John T. Berger

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.).

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.

Dilated cardiomyopathy following right ventricular pacing for AV block in young patients: resolution after upgrading to biventricular pacing systems.

Introduction: Cardiac resynchronization therapy (CRT) has been demonstrated to result in clinical improvement in older adult patients with dilated cardiomyopathy (DCM), specifically those with left bundle branch block and prolonged QRS duration. We sought to demonstrate the benefits of CRT on improvement in cardiac function and clinical outcome in young patients that developed congestive heart failure (CHF) and DCM following cardiac pacing for AV block.

Pediatric intensive care outcomes: development of new morbidities during pediatric critical care.

Objective: To investigate significant new morbidities associated with pediatric critical care. Design: Randomly selected, prospective cohort. Setting: PICU patients from eight medical and cardiac PICUs. Patients: This was a randomly selected, prospective cohort of PICU patients from eight medical and cardiac PICUs. Measurements and Main Results: The main outcomes measures were hospital discharge functional status measured by Functional Status Scale scores and new morbidity defined as an increase in the Functional Status Scale of more than or equal to 3. Of the 5,017 patients, there were 242 new morbidities (4.8%), 99 PICU deaths (2.0%), and 120 hospital deaths (2.4%). Both morbidity and mortality rates differed (p < 0.001) among the sites. The worst functional status profile was on PICU discharge and improved on hospital discharge. On hospital discharge, the good category decreased from a baseline of 72% to 63%, mild abnormality increased from 10% to 15%, moderate abnormality status increased from 13% to 14%, severe status increased from 4% to 5%, and very severe was unchanged at 1%. The highest new morbidity rates were in the neurological diagnoses (7.3%), acquired cardiovascular disease (5.9%), cancer (5.3%), and congenital cardiovascular disease (4.9%). New morbidities occurred in all ages with more in those under 12 months. New morbidities involved all Functional Status Scale domains with the highest proportions involving respiratory, motor, and feeding dysfunction. Conclusions: The prevalence of new morbidity was 4.8%, twice the mortality rate, and occurred in essentially all types of patients, in relatively equal proportions, and involved all aspects of function. Compared with historical data, it is possible that pediatric critical care has exchanged improved mortality rates for increased morbidity rates.

Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children

Background Targeted temperature management is recommended for comatose adults and children after out‐of‐hospital cardiac arrest; however, data on temperature management after in‐hospital cardiac arrest are limited. Methods In a trial conducted at 37 childrens hospitals, we compared two temperature interventions in children who had had in‐hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours 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 score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS‐II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS‐II score of at least 70 before the cardiac arrest. Results The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS‐II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS‐II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1‐year survival, the rate of 1‐year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood‐product use, infection, and serious adverse events, as well as 28‐day mortality, did not differ significantly between groups. Conclusions Among comatose children who survived in‐hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA‐IH ClinicalTrials.gov number, NCT00880087.)

Follow-up study of complicated grief among parents eighteen months after a child's death in the pediatric intensive care unit.

OBJECTIVE We previously demonstrated that parents whose children die in a pediatric intensive care unit (PICU) have a high level of complicated grief symptoms 6 months after the death. In this study, we investigate the change in the extent of complicated grief symptoms among these parents between 6 and 18 months postdeath and identify factors predicting improvement. METHODS One hundred thirty-eight parents of 106 children completed surveys at 6 and 18 months. Surveys included the Inventory of Complicated Grief (ICG), measures of grief avoidance, attachment, caregiving and social support, and demographics. Multivariable analysis was performed using generalized estimating equations to identify characteristics independently associated with improvement in ICG score. RESULTS ICG scores were 33.4 ± 13.6 at 6 months and 28.0 ± 13.5 at 18 months, representing an improvement in ICG score of 5.4 + 8.0 (95% confidence interval [CI] 4.1-6.8, p < 0.001). Variables independently associated with greater improvement in ICG score included traumatic death and greater grief avoidance. Variables independently associated with less improvement included being the biological parent and having more responsive caregiving. Parents with one or two surviving children had more improvement in ICG score than those with no surviving children whereas parents with three or more surviving children had less improvement. CONCLUSION Complicated grief symptoms decrease among parents between 6 and 18 months after their childs death in the PICU; however, high symptom levels persists for some. Better understanding of the trajectory of complicated grief will allow parents at risk for persistent distress to receive professional support.

