Kimberly Peterson

Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents--second edition.

Author Affiliations Patrick M. Kochanek, MD, FCCM, Professor and Vice Chair, Department of Critical Care Medicine, University of Pittsburgh School of Medicine Nancy Carney, PhD, Associate Professor, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University P. David Adelson, MD, FACS, FAAP, Director, Barrow Neurological Institute at Phoenix Children’s Hospital, Chief, Pediatric Neurosurgery/ Children’s Neurosciences Stephen Ashwal, MD, Distinguished Professor of Pediatrics and Neurology, Chief of the Division of Child Neurology, Department of Pediatrics, Loma Linda University School of Medicine Michael J. Bell, MD, Associate Professor of Critical Care Medicine, University of Pittsburgh School of Medicine Susan Bratton, MD, MPH, FAAP, Professor of Pediatric Critical Care Medicine, University of Utah School of Medicine Susan Carson, MPH, Senior Research Associate, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University Randall M. Chesnut, MD, FCCM, FACS, Professor of Neurological Surgery, Orthopedics and Sports Medicine, University of Washington School of Medicine Jamshid Ghajar, MD, PhD, FACS, Clinical Professor of Neurological Surgery, Weill Cornell Medical College, President of the Brain Trauma Foundation Brahm Goldstein, MD, FAAP, FCCM, Senior Medical Director, Clinical Research, Ikaria, Inc., Professor of Pediatrics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School Gerald A. Grant, MD, Associate Professor of Surgery and Pediatrics, Duke University School of Medicine Niranjan Kissoon, MD, FAAP, FCCM, Professor of Paediatrics and Emergency Medicine, British Columbia’s Children’s Hospital, University of British Columbia Kimberly Peterson, BSc, Research Associate, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University Nathan R. Selden, MD, PhD, FACS, FAAP, Campagna Professor and Vice Chair of Neurological Surgery, Oregon Health & Science University Robert C. Tasker, MBBS, MD, FRCP, Chair and Director, Neurocritical Care, Children’s Hospital Boston, Professor of Neurology and Anesthesia, Harvard Medical School Karen A. Tong, MD, Associate Professor of Radiology, Loma Linda University Monica S. Vavilala, MD, Professor of Anesthesiology and Pediatrics, University of Washington School of Medicine Mark S. Wainwright, MD, PhD, Director, Pediatric Neurocritical Care, Associate Professor of Pediatrics, Northwestern University Feinberg School of Medicine Craig R. Warden, MD, MPH, MS, Professor of Emergency Medicine and Pediatrics, Chief, Pediatric Emergency Services, Oregon Health & Science University/Doernbecher Children’s Hospital

Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Spine Fusion: A Systematic Review and Meta-analysis

BACKGROUND Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used as a bone graft substitute in spinal fusion, which unites (fuses) bones in the spine. The accuracy and completeness of journal publications of industry-sponsored trials on the effectiveness and harms of rhBMP-2 has been called into question. PURPOSE To independently assess the effectiveness and harms of rhBMP-2 in spinal fusion and reporting bias in industry-sponsored journal publications. DATA SOURCES Individual-patient data (IPD) from 17 industry-sponsored studies; related internal documents; and searches of MEDLINE (1996 to August 2012), other databases, and reference lists. STUDY SELECTION Randomized, controlled trials (RCTs) and cohort studies of rhBMP-2 versus any control and uncontrolled studies of harms. DATA EXTRACTION Effectiveness outcomes in IPD were recalculated using consistent definitions. Study characteristics and results were abstracted by 1 investigator and confirmed by another. Two investigators independently assessed quality using predefined criteria. DATA SYNTHESIS Thirteen RCTs and 31 cohort studies were included. For lumbar spine fusion, rhBMP-2 and iliac crest bone graft were similar in overall success, fusion, and other effectiveness measures and in risk for any adverse event, although rates were high across interventions (77% to 93% at 24 months from surgery). For anterior lumbar interbody fusion, rhBMP-2 was associated with nonsignificantly increased risk for retrograde ejaculation and urogenital problems. For anterior cervical spine fusion, rhBMP-2 was associated with increased risk for wound complications and dysphagia. At 24 months, the cancer risk was increased with rhBMP-2 (risk ratio, 3.45 [95% CI, 1.98 to 6.00]), but event rates were low and cancer was heterogeneous. Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting. LIMITATIONS Outcome assessment was not blinded, and ascertainment of harms in trials was poor. No trials were truly independent of industry sponsorship. CONCLUSION In spinal fusion, rhBMP-2 has no proven clinical advantage over bone graft and may be associated with important harms, making it difficult to identify clear indications for rhBMP-2. Earlier disclosure of all relevant data would have better informed clinicians and the public than the initial published trial reports did. PRIMARY FUNDING SOURCE Yale University and Medtronic.

