and outcome measures were also noted. There was immediate improvement in oxygenation and moderation of ventilator support associated with surfactant administration in 24 of 29 patients. A modest but statistically insignificant effect was seen with subsequent doses. The only complications occurred in three patients who developed airleaks, two of which were coincident with surfactant administration. The overall mortality rate was 14%, which compares favorably with other published series. CONCLUSIONS Administration of calfs lung surfactant appears to be safe and is associated with rapid improvement in oxygenation and moderation of ventilator support in children with acute hypoxemic respiratory failure. These results set the stage for a randomized, controlled study.

Defining acute lung disease in children with the oxygenation saturation index.

Objective: To evalute whether a formula could be derived using oxygen saturation (Spo2) to replace Pao2 that would allow identification of children with acute lung injury and acute respiratory distress syndrome. Definitions of acute lung injury and acute respiratory distress syndrome require arterial blood gases to determine the Pao2/Fio2 ratio of 300 (acute lung injury) and 200 (acute respiratory distress syndrome). Design: Post hoc data analysis of measurements abstracted from two prospective databases of randomized controlled trials. Setting: Academic pediatric intensive care units. Patients: A total of 255 children enrolled in two large prospective trials of therapeutic intervention for acute lung disease: calfactant and prone positioning. Interventions: Data were abstracted including Pao2, Paco2, pH, Fio2, and mean airway pressure. Repeated-measures analyses, using linear mixed-effects models, were used to build separate prediction equations for the Spo2/Fio2 ratio, oxygenation index [(Fio2 × Mean Airway Pressure)/Pao2], and oxygen saturation index [(Fio2 × Mean Airway Pressure)/Spo2 ]. A generalization of R2 was used to measure goodness-of-fit. Generalized estimating equations with a logit link were used to calculate the sensitivity and specificity for the cutoffs of Pao2/Fio2 ratio of 200 and 300 and equivalent values of Spo2/Fio2 ratio, oxygenation index, and oxygen saturation index. Measurements and Main Results: An Spo2/Fio2 ratio of 253 and 212 would equal criteria for acute lung injury and acute respiratory distress syndrome, respectively. An oxygenation index of 5.3 would equal acute lung injury criteria, and an oxygenation index of 8.1 would qualify for acute respiratory distress syndrome. An oxygen saturation index, which includes the mean airway pressure and the noninvasive measure of oxygenation, of 6.5 would be equivalent to the acute lung injury criteria, and an oxygen saturation index of 7.8 would equal acute respiratory distress syndrome criteria. Conclusions: Noninvasive methods of assessing oxygenation may be utilized with reasonable sensitivity and specificity to define acute lung injury and acute respiratory distress syndrome, and, with prospective validation, have the potential to increase the number of children enrolled into clinical trials.

Comparison of SpO2 to PaO2 based markers of lung disease severity for children with acute lung injury.

Objective:Given pulse oximetry is increasingly substituting for arterial blood gas monitoring, noninvasive surrogate markers for lung disease severity are needed to stratify pediatric risk. We sought to validate prospectively the comparability of SpO2/Fio2 to PaO2/Fio2 and oxygen saturation index to oxygenation index in children. We also sought to derive a noninvasive lung injury score. Design:Prospective, multicentered observational study in six pediatric intensive care units. Patients:One hundred thirty-seven mechanically ventilated children with SpO2 80% to 97% and an indwelling arterial catheter. Interventions:Simultaneous blood gas, pulse oximetry, and ventilator settings were collected. Derivation and validation data sets were generated, and linear mixed modeling was used to derive predictive equations. Model performance and fit were evaluated using the validation data set. Measurements and Main Results:One thousand one hundred ninety blood gas, SpO2, and ventilator settings from 137 patients were included. Oxygen saturation index had a strong linear association with oxygenation index in both derivation and validation data sets, given by the equation oxygen saturation index = 2.76 1 0.547*oxygenation index (derivation). 1/SpO2/Fio2 had a strong linear association with 1/PaO2/Fio2 in both derivation and validation data sets given by the equation 1/SpO2/Fio2 = 0.00232 1 0.443/PaO2/Fio2 (derivation). SpO2/Fio2 criteria for acute respiratory distress syndrome and acute lung injury were 221 (95% confidence interval 215–226) and 264 (95% confidence interval 259–269). Multivariate models demonstrated that oxygenation index, serum pH, and Paco2 were associated with oxygen saturation index (p < .05); and 1/PaO2/Fio2, mean airway pressure, serum pH, and Paco2 were associated with 1/SpO2/Fio2 (p < .05). There was strong concordance between the derived noninvasive lung injury score and the original pediatric modification of lung injury score with a mean difference of 20.0361 &agr;0.264 sd. Conclusions:Lung injury severity markers, which use SpO2, are adequate surrogate markers for those that use PaO2 in children with respiratory failure for SpO2 between 80% and 97%. They should be used in clinical practice to characterize risk, to increase enrollment in clinical trials, and to determine disease prevalence. (Crit Care Med 2012; 40:–1316)