Relationship Between the Functional Status Scale and the Pediatric Overall Performance Category and Pediatric Cerebral Performance Category Scales

IMPORTANCE Functional status assessment methods are important as outcome measures for pediatric critical care studies. OBJECTIVE To investigate the relationships between the 2 functional status assessment methods appropriate for large-sample studies, the Functional Status Scale (FSS) and the Pediatric Overall Performance Category and Pediatric Cerebral Performance Category (POPC/PCPC) scales. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study with random patient selection at 7 sites and 8 childrens hospitals with general/medical and cardiac/cardiovascular pediatric intensive care units (PICUs) in the Collaborative Pediatric Critical Care Research Network. Participants included all PICU patients younger than 18 years. MAIN OUTCOMES AND MEASURES Functional Status Scale and POPC/PCPC scores determined at PICU admission (baseline) and PICU discharge. We investigated the association between the baseline and PICU discharge POPC/PCPC scores and the baseline and PICU discharge FSS scores, the dispersion of FSS scores within each of the POPC/PCPC ratings, and the relationship between the FSS neurologic components (FSS-CNS) and the PCPC. RESULTS We included 5017 patients. We found a significant (P < .001) difference between FSS scores in each POPC or PCPC interval, with an FSS score increase with each worsening POPC/PCPC rating. The FSS scores for the good and mild disability POPC/PCPC ratings were similar and increased by 2 to 3 points for the POPC/PCPC change from mild to moderate disability, 5 to 6 points for moderate to severe disability, and 8 to 9 points for severe disability to vegetative state or coma. The dispersion of FSS scores within each POPC and PCPC rating was substantial and increased with worsening POPC and PCPC scores. We also found a significant (P < .001) difference between the FSS-CNS scores between each of the PCPC ratings with increases in the FSS-CNS score for each higher PCPC rating. CONCLUSIONS AND RELEVANCE The FSS and POPC/PCPC system are closely associated. Increases in FSS scores occur with each higher POPC and PCPC rating and with greater magnitudes of change as the dysfunction severity increases. However, the dispersion of the FSS scores indicated a lack of precision in the POPC/PCPC system when compared with the more objective and granular FSS. The relationship between the PCPC and the FSS-CNS paralleled the relationship between the FSS and POPC/PCPC system.

Critical care for pediatric asthma: Wide care variability and challenges for study

Objectives: To describe pediatric severe asthma care, complications, and outcomes to plan for future prospective studies by the Collaborative Pediatric Critical Care Research Network. Design: Retrospective cohort study. Setting: Pediatric intensive care units in the United States that submit administrative data to the Pediatric Health Information System. Patients: Children 1–18 yrs old treated in a Pediatric Health Information System pediatric intensive care unit for asthma during 2004-2008. Interventions: None. Measurements and Main Results: Thirteen-thousand five-hundred fifty-two children were studied; 2,812 (21%) were treated in a Collaborative Pediatric Critical Care Research Network and 10,740 (79%) were treated in a non-Collaborative Pediatric Critical Care Research Network pediatric intensive care unit. Medication use in individual Collaborative Pediatric Critical Care Research Network centers differed widely: ipratropium bromide (41%–84%), terbutaline (11%–74%), magnesium sulfate (23%–64%), and methylxanthines (0%–46%). Complications including pneumothorax (0%–0.6%), cardiac arrest (0.2%–2%), and aspiration (0.2%–2%) were rare. Overall use of medical therapies and complications at Collaborative Pediatric Critical Care Research Network centers were representative of pediatric asthma care at non-Collaborative Pediatric Critical Care Research Network pediatric intensive care units. Median length of pediatric intensive care unit stay at Collaborative Pediatric Critical Care Research Network centers was 1 to 2 days and death was rare (0.1%–3%). Ten percent of children treated at Collaborative Pediatric Critical Care Research Network centers received invasive mechanical ventilation compared to 12% at non-Collaborative Pediatric Critical Care Research Network centers. Overall 44% of patients who received invasive mechanical ventilation were intubated in the pediatric intensive care unit. Children intubated outside the pediatric intensive care unit had significantly shorter median ventilation days (1 vs. 3), pediatric intensive care unit days (2 vs. 4), and hospital days (4 vs. 7) compared to those intubated in the pediatric intensive care unit. Among children who received mechanical respiratory support, significantly more (41% vs. 25%) were treated with noninvasive ventilation and significantly fewer (41% vs. 58%) were intubated before pediatric intensive care unit care when treated in a Pediatric Health Information System hospital emergency department. Conclusions: Marked variations in medication therapies and mechanical support exist. Death and other complications were rare. More than half of patients treated with mechanical ventilation were intubated before pediatric intensive care unit care. Site of respiratory mechanical support initiation was associated with length of stay.

