International Survey of Critically Ill Children With Acute Neurologic Insults: The Prevalence of Acute Critical Neurological Disease in Children: A Global Epidemiological Assessment Study*

Fink, Ericka L. MD, MS; Kochanek, Patrick M. MD; Tasker, Robert C. MBBS, MD; Beca, John MBChB; Bell, Michael J. MD; Clark, Robert S. B. MD; Hutchison, Jamie MD; Vavilala, Monica S. MD; Fabio, Anthony PhD, MPH; Angus, Derek C. MD, MPH; Watson, R. Scott MD, MPH; on behalf of the Prevalence of Acute critical Neurological Disease in Children: A Global Epidemiological Assessment (PANGEA) Investigators, Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, and Pediatric Neurocritical Care Research Group (PNCRG)

Pediatric Critical Care Medicine: April 2017 - Volume 18 - Issue 4 - p 330–342
doi: 10.1097/PCC.0000000000001093
Feature Articles

Objective: The international scope of critical neurologic insults in children is unknown. Our objective was to assess the prevalence and outcomes of children admitted to PICUs with acute neurologic insults.

Design: Prospective study.

Setting: Multicenter (n = 107 PICUs) and multinational (23 countries, 79% in North America and Europe).

Patients: Children 7 days to 17 years old admitted to the ICU with new traumatic brain injury, stroke, cardiac arrest, CNS infection or inflammation, status epilepticus, spinal cord injury, hydrocephalus, or brain mass.

Interventions: None.

Measurements and Main Results: We evaluated the prevalence and outcomes of children with predetermined acute neurologic insults. Child and center characteristics were recorded. Unfavorable outcome was defined as change in pre-post insult Pediatric Cerebral Performance Category score greater than or equal to 2 or death at hospital discharge or 3 months, whichever came first. Screening data yielded overall prevalence of 16.2%. Of 924 children with acute neurologic insults, cardiac arrest (23%) and traumatic brain injury (19%) were the most common. All-cause mortality at hospital discharge was 12%. Cardiac arrest subjects had highest mortality (24%), and traumatic brain injury subjects had the most unfavorable outcomes (49%). The most common neurologic insult was infection/inflammation in South America, Asia, and the single African site but cardiac arrest in the remaining regions.

Conclusions: Neurologic insults are a significant pediatric international health issue. They are frequent and contribute substantial morbidity and mortality. These data suggest a need for an increased focus on acute critical neurologic diseases in infants and children including additional research, enhanced availability of clinical resources, and the development of new therapies.

1Division of Pediatric Critical Care Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA.

2Department of Critical Care Medicine, Safar Center for Resuscitation Research, Pittsburgh, PA.

3Department of Epidemiology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

4Department of Critical Care Medicine, Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Pittsburgh, PA.

5Departments of Neurology and Anaesthesia (Pediatrics), Harvard Medical School and Boston Children’s Hospital, Boston, MA.

6Division of Pediatric Intensive Care, Starship Children’s Hospital, Auckland, New Zealand.

7Departments of Critical Care and Paediatrics, Hospital for Sick Children, Toronto, ON, Canada.

8Injury Prevention and Research Center and Harborview Medical Center at the University of Washington, Seattle, WA.

9Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

10Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.

11Center for Child Health, Behavior, and Development, Seattle Children’s Research Institute, Seattle, WA.

*See also p. 385.

The PANGEA Investigators are listed in Appendix 1.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal).

Supported, in part, by Laerdal Foundation and Department of Critical Care Medicine (University of Pittsburgh Medical Center).

Dr. Fink’s institution received funding from Laerdal Foundation, National Institutes of Health (NIH), and Patient Centered Outcomes Research Institute. She received funding from the Department of Critical Care Medicine (University of Pittsburgh Medical Center). Dr. Kochanek received funding from Society of Critical Care Medicine (SCCM; stipend for serving as the Editor-in-Chief of Pediatric Critical Care Medicine), serving as an expert witness on several cases over the past 36 months, and has received honoraria from numerous lectures at national meetings and/or as a guest professor at various institutions of higher education. He has also received stipends for editing/authoring books and/or chapters. Dr. Hutchison’s institution received funding from Canadian Institutes of Health Research, NIH, and Ontario Neurotrauma Foundation. Dr. Watson’s institution received funding from NIH (grant unrelated to the article). He has received funding from SCCM (board review course honorarium and travel), Centers for Disease Control and Prevention (CDC; travel to CDC workshop), and NIH (honorarium for grant review). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: finkel@ccm.upmc.edu

Article Outline

Acute neurologic insults due to trauma and nontraumatic cause are leading causes of morbidity and mortality in children (1–3). Surviving children are at increased risk of cognitive, physical, and psychologic disability, and their families suffer marked emotional, social, and financial strain (4–11). Treatment recommendations are largely based on level II or lower evidence due to the lack of high-quality prospective research (12–14). Cross-sectional epidemiologic data can guide allocation of resources to prevent and/or treat these conditions and optimize prospective study design of clinical investigations (15).

The Prevalence of Acute critical Neurological disease in children: a Global Epidemiological Assessment (PANGEA) research program was established with an ultimate goal to provide data to inform clinical research and healthcare priorities that will lead to future breakthroughs in improving outcome for all children. The aim of this initial report was to describe and better understand the prevalence and outcome of children with acute neurologic insults in PICUs in largely academic and resource-rich settings.

