John Beca

Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial

BACKGROUND On the basis of mixed results from previous trials, we assessed whether therapeutic hypothermia for 48-72 h with slow rewarming improved mortality in children after brain injury. METHODS In this phase 3, multicenter, multinational, randomised controlled trial, we included patients with severe traumatic brain injury who were younger than 18 years and could be enrolled within 6 h of injury. We used a computer-generated randomisation sequence to randomly allocate patients (1:1; stratified by site and age [<6 years, 6-15 years, 16-17 years]) to either hypothermia (rapidly cooled to 32-33°C for 48-72 h, then rewarmed by 0·5-1·0°C every 12-24 h) or normothermia (maintained at 36·5-37·5°C). The primary outcome was mortality at 3 months, assessed by intention-to-treat analysis; secondary outcomes were global function at 3 months after injury using the Glasgow outcome scale (GOS) and the GOS-extended pediatrics, and the occurrence of serious adverse events. Investigators assessing outcomes were masked to treatment. This trial is registered with ClinicalTrials.gov, number NCT00222742. FINDINGS The study was terminated early for futility after an interim data analysis on data for 77 patients (enrolled between Nov 1, 2007, and Feb 28, 2011): 39 in the hypothermia group and 38 in the normothermia group. We detected no between-group difference in mortality 3 months after injury (6 [15%] of 39 patients in the hypothermia group vs two [5%] of 38 patients in the normothermia group; p=0·15). Poor outcomes did not differ between groups (in the hypothermia group, 16 [42%] patients had a poor outcome by GOS and 18 [47%] had a poor outcome by GOS-extended paediatrics; in the normothermia group, 16 [42%] patients had a poor outcome by GOS and 19 [51%] of 37 patients had a poor outcome by GOS-extended paediatrics). We recorded no between-group differences in the occurrence of adverse events or serious adverse events. INTERPRETATION Hypothermia for 48 h with slow rewarming does not reduce mortality of improve global functional outcome after paediatric severe traumatic brain injury. FUNDING National Institute of Neurological Disorders and Stroke and National Institutes of Health.

Neurodevelopmental Outcomes After Cardiac Surgery in Infancy

BACKGROUND: Neurodevelopmental disability is the most common complication for survivors of surgery for congenital heart disease (CHD). METHODS: We analyzed individual participant data from studies of children evaluated with the Bayley Scales of Infant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome was Psychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI). RESULTS: Among 1770 subjects from 22 institutions, assessed at age 14.5 ± 3.7 months, PDIs and MDIs (77.6 ± 18.8 and 88.2 ± 16.7, respectively) were lower than normative means (each P < .001). Later calendar year of birth was associated with an increased proportion of high-risk infants (complexity of CHD and prevalence of genetic/extracardiac anomalies). After adjustment for center and type of CHD, later year of birth was not significantly associated with better PDI or MDI. Risk factors for lower PDI were lower birth weight, white race, and presence of a genetic/extracardiac anomaly (all P ≤ .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95% confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight, male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P < .001). After adjustment for these factors, MDIs improved over time (0.38 points/year, 95% confidence interval 0.05 to 0.71; P = .02). CONCLUSIONS: Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infants undergo cardiac surgery and survive, a growing population will require significant societal resources.

Extracorporeal Membrane Oxygenation for Treating Severe Cardiac and Respiratory Failure in Adults: Part 2: Technical Considerations

i a N THIS SECOND OF 2 articles on the use of extracorporeal membrane oxygenation (ECMO) for treating severe cardiac nd respiratory failure in adults, the physiology, technical coniderations, and complications of this technique are reviewed. lthough ECMO remains a technically and logistically deanding undertaking, recent advances in the design of circuit omponents, particularly the oxygenator, have improved the ase of use and durability of the technique, such that extracororeal support can be maintained relatively safely for several eeks.