Increases in serum levels of troponin I are associated with cardiac dysfunction and disease severity in pediatric patients with septic shock.

Objectives: Myocardial cell injury may contribute to cardiac dysfunction in septic shock. Troponin I is a biochemical marker of myocardial cell injury and death. We hypothesized that troponin I is increased in pediatric patients with septic shock and correlates with cardiac dysfunction and disease severity. Design: Prospective, observational study. Setting: Children’s medical center. Patients: Twenty-three patients with septic shock and cardiovascular failure were enrolled. Measurements and Main Results: Serum troponin I was measured at admission and serially over 72 hrs. Within 24 hrs of study enrollment, echocardiograms were performed to determine left ventricular ejection fraction, systolic fractional shortening, heart rate corrected mean velocity of circumferential fiber shortening, and end-systolic wall stress. Requirement for inotropic support (stratified as low, moderate, or high), number of organ system failures, and other demographic data (including Pediatric Risk of Mortality III) were collected. Troponin I was increased on admission in 13 of 23 patients (57%) and at 12 hrs in ten of 22 patients (46%). In all cases, troponin I was maximal within 12 hrs of admission. Admission troponin I was inversely correlated to ejection fraction and fractional shortening and directly correlated to wall stress. Patients who had increased admission troponin I had lower heart rate corrected mean velocity of circumferential fiber shortening (preload and heart rate independent measure of left ventricular systolic function) and higher wall stress (measure of afterload) compared with patients with normal troponin I. Admission troponin I correlated with Pediatric Risk of Mortality III and organ system failure but did not correlate with requirement for inotropic support. Conclusions: Troponin I was increased in >50% of septic children early in their illness. Increased admission troponin I was associated with decreased measures of systolic cardiac function, as measured by echocardiography, and correlated with severity of illness. Early myocardial cell injury may contribute to the development of subsequent organ failure in septic shock, and measuring troponin I on admission may be helpful in assessing severity of sepsis.

Critical Pertussis Illness in Children: A Multicenter Prospective Cohort Study*

Objective: Pertussis persists in the United States despite high immunization rates. This report characterizes the presentation and acute course of critical pertussis by quantifying demographic data, laboratory findings, clinical complications, and critical care therapies among children requiring admission to the PICU. Design: Prospective cohort study. Setting: Eight PICUs comprising the Eunice Kennedy Shriver National Institute for Child Health and Human Development Collaborative Pediatric Critical Care Research Network and 17 additional PICUs across the United States. Patients: Eligible patients had laboratory confirmation of pertussis infection, were younger than 18 years old, and died in the PICU or were admitted to the PICU for at least 24 hours between June 2008 and August 2011. Interventions: None. Measurements and Main Results: A total of 127 patients were identified. Median age was 49 days, and 105 (83%) patients were less than 3 months old. Fifty-five (43%) patients required mechanical ventilation and 12 patients (9.4%) died during initial hospitalization. Pulmonary hypertension was found in 16 patients (12.5%) and was present in 75% of patients who died, compared with 6% of survivors (p < 0.001). Median WBC was significantly higher in those requiring mechanical ventilation (p < 0.001), those with pulmonary hypertension (p < 0.001), and nonsurvivors (p < 0.001). Age, sex, and immunization status did not differ between survivors and nonsurvivors. Fourteen patients received leukoreduction therapy (exchange transfusion [12], leukopheresis [1], or both [1]). Survival benefit was not apparent. Conclusions: Pulmonary hypertension may be associated with mortality in pertussis critical illness. Elevated WBC is associated with the need for mechanical ventilation, pulmonary hypertension, and mortality risk. Research is indicated to elucidate how pulmonary hypertension, immune responsiveness, and elevated WBC contribute to morbidity and mortality and whether leukoreduction might be efficacious.