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MATERIALS AND METHODS

PANGEA Research Program

At the inception of the PANGEA research program (NCT02381977), an international steering committee was formed, and individual PICUs were recruited from professional networks that included: Pediatric Acute Lung Injury VEntilation study from North America and Europe (16), the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) and the Pediatric Neurocritical Care Research Group (PNCRG) from North America, the Canadian Critical Care Trials Group, the European Society for Pediatric and Neonatal Intensive Care, the Australia and New Zealand Intensive Care Society, and the World Federation of Pediatric Intensive and Critical Care Societies. Participation was voluntary, and no remuneration was given for involvement. Investigators needed to be fluent in English and have the ability to record data using the study’s internet-based platform. Local regulatory approval was obtained at each study site. The Data Coordinating Center was accepted as an exempt protocol by the University of Pittsburgh Institutional Review Board. All centers reported to have obtained a waiver of informed consent, allowing for prevalence calculation.

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Case Definitions

The international steering committee agreed on the case definitions for acute neurologic insult in the critically ill child (supplementary data, Supplemental Digital Content 1, http://links.lww.com/PCC/A390). The inclusion criteria were as follows: 7 days to 17 years old on the study day; admission to the PICU; and a primary diagnosis of traumatic brain injury, stroke, cardiac arrest, CNS infection or inflammation, status epilepticus, spinal cord lesion, hydrocephalus, or brain mass. If a child had suffered a perinatal or remote (> 6 mo prior to hospitalization) CNS insult without a new, acute neurologic insult, they did not meet the inclusion criteria.

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Point Prevalence Study Design

Four study dates during a 1-year period were chosen, avoiding weekends and holidays to encourage participation: November 29, 2011; February 28, 2012; May 22, 2012; and July 24, 2012. Centers were instructed to screen all patients in their PICU at 9:00 AM local time. Centers recorded the number of children meeting study inclusion criteria, and all but 10 centers provided the total number of children in their PICU on the study day. Based on feedback from study centers, hydrocephalus and brain mass categories were added at the second study date.

A Case Report Form (CRF) with inclusion and exclusion criteria, study definitions, and guide to data collection was provided to centers and posted as a secure electronic-CRF on the study website (www.pangeastudy.com). CRF composition was based on prior studies, perceived needs of the research community, input by the Steering Committee, and feedback from PALISI and PNCRG members. Professionals at the Biomedical Telematic Laboratory of the Health Respiratory Network of Fronds de Recherche Sante Quebec, University of Sherbrooke, Canada, designed and maintained the secure website and securely transferred collected study data to the data coordinating center. Data were collected on hospital and study subject characteristics, details about the child’s acute neurologic insult, monitoring used, therapies, testing, and outcomes. Details on monitoring and treatments are not included in this article but will be part of secondary data analysis. Components of the Pediatric Index of Mortality (PIM) 2 scores were embedded into the CRF to allow determination of mortality risk (17).

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Outcomes

PICU prevalence of acute neurologic insult was the primary outcome. Secondary outcomes included all-cause mortality, outcome status using the Pediatric Cerebral Performance Category (PCPC) score (unfavorable outcome = change in PCPC preinsult to study endpoint ≥ 2 or death), length of hospital and ICU stay, frequency of new morbidity, and disposition at PICU and hospital discharge. The study’s endpoint was hospital discharge or 3 months after the study day, whichever came first. PCPC is a practical, gross measure of neurologic status that performs well in comparison with other validated testing instruments (18). More detailed neuropsychologic outcomes were not possible in this study. Centers collected information on the following a priori-specified newly acquired morbidities during this hospital stay: hypertonia, dysautonomia, and placement of a cerebrospinal fluid shunt, surgically placed feeding tube, or tracheostomy tube. These morbidities were chosen by the primary investigator and steering committee with consideration of prior literature and potential for long-term impact on patients and families, recognizing that the list is not complete and was developed prior to the availability of the Functional Status Score, recently validated in children (19, 20). Cause of death was taken from the death certificate.

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Data Management

Data entry was performed by site ICU faculty, ICU fellows, research assistants, or study coordinators depending on resources available at the site. Primary data collection and data quality were managed by site PI. Centers were provided with the CRF that included the study protocol with written instructions and were given opportunities to discuss questions electronically or over the phone. Centers were provided with regular study updates via e-mail. Personnel from the Clinical Research, Investigation, and Systems Modeling of Acute illness Center (Department of Critical Care Medicine, University of Pittsburgh) assisted in secondary data quality monitoring along with the study PI and coordinator. Data were screened for missing or implausible information, and queries were issued to the site.

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Statistical Analysis

Descriptive statistics are presented as median (interquartile range [IQR]). Data were analyzed using Kruskall-Wallis, Mann-Whitney, Fisher exact, and chi-square tests as appropriate. The numerator and denominator for the prevalence calculation came from the screening form. Ten sites did not provide complete screening data (although they did submit all other forms for children who met entry criteria) and thus were excluded from prevalence calculations. Statistical analysis by region was not performed due to the small number of centers and subjects of some regions. The majority of variables had less than 10% missing data, and missing data were not imputed (thus sample sizes for variables and denominators varied slightly). All p values were two-sided, and p value less than 0.05 was considered statistically significant. The Statistical Package for the Social Sciences version 20 (IBM Corp., Armonk, NY) and Stata version 12 (StataCorp, College Station, TX) were used for statistical analyses. This article was written according to the STrengthening the Reporting of OBservational studies in Epidemiology statement (21).