New White Matter Brain Injury After Infant Heart Surgery Is Associated With Diagnostic Group and the Use of Circulatory Arrest

Background— Abnormalities on magnetic resonance imaging scans are common both before and after surgery for congenital heart disease in early infancy. The aim of this study was to prospectively investigate the nature, timing, and consequences of brain injury on magnetic resonance imaging in a cohort of young infants undergoing surgery for congenital heart disease both with and without cardiopulmonary bypass. Methods and Results— A total of 153 infants undergoing surgery for congenital heart disease at <8 weeks of age underwent serial magnetic resonance imaging scans before and after surgery and at 3 months of age, as well as neurodevelopmental assessment at 2 years of age. White matter injury (WMI) was the commonest type of injury both before and after surgery. It occurred in 20% of infants before surgery and was associated with a less mature brain. New WMI after surgery was present in 44% of infants and at similar rates after surgery with or without cardiopulmonary bypass. The most important association was diagnostic group (P<0.001). In infants having arch reconstruction, the use and duration of circulatory arrest were significantly associated with new WMI. New WMI was also associated with the duration of cardiopulmonary bypass, postoperative lactate level, brain maturity, and WMI before surgery. Brain immaturity but not brain injury was associated with impaired neurodevelopment at 2 years of age. Conclusions— New WMI is common after surgery for congenital heart disease and occurs at the same rate in infants undergoing surgery with and without cardiopulmonary bypass. New WMI is associated with diagnostic group and, in infants undergoing arch surgery, the use of circulatory arrest.

Pre-operative brain injury in newborn infants with transposition of the great arteries occurs at rates similar to other complex congenital heart disease and is not related to balloon atrial septostomy.

OBJECTIVES The goal of this study was to determine the prevalence and pattern of pre-operative brain injury in infants with transposition of the great arteries (TGA) compared with other complex congenital heart disease (CHD) and to define the risk of balloon atrial septostomy (BAS) for the development of brain injury. BACKGROUND It has recently been suggested that infants with TGA are at increased risk of pre-operative brain injury, in particular, stroke, and that this is strongly associated with having a BAS. METHODS Sixty-four newborn infants with TGA (n = 44), hypoplastic left heart syndrome (n = 13), or pulmonary atresia (n = 7) had magnetic resonance imaging (MRI) scans performed before surgery. RESULTS Thirty-three (75%) of the infants with TGA had a BAS. Brain injury occurred in 19 (30%) infants: white matter injury (WMI) in 17 (27%), and stroke in 3 (5%). There was no difference in the prevalence or pattern of brain injury between diagnostic groups. There was no association between BAS and brain injury in infants with TGA. There was a trend toward increased brain injury in TGA with an intact interventricular septum compared with TGA with a ventricular septal defect (38% vs. 8%, p = 0.075). There was no association between brain injury and any clinical variables. CONCLUSIONS Pre-operative brain injury on MRI scan was present in 30% of infants with CHD. The predominant pattern was WMI. The rates and patterns of pre-operative brain injury are similar in infants with TGA compared with other complex CHD, and BAS does not increase the risk of pre-operative brain injury.

Regional alterations in cerebral growth exist preoperatively in infants with congenital heart disease

OBJECTIVES Magnetic resonance imaging has been used to define the neurologic abnormalities in infants with congenital heart disease (CHD), including preoperative injury and delayed brain maturation. The present study used qualitative scoring, cerebral biometry, and diffusion imaging to characterize the preoperative brain abnormalities in infants with CHD, including the identification of regions of greater vulnerability. METHODS A total of 67 infants with CHD had preoperative magnetic resonance imaging scans available for analysis of brain injury using qualitative scoring and brain development using qualitative scoring, metrics, and diffusion imaging. RESULTS Qualitative abnormalities were common, with 42% of infants having preoperative focal white matter lesions. Infants with CHD had smaller brain measures in the frontal lobe, parietal lobe, cerebellum, and brainstem (P < .001), with the frontal lobe and brainstem displaying the greatest alterations (P < .001). A smaller brain size in the frontal and parietal lobes correlated with delayed white matter microstructure reflected by diffusion imaging. CONCLUSIONS Infants with CHD commonly display brain injury and delayed brain development. Regional alterations in brain size are present, with the frontal lobe and brainstem demonstrating the greatest alterations. This might reflect a combination of developmental vulnerability and regional differences in cerebral circulation.

Hypothermia for traumatic brain injury in children - a Phase II randomized controlled trial