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RESULTS

Study Center Characteristics

Of the 107 hospitals participating in the PANGEA consortium, 79% were located in North America or Europe (see Fig. 1 and Acknowledgments for full list of centers and site personnel). Eighty-six percent of collaborating PICUs were affiliated with a university academic medical center, 75% were located in pediatric hospitals, and there was a wide range in the number of PICU beds and admissions per year (Table 1). The median number of PICU faculty was 8 (6–14), and 69% of centers provide 24-hour, in-house faculty PICU coverage. Seventy-four percent of hospitals reported a PICU fellowship training program. Forty-eight percent of the centers reported that they provided a dedicated neurocritical care service, whereas 10% had a PICU follow-up clinic. Most centers were capable of intracranial pressure (93%) and continuous electroencephalography monitoring (78%), but only 14% of centers were able to invasively monitor brain tissue oxygenation.

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Point Prevalence and Subject Characteristics

Participating centers who provided complete data (n = 97) screened 5,135 children over the four study days, and 831 met study criteria with resulting prevalence of acute neurologic insults of 16.2% (95% CI, 15.2–17.2). Total number of subjects enrolled from all 107 centers was 924. The number of subjects enrolled per site ranged from 0 to 113 over the four study dates. Thirteen centers enrolled 20 or more subjects into the study. Subjects encompassed the full age range (median [IQR], 48 [9–120] mo). Females accounted for the 41% of subjects, and 51% were Caucasian, non-Hispanic ethnicity (Table 2). Sixty-two percent of subjects had public insurance or universal healthcare, and 4% had no health insurance. Fifty-eight percent of subjects had a comorbid condition with neurologic being most common (29%), and 61% of subjects had normal PCPC scores before this neurologic event and ICU admission.

Cardiac arrest was the most frequent neurologic insult (23%), followed by traumatic brain injury (19%), status epilepticus (17%), and CNS infection/inflammation (Table 3).

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Outcomes

All-cause mortality was 105 (12%). Children admitted after a cardiac arrest had the highest mortality (24%) and PIM (6.6 [2.4–20.6]), both p values less than 0.001 versus other neurologic insults (Table 3). Cause of death was provided in 49 subjects who died. The most common causes of death were withdrawal of support due to poor neurologic status (25%), brain death (11%), and cardiovascular failure (10%). Of subjects with a pre-ICU PCPC of 1 (no disability) with PCPC at hospital discharge or 3 months available, 211 of 475 (44%) remained PCPC of 1. The remainder of subjects with a pre-ICU PCPC of 1 had PCPC 2 (18%), PCPC 3 (11%), PCPC 4 (13%), PCPC 5 (4%), and PCPC 6 (9%) at the later time point. Subjects with traumatic brain injury had the highest rate of normal baseline PCPC (82%). Thirty-two percent of subjects had unfavorable outcome, which was most common in subjects with traumatic brain injury (49%) (p < 0.001).

Hospital and PICU length of stay were 22 (8–55) and 13 (4–33) days, respectively, and were longest in children with cardiac arrest (both p < 0.001). At the study’s endpoint, 58% of subjects were discharged home, and 17% were admitted to an inpatient rehabilitation center. Subjects with traumatic brain injury and spinal cord lesion had the highest frequency of rehabilitation disposition (28% and 37%, respectively).

The frequency of new morbidities differed by insult. Feeding tubes were most frequently placed in children with cardiac arrest (30%), and tracheostomy tubes were most frequently placed in children with spinal cord lesion (33%).

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Regional Data

Subject and PICU characteristics varied by region, including age, type of insurance, number of PICU beds, and neurocritical care service (Tables 1, 2, and 4). Prevalence of acute neurologic insults was highest in North America (18.0 [16.7–19.3]) and Africa (15.8 [6.0–31.3]) and lowest in Asia (9.8 [6.1–14.7]) and Europe (12.7 [10.7–14.8]). The most common acute neurologic insult was cardiac arrest in North America, Europe, and Oceania, whereas CNS infection/inflammation was most prevalent in South America, Asia, and Africa (Supplemental Fig. 1, Supplemental Digital Content 2, http://links.lww.com/PCC/A391). PIM2 scores were highest in Oceania and lowest in South America and Asia. Length of stay was longest in Africa and shortest in Oceania and Asia. Mortality was 10–14% except at the single center in Africa, where no subjects died, but 50% had unfavorable outcome.

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DISCUSSION

There are three chief findings of this study: 1) Acute neurologic insults are common among PICU patients, with global hypoxia-ischemia due to cardiac arrest being the most frequent insult; 2) The consequences of acute neurologic insults are serious: mortality was 4–6 times that of published PICU mortality rates (19), subjects had long length of stay, and survivors frequently acquired new morbidities; and 3) Many regional differences exist among center and subject characteristics with acute neurologic insults.

Our study population, and therefore our findings and implications, largely reflect critically ill children admitted to ICUs in academic pediatric hospitals in North America, Europe, and Oceania. The prevalence of acute neurologic insults is consistent with an analysis of 3 million pediatric hospital discharges in 11 U.S. states by Moreau et al (2) in which children with neurologic insults prompted 10% of pediatric hospital admissions but were responsible for 3 times the proportion of PICU admissions, longer length of stay, higher mortality, and higher cost versus children with nonneurologic diagnoses. Factors that may affect prevalence include the relatively long length of stay of children with acute neurologic insults (also seen in Moreau et al [2]), and occurrence of adverse events associated with long length of stay and severe illness (e.g., hospital-acquired infection) or additional organ insults/injuries (e.g., renal failure or acute respiratory distress syndrome); though these were not assessed in PANGEA (2, 22). The frequency of new morbidities including the need for new surgical technologic supports was high, especially in children with cardiac arrest.

Cardiac arrest, the neurologic insult with the highest mortality rate, was also the most common insult overall. Cardiac arrest causes global hypoxia-ischemia, which can lead to varying degrees of postresuscitation syndrome in which brain injury is often the most significant organ affected long term (23). Notably, other neurologic insults are associated with organ injury outside the CNS, which can affect outcome (24–26). Traumatic brain injury was the second most common insult overall in PANGEA, and unintentional injury is the leading cause of death for children of 10–19 years old worldwide (27). Although traumatic brain injury subjects had the highest frequency of unfavorable outcome, children with neurologic insults often have great potential for rehabilitation, and assessment of longer term outcomes is needed (28).

The growth of pediatric neurocritical care services in PICUs and development of a pediatric neurocritical care research network reflect the specialty’s acknowledgement and commitment to improve outcomes for children with acute neurologic insults (29–31). In PANGEA, nearly half of centers reported having a neurocritical care service (of variable make-up), more than double that of a recent survey (32). Data are needed to elucidate the optimal configuration and integration of neurocritical care services that affect outcomes (29, 30, 33, 34). Few centers reported having ICU follow-up clinics, an innovative multidisciplinary effort to address recovery from critical illness (35).

Although exploratory in this study, regional epidemiologic and center differences are important to investigate before planning prospective research studies, allocating healthcare resources, and developing advocacy programs (36–39). For example, CNS infection/inflammation was the most frequent neurologic insult in South America, Asia, and the single African site compared with cardiac arrest in the remaining regions. Overall prevalence of acute neurologic insult was highest in North America, nearly double that found in Asian centers, but not the highest length of stay. Centers in Oceania had the highest median risk of mortality scores but not the highest unadjusted mortality rate. Regions showed differences in patient age, sex, and health insurance status, variables associated with outcome (40–42). Additionally, regions differed in terms of monitoring and testing capabilities and numbers of personnel providing care in the ICU and in a neurocritical care service and hospital beds. These findings speak to the idea that the optimal delivery of healthcare for neurocritical care patients may differ regionally.

These findings, taken together with a dearth of efficacious neuroprotective therapies and overall lack of high-quality evidence to support care, represent a compelling case for the need for increased research and healthcare resources to assist in improving outcomes for children with acute neurologic insults. Transformational ideas to address these issues are critically needed (43, 44).

The strengths and limitations of the point prevalence/cross-sectional method of study have been reviewed, and limitations include: 1) findings lack cause and effect conclusiveness; rather serving as more descriptive purposes and 2) potential underestimation of rapidly fatal disease processes and infrequently used medications and interventions (15). Centers participating in PANGEA are from middle- and high-income regions. Therefore, our results are not fully representative of the global health problem of children with neurologic insult in need of pediatric critical care in resource-limited settings, where most child mortality occurs. PANGEA is also conducting research into the epidemiology and outcomes of acute neurologic insult in these settings (45, 46). Children who died prior to reaching medical care and children with milder injuries who did not require ICU resources were not included in this study. Most participating ICUs were academic, reflecting regionalization typical of pediatric critical care but may limit the generalization of findings. Unfavorable outcome was based on change in PCPC score, which may be less informative in infants than in older children. The wide range of regions and centers collecting PCPC data using the medical chart may have limited its reliability. The deliberate avoidance of choosing study dates on weekends and major holidays may increase the chance of sampling bias. This study focused on primary neurologic insults; inclusion of subjects with secondary neurologic insults, a common cause of mortality and morbidity in critically ill children, would also be valuable to inform our long-term objective of improving outcomes for these children.

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CONCLUSION

Children with acute neurologic insults are common in ICUs and are associated with high morbidity and mortality rates and prolonged ICU stays, posing significant challenges to public, family, and individual health. These data suggest a vital need for resources to assist in the challenge of improving outcomes for these children throughout the span of the periods of emergency care through to rehabilitation.

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ACKNOWLEDGMENTS

We thank the nonfinancial support of the following groups committed to the provision of excellent clinical care and research: Pediatric Acute Lung Injury and Sepsis Investigators (PALISI), Australian and New Zealand Intensive Care Society (ANZICS), European Society of Paediatric Neonatal Intensive Care (ESPNIC), Canadian Critical Care Trials Group (CCCTG), World Federation of Pediatric Intensive and Critical Care (WFPICCS), and Pediatric Neurocritical Care Research Group (PNCRG). In addition, we thank Carrie Pidro (PANGEA study coordinator) and Kyle Landis (PANGEA data management). We are grateful to the staff, nurses, and physicians of all ICUs in this study for their generous efforts to help improve the outcomes of children with critical illness.