Objectives:To perform a pilot study to assess the feasibility of performing a phase III trial of therapeutic hypothermia started early and continued for at least 72 hours in children with severe traumatic brain injury. Design:Multicenter prospective randomized controlled phase II trial. Setting:All eight of the PICUs in Australia and New Zealand and one in Canada. Patients:Children 1–15 years old with severe traumatic brain injury and who could be randomized within 6 hours of injury. Interventions:The control group had strict normothermia to a temperature of 36–37°C for 72 hours. The intervention group had therapeutic hypothermia to a temperature of 32–33°C for 72 hours followed by slow rewarming at a rate compatible with maintaining intracranial pressure and cerebral perfusion pressure. Measurements and Main Results:Of 764 children admitted to PICU with traumatic brain injury, 92 (12%) were eligible and 55 (7.2%) were recruited. There were five major protocol violations (9%): three related to recruitment and consent processes and two to incorrect temperature management. Rewarming took a median of 21.5 hours (16–35 hr) and was performed without compromise in the cerebral perfusion pressure. There was no increase in any complications, including infections, bleeding, and arrhythmias. There was no difference in outcomes 12 months after injury; in the therapeutic hypothermia group, four (17%) had a bad outcome (pediatric cerebral performance category, 4–6) and three (13%) died, whereas in the normothermia group, three (12%) had a bad outcome and one (4%) died. Conclusions:Early therapeutic hypothermia in children with severe traumatic brain injury does not improve outcome and should not be used outside a clinical trial. Recruitment rates were lower and outcomes were better than expected. Conventional randomized controlled trials in children with severe traumatic brain injury are unlikely to be feasible. A large international trials group and alternative approaches to trial design will be required to further inform practice.

Delirium in Critically Ill Children: An International Point Prevalence Study*

Objectives: To determine prevalence of delirium in critically ill children and explore associated risk factors. Design: Multi-institutional point prevalence study. Setting: Twenty-five pediatric critical care units in the United States, the Netherlands, New Zealand, Australia, and Saudi Arabia. Patients: All children admitted to the pediatric critical care units on designated study days (n = 994). Intervention: Children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the bedside nurse. Demographic and treatment-related variables were collected. Measurements and Main Results: Primary study outcome measure was prevalence of delirium. In 159 children, a final determination of mental status could not be ascertained. Of the 835 remaining subjects, 25% screened positive for delirium, 13% were classified as comatose, and 62% were delirium-free and coma-free. Delirium prevalence rates varied significantly with reason for ICU admission, with highest delirium rates found in children admitted with an infectious or inflammatory disorder. For children who were in the PICU for 6 or more days, delirium prevalence rate was 38%. In a multivariate model, risk factors independently associated with development of delirium included age less than 2 years, mechanical ventilation, benzodiazepines, narcotics, use of physical restraints, and exposure to vasopressors and antiepileptics. Conclusions: Delirium is a prevalent complication of critical illness in children, with identifiable risk factors. Further multi-institutional, longitudinal studies are required to investigate effect of delirium on long-term outcomes and possible preventive and treatment measures. Universal delirium screening is practical and can be implemented in pediatric critical care units.

Cortical Folding is Altered before surgery in Infants with Congenital Heart Disease

Infants with congenital heart disease have altered brain development. We characterized cortical folding, a critical part of brain development, in congenital heart disease infants and demonstrated an overall decrease in cortical surface area and cortical folding with regional alterations in the right lateral sulcus and left orbitofrontal region, cingulate region, and central sulcus. These abnormalities were present prior to surgery.

Amplitude-Integrated Electroencephalography and Brain Injury in Infants Undergoing Norwood-Type Operations

BACKGROUND Perioperative brain injury is common in infants undergoing cardiac surgery. Amplitude-integrated electroencephalography (aEEG) provides real-time neurologic monitoring and can identify seizures and abnormalities of background cerebral activity. We aimed to determine the incidence of perioperative electrical seizures, and to establish the background pattern of aEEG, in neonates undergoing Norwood-type palliations for complex congenital heart disease in relation to outcome at 2 years. METHODS Thirty-nine full-term neonates undergoing Norwood-type operations underwent aEEG monitoring before and during surgery and for 72 hours postoperatively. The perfusion strategy included full-flow moderately hypothermic cardiopulmonary bypass with antegrade cerebral perfusion. Amplitude-integrated electroencephalography tracings were reviewed for seizure activity and background pattern. Survivors underwent neurodevelopmental outcome assessment using the Bayley Scales of Infant Development (3rd edition) at 2 years of age. RESULTS Thirteen (33%) infants had electrical seizures, including 9 with intraoperative seizures and 7 with postoperative seizures. Seizures were associated with significantly increased mortality, but not with neurodevelopmental impairment in survivors. Delay in recovery of the aEEG background beyond 48 hours was also associated with increased mortality and worse motor development. CONCLUSIONS Perioperative seizures were common in this cohort. Intraoperative seizures predominantly affected the left hemisphere during antegrade cerebral perfusion. Delayed recovery in aEEG background was associated with increased risk of early mortality and worse motor development. Ongoing monitoring is essential to determine the longer-term significance of these findings.