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REFERENCES

1. Au AK, Carcillo JA, Clark RS, et al. Brain injuries and neurological system failure are the most common proximate causes of death in children admitted to a pediatric intensive care unit. Pediatr Crit Care Med 2011; 12:566–571.
2. Moreau JF, Fink EL, Hartman ME, et al. Hospitalizations of children with neurologic disorders in the United States. Pediatr Crit Care Med 2013; 14:801–810.
3. Peden M, Oyegbite K, Ozanne-Smith J, et al. World Report on Child Injury Prevention2008
4. Shi J, Xiang H, Wheeler K, et al. Costs, mortality likelihood and outcomes of hospitalized US children with traumatic brain injuries. Brain Inj 2009; 23:602–611.
5. Ronco R, King W, Donley DK, et al. Outcome and cost at a children’s hospital following resuscitation for out-of-hospital cardiopulmonary arrest. Arch Pediatr Adolesc Med 1995; 149:210–214.
6. Gilbert DL, Glauser TA. Complications and costs of treatment of refractory generalized convulsive status epilepticus in children. J Child Neurol 1999; 14:597–601.
7. Aitken ME, McCarthy ML, Slomine BS, et al; CHAT Study Group: Family burden after traumatic brain injury in children. Pediatrics 2009; 123:199–206.
8. Hurvitz E, Warschausky S, Berg M, et al. Long-term functional outcome of pediatric stroke survivors. Top Stroke Rehabil 2004; 11:51–59.
9. Jones S, Rantell K, Stevens K, et al; United Kingdom Pediatric Intensive Care Outcome Study Group: Outcome at 6 months after admission for pediatric intensive care: A report of a national study of pediatric intensive care units in the United Kingdom. Pediatrics 2006; 118:2101–2108.
10. Knoester H, Bronner MB, Bos AP, et al. Quality of life in children three and nine months after discharge from a paediatric intensive care unit: A prospective cohort study. Health Qual Life Outcomes 2008; 6:21
11. Stancin T, Drotar D, Taylor HG, et al. Health-related quality of life of children and adolescents after traumatic brain injury. Pediatrics 2002; 109:E34
12. Moler FW, Silverstein FS, Holubkov R, et al; THAPCA Trial Investigators: Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med 2015; 372:1898–1908.
13. Hutchison JS, Ward RE, Lacroix J, et al; Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group: Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008; 358:2447–2456.
14. Adelson PD, Wisniewski SR, Beca J, et al; Paediatric Traumatic Brain Injury Consortium: Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): A phase 3, randomised controlled trial. Lancet Neurol 2013; 12:546–553.
15. Weiss SL, Fitzgerald JC, Faustino EV, et al; Pediatric Acute Lung Injury and Sepsis Investigators Network and Australia and New Zealand Intensive Care Society Investigators: Understanding the global epidemiology of pediatric critical illness: The power, pitfalls, and practicalities of point prevalence studies. Pediatr Crit Care Med 2014; 15:660–666.
16. Santschi M, Jouvet P, Leclerc F, et al; PALIVE Investigators; Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI); European Society of Pediatric and Neonatal Intensive Care (ESPNIC): Acute lung injury in children: Therapeutic practice and feasibility of international clinical trials. Pediatr Crit Care Med 2010; 11:681–689.
17. Slater A, Shann F, Pearson G; Paediatric Index of Mortality (PIM) Study Group: PIM2: A revised version of the Paediatric Index of Mortality. Intensive Care Med 2003; 29:278–285.
18. Fiser DH, Long N, Roberson PK, et al. Relationship of Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores at pediatric intensive care unit discharge with outcome measures collected at hospital discharge and 1- and 6-month follow-up assessments. Crit Care Med 2000; 28:2616–2620.
19. Pollack MM, Holubkov R, Funai T, et al. Relationship between the functional status scale and the Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scales. JAMA Pediatr 2014; 168:671–676.
20. Pollack MM, Holubkov R, Funai T, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network: Pediatric intensive care outcomes: Development of new morbidities during pediatric critical care. Pediatr Crit Care Med 2014; 15:821–827.
21. von Elm E, Altman DG, Egger M, et al; STROBE Initiative: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Lancet 2007; 370:1453–1457.
22. Stambouly JJ, McLaughlin LL, Mandel FS, et al. Complications of care in a pediatric intensive care unit: A prospective study. Intensive Care Med 1996; 22:1098–1104.
23. Moler FW, Meert K, Donaldson AE, et al; Pediatric Emergency Care Applied Research Network: In-hospital versus out-of-hospital pediatric cardiac arrest: A multicenter cohort study. Crit Care Med 2009; 37:2259–2267.
24. Gruber A, Reinprecht A, Illievich UM, et al. Extracerebral organ dysfunction and neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med 1999; 27:505–514.
25. Zygun DA, Doig CJ, Gupta AK, et al. Non-neurological organ dysfunction in neurocritical care. J Crit Care 2003; 18:238–244.
26. Kemp CD, Johnson JC, Riordan WP, et al. How we die: The impact of nonneurologic organ dysfunction after severe traumatic brain injury. Am Surg 2008; 74:866–872.
27. Berger RP, Fromkin JB, Stutz H, et al. Abusive head trauma during a time of increased unemployment: A multicenter analysis. Pediatrics 2011; 128:637–643.
28. Kramer ME, Suskauer SJ, Christensen JR, et al. Examining acute rehabilitation outcomes for children with total functional dependence after traumatic brain injury: A pilot study. J Head Trauma Rehabil 2013; 28:361–370.
29. LaRovere KL, Graham RJ, Tasker RC; Pediatric Critical Nervous System Program (pCNSp): Pediatric neurocritical care: A neurology consultation model and implication for education and training. Pediatr Neurol 2013; 48:206–211.
30. Bell MJ, Carpenter J, Au AK, et al. Development of a pediatric neurocritical care service. Neurocrit Care 2009; 10:4–10.
31. Bell MJ, Pineda JA, Vavilala MS, et al. Neurocritical Care Research Networks–pediatric considerations. Neurocrit Care 2012; 17:468–469; author reply 470.
32. Murphy SA, Bell MJ, Clark ME, et al. Pediatric neurocritical care: A short survey of current perceptions and practices. Neurocrit Care 2015; 23:149–158.
33. Wainwright MS, Grimason M, Goldstein J, et al. Building a pediatric neurocritical care program: A multidisciplinary approach to clinical practice and education from the intensive care unit to the outpatient clinic. Semin Pediatr Neurol 2014; 21:248–254.
34. Suarez JI, Zaidat OO, Suri MF, et al. Length of stay and mortality in neurocritically ill patients: Impact of a specialized neurocritical care team. Crit Care Med 2004; 32:2311–2317.
35. Samuel VM, Colville GA, Goodwin S, et al. The value of screening parents for their risk of developing psychological symptoms after PICU: A feasibility study evaluating a pediatric intensive care follow-up clinic. Pediatr Crit Care Med 2015; 16:808–813.
36. Jayaram N, Spertus JA, Nadkarni V, et al; American Heart Association’s Get with the Guidelines-Resuscitation Investigators: Hospital variation in survival after pediatric in-hospital cardiac arrest. Circ Cardiovasc Qual Outcomes 2014; 7:517–523.
37. Van Cleve W, Cleve WV, Kernic MA, et al; PEGASUS (Pediatric Guideline Adherence and Outcomes) Project: National variability in intracranial pressure monitoring and craniotomy for children with moderate to severe traumatic brain injury. Neurosurgery 2013; 73:746–752; quiz 752.
38. Bell MJ, Adelson PD, Hutchison JS, et al; Multiple Medical Therapies for Pediatric Traumatic Brain Injury Workgroup: Differences in medical therapy goals for children with severe traumatic brain injury-an international study. Pediatr Crit Care Med 2013; 14:811–818.
39. Giuliano JS Jr, Markovitz BP, Brierley J, et al; Sepsis PRevalence, OUtcomes, and Therapies Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators Network: Comparison of pediatric severe sepsis managed in U.S. and European ICUs. Pediatr Crit Care Med 2016; 17:522–530.
40. Spencer CS, Gaskin DJ, Roberts ET. The quality of care delivered to patients within the same hospital varies by insurance type. Health Aff (Millwood) 2013; 32:1731–1739.
41. Kraus JF, Peek-Asa C, McArthur D. The independent effect of gender on outcomes following traumatic brain injury: A preliminary investigation. Neurosurg Focus 2000; 8:e5
42. Morrison WE, Arbelaez JJ, Fackler JC, et al. Gender and age effects on outcome after pediatric traumatic brain injury. Pediatr Crit Care Med 2004; 5:145–151.
43. Stoll BJ, Stevenson DK, Wise PH. The transformation of child health research: Innovation, market failure, and the public good. JAMA 2013; 309:1779–1780.
44. Zimmerman JJ, Anand KJ, Meert KL, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network: Research as a standard of care in PICU. Pediatr Crit Care Med 2016; 17:e13–e21.
45. Chandran A, Hyder AA, Peek-Asa C. The global burden of unintentional injuries and an agenda for progress. Epidemiol Rev 2010; 32:110–120.
46. Liu L, Johnson HL, Cousens S, et al; Child Health Epidemiology Reference Group of WHO and UNICEF: Global, regional, and national causes of child mortality: An updated systematic analysis for 2010 with time trends since 2000. Lancet 2012; 379:2151–2161.
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APPENDIX 1. THE PANGEA INVESTIGATORS

North America—United States: Craig Smith, MD and Claire Ryan (Ann & Robert H. Lurie Children’s Hospital of Chicago); Josh Koch, MD (Children’s Medical Center of Dallas/University of Texas Southwestern Medical Center); Karen Walson, MD (Children’s Healthcare of Atlanta); Edward Truemper, MD (Children’s Hospital and Medical Center, Omaha); Heidi Flori, MD and Julie Simon, (Children’s Hospital and Research Center Oakland); Jennifer Exo, DO (Children’s Hospital Colorado); Barry Markovitz, MD, MPH and Rica Morzov, RN, BSN, CPN (Children’s Hospital Los Angeles); Kerri LaRovere, MD (Boston Children’s Hospital); Akira Nishisaki, Judy Verger, RN, PhD, FCCM, Janice Prodell, RN, CCRC, Martha Sisko, BSN, RN, MS, CCRC Sheila McGowan, BSN, RN, Tesa Idell, Carolann Twelves, RN, BSN, William Kamens, Brooke Park, BSN, RN, and Mary Ann Diliberto, BS, RN, CCRC (Children’s Hospital of Philadelphia); Ericka Fink, MD, MS and Alan Abraham (Children’s Hospital of Pittsburgh); Sheila Hanson, MD and Kathy Murkowski, RRT, CCRC (Children’s Hospital of Wisconsin); Jeffrey Nowak, MD, Erin Zielinski, and Alison Overman (Children’s Hospitals and Clinics of Minnesota); Kelly Tieves, DO, MS, Trisha Williams, RN, BSN, CPN, and Amber Hughes-Schalk (Children’s Mercy Hospital); Nathan Dean, MD, Aparna Bala, and Anne Watson (Children’s National Medical Center); Derek Wheeler, MD, MMM, Sharon Banschbach, Eileen Beckman, and Erin Frank (Cincinnati Children’s Hospital Medical Center); Sholeen Nett, MD, PhD and J. Dean Jarvis, BSN, MBA, CCRP (Dartmouth-Hitchcock Medical Center); Renee Higgerson, MD, LeeAnn Christie, MSN, RN, and Jodie Reed, FNP, ACNP (Dell Children’s Medical Center of Central Texas); Ira Cheifetz, MD, Samantha Tate, Tammy Uhl, and Karin Reuter-Rice, PhD, NP, FCCM (Duke University Medical Center); Catherine Haskins-Kiefer, MSN, RN, NE-BC, Pamela Hendricks, MSN, RN, CCRN, Jeanette Green, and Robin Barron-Nelson, MSN, RN (Florida Hospital for Children); Steven Baisch, MD, Jody Evenson, and Heather Wendorf, MPH, CCRC (Gillette Children’s Hospital); David McKinley, MD and Jennifer Sankey, RN (Janet Weis Children’s Hospital Geisinger Medical Center); Melania Bembea, MD, MPH, Corina Noje, MD, and Elizabeth White (Johns Hopkins University); Nicole O’Brien, MD and Tensing Maa, MD (Nationwide Children’s Hospital); Edward Truemper, MD, Machelle Zink, MEd, and Brenda Weidner, MD (Nebraska Medical Center); Katherine Biagas, MD and Monique Superville (New York Presbyterian Hospital/Columbia University); Chani Traube, MD and Charlene Carlo (NY Presbyterian Hospital-Weill Cornell Medical College); Neal Thomas, MD, MSc and Debbie Spear, RN, CCRN (Penn State Hershey Children’s Hospital); Sandra Buttram, MD and Aimee Franken, CPNP-AC (Phoenix Children’s Hospital); Tell Bennett, MD and Eun Hea Kim (Primary Children’s Hospital/University of Utah); Mara Nitu, MD and Christi Rider, LPN (Riley Hospital for Children); Monica S. Vavilala, MD and Dawn Lum (Seattle Children’s Hospital & Harborview Medical Center, University of Washington); Margaret Parker, MD, MCCM and Kathleen Culver, DNP, RN, CPNP-AC (Stony Brook University); Laura Loftis, MD and Nancy Jaimon, MSN, BSN (Texas Children’s Hospital); David Shellington, MD and Jennifer Foley (University of California, San Diego/Rady Children’s Hospital of San Diego); Jose Irazuzta, MD and Tricia Alleyne, MD (University of Florida College of Medicine); Scot Bateman, MD and Michael Sylvia, MD (University of Massachusetts Memorial Children’s Medical Center); Jill M. Cholette, MD (University of Rochester Medical Center); Douglas Willson, MD and Robin Kelly (University of Virginia Children’s Hospital); Jose Pineda, MD, Tina Hicks, Dana Middleton, and Tina Day, CCRC (Washington University School of Medicine); Simon Li, MD (Westchester Medical Center); Sarah Kandil, MD and John Giuliano, MD (Yale University). Canada: Peter Skippen, MD, David Wensley, and Gordon Krahn (BC Children’s Hospital); Macha Bourdages, MD, Marc-Andre Dugas, and Louise Gosselin (Centre Hospitalier Universitaire de Québec); Miriam Santschi, MD (Centre Hospitalier Universitaire de Sherbrooke); Douglas Fraser, MD and Chris Blom (Children’s Hospital, London Health Sciences Centre); Philippe Jouvet, MD, PhD, Nicole Poitras, Laurence Bertout, and Mariana Dumitrascu (Hôpital Ste-Justine, Montreal); Ronald Gottesman, MD and Karen Trudel, MDCM (McGill University Health Center, Montreal); Jamie Hutchison, MD, Sathishkumar Kandath, MD, Judith Van Huyse, RN, CCRP, and Kelly Fusco (The Hospital for Sick Children, Toronto). South America—Argentina: Pablo Niera, MD (Hospital de Ninos Ricardo Gutierrez); Thomas Iolster, MD (Hospital Universitario Austral). Brazil: Maria Barbosa, MD, Vanessa Soares, MD, MSc, and Fernanda Lima, MD (Rede D’Or). Chile: Raul Bustos Betanzo, MD (Hospital Guillermo Grant Benavente). Columbia: Mauricio Fernández Laverde, MD (CES Universidad). Peru: Rosario Becerra, MD (Instituto Nacional de Salud de Nino). Europe—France: Julia Guilbert, MD and Pierre-Louis Léger (Armand-Trousseau Children’s Hospital); Benedicte Ringuier, MD (Centre Hospitalier Universitaire D’Angers); Olivier Brissaud, MD (CHU de Bordeaux); Valerie Payen, MD (CHU de Grenoble); Christopher Milesi, MD (CHU de Montepellier); Jean-Michel Liet, MD, PhD and Arnaud Legrand (CHU Nantes); Audrey Breining, MD and Julie Bienz (Hôpital de Hautepierre/CHRU Strasbourg); Etienne Javouhey, MD, PhD, Tiphanie Ginhoux, PhD, and Sonia Courtil-Teyssedre, MD (EPICIME-CIC 1407 de Lyon, Inserm, Service de Pharmacotoxicologie, CHU-Lyon, F-69677, Bron, France); Jean Bergounioux, MD (Hôpital Necker Enfants Malade); Philippe Sachs, MD (Hôpital Robert Debré); Francis Leclerc, MD, PhD and Marie-Emilie Lampin, MD (University Hospital of Lille). Italy: Angela Amigoni, MD and Antonio Marzollo, MD (University of Padua). Latvia: Arta Barzdina, MD (University Children’s Hospital Riga). Netherlands: Dick Tibboel, MD and Karin Geleijns, MD, PhD (Erasmus Medical Center); Sjef van Gestel, MD (University Medical Center Utrecht). Portugal: Alexandra Dinis, MD (Hospital Pediátrico de Coimbra). Spain: Juan García-Iñiguez, MD, PhD and Paula Madurga-Revilla, MD (Children’s Hospital Miguel Servet of Zaragoza); Federico Martinon-Torres, MD, PhD and Maria José De Castro (Hospital Clínico Universitario de Santiago de Compostela); Jesus Lopez-Herce, MD and Javier Urbano (Hospital General Universitario Gregorio Marañón de Madrid and Red SAMID); Patricia García-Soler, MD (Hospital Regional Universitario Materno Infantil de Málaga); Francisco Fernandez-Carrion, MD (Hospital Universitario de Salamanca); Romy Rossich, MD (Hospital Vall Hebron); David Arjona, MD and Raul Borrego (Hospital Virgen de la Salud). Switzerland: Oliver Karam, MD, MSc (Geneva University Hospital). Turkey: Oguz Dursun, MD and Hakan Tekguc, MD (Akdeniz University School of Medicine); Tanil Kendirli, MD, Caglar Odek, MD, and Ayhan Yaman, MD (Ankara University School of Medicine); Ali Arslankoylu, MD (Mersin University Faculty of Medicine). United Kingdom: Lyvonne Tume, RN, PhD (Alder Hey Children’s NHS Foundation Trust); Barney Scholefield, MBBS, MRCPH, PhD and Helen Winmill (Birmingham Children’s Hospital); Sarah Morley, MD, Deborah White, and Bina Mukhtyar (Cambridge University Hospitals NHS Trust); Rachel Agbeko, MD, PhD, FRCPCH (Great North Children’s Hospital Newcastle upon Tyne); Mark Peters, MD and Amy Jones (Great Ormond Street Hospital); David Inwald, MB, FRCPCH, Amy Brewer, and Amina Abdulla (Imperial College Healthcare NHS Trust); Akash Deep, MD, FRCPCH and Eniola Nsirim (King’s College Hospital); Alison Shefler, MD and Rohit Joshi, MBBS (Oxford University Hospitals NHS Trust); Gnanalingham Muhuntha, FRCPCH, FFICM, PhD, Philip Hudnott, MD, and Maria MacDonald (Royal Manchester Children’s Hospital); John Pappachan, MA, MBBChir, FRCA (Southampton General Hospital); Martin Peter Gray, MRCP, FFICM (St. Georges Hospital); Kay Rushforth, MD (The General Infirmary at Leeds). Arabian Peninsula—Oman: Anas-Alwogud Abdelmogheth, MD, AL Futaisi Amna Mohamed, Naga Ram Dhande, Rana Ali Abdulrahim, Safiya Saleh, and Safia Al-Hasani (Sultan Qaboos University Hospital). Africa—South Africa: Andrew Argent, MD and Shamiel Salie (University of Cape Town, School of Child and Adolescent Health/Red Cross War Memorial Hospital). India: Suchitra Ranjit, MD and Indira Jayakumar, DCH, DNB (Apollo Children’s Hospital); Shrishu Kamath, MD and Anitha V. P., DCH (Mehta Children’s Hospital). China: Hon Ming Cheung, MD (Prince of Wales Hospital, Hong Kong); Ying Wang, MD (Shanghai Children’s Medical Center). Oceana—Australia: Marino Festa, MBBS, MRCP, MD(Res), FCICM, Karen Walker, RGN, RSCN, BAppSC, MN, PhD, and Nicola Watts, Bpsyc (Hons), PhD (Children’s Hospital at Westmead); Simon Erickson, MD, FFICANZCA, FCICM (Princess Margaret Hospital for Children); Anthony Slater, MB BS, FCICM and Debbie Long (Royal Children’s Hospital-Brisbane); Warwick Butt, MD and Carmel Delzoppo (Royal Children’s Hospital-Melbourne); Michael Yung, MD, Subodh Ganu, MBBS, MD, FCICM, MClinEpi, and Georgia Letton (Women and Children’s Hospital Adelaide). New Zealand: John Beca, MBChB, Claire Sherring, Miriam Rea, and Tracey Bushell (Starship Children’s Hospital).

child; epidemiology; international; neurocritical care; outcomes

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