The predictive validity of quality of evidence grades for the stability of effect estimates was low: a meta-epidemiological study

OBJECTIVE To determine the predictive validity of the U.S. Evidence-based Practice Center (EPC) approach to GRADE (Grading of Recommendations Assessment, Development and Evaluation). STUDY DESIGN AND SETTING Based on Cochrane reports with outcomes graded as high quality of evidence (QOE), we prepared 160 documents which represented different levels of QOE. Professional systematic reviewers dually graded the QOE. For each document, we determined whether estimates were concordant with high QOE estimates of the Cochrane reports. We compared the observed proportion of concordant estimates with the expected proportion from an international survey. To determine the predictive validity, we used the Hosmer-Lemeshow test to assess calibration and the C (concordance) index to assess discrimination. RESULTS The predictive validity of the EPC approach to GRADE was limited. Estimates graded as high QOE were less likely, estimates graded as low or insufficient QOE more likely to remain stable than expected. The EPC approach to GRADE could not reliably predict the likelihood that individual bodies of evidence remain stable as new evidence becomes available. C-indices ranged between 0.56 (95% CI, 0.47 to 0.66) and 0.58 (95% CI, 0.50 to 0.67) indicating a low discriminatory ability. CONCLUSION The limited predictive validity of the EPC approach to GRADE seems to reflect a mismatch between expected and observed changes in treatment effects as bodies of evidence advance from insufficient to high QOE.

A case study of pooled-studies publications indicated potential for both valuable information and bias

OBJECTIVES Pooled-studies publications (PSPs) present statistical analyses of multiple randomized controlled trials without a systematic literature search or critical appraisal. We explored the characteristics of PSPs and their potential impact on a systematic review (SR). STUDY DESIGN AND SETTING We systematically evaluated PSPs excluded from an SR of second-generation antidepressants. We analyzed their basic characteristics, risk of bias, and the effect of new data on review conclusions. RESULTS We identified 57 PSPs containing a median of five trials (range, 2-11) and 1,233 patients (range, 117-2,919). Ninety-six percent of PSPs were industry funded, and 49% of PSPs contained unpublished data. The median number of citations for PSPs was 29 (range, 0-549). Only 7% planned pooling a priori, and 19% combined trials with identical protocols. Fifty-nine percent of PSPs eligible for general efficacy provided no new data. For some subgroups and accompanying symptoms (e.g., anxiety, insomnia, melancholia, fatigue, sex, and race), more than 30% of PSPs presented entirely new data or data that could alter the strength of the evidence available in the SR. CONCLUSION In this case study, PSPs provided new information on subgroups and secondary outcomes; however, guidance for reviewers and development of a system to assess their susceptibility to bias are required.

Chapter 9. Temperature control

Moderate hypothermia (32–33°C) beginning early after severe TBI for 48 hrs, duration may be considered. *After completion of these guidelines, the committee became aware that the Cool Kids trial of hypothermia in pediatric TBI was stopped because of futility. The implications of this development on the recommendations in this section may need to be considered by the treating physician when details of the study are published.

Chapter 7. Neuroimaging

Early neuroimaging has assumed an increasingly important role in evaluating the extent and severity of traumatic brain injury (TBI) in children (1). CT is important for the rapid detection of different types of intracranial injury including extra-axial hemorrhage (e.g., subdural or epidural hematomas), acute hydrocephalus, fractures, or other intracranial lesions that may require acute neurosurgical intervention. The early use of CT is also useful for triage of patients to detect those who are likely to need neurosurgery, require management in an intensive care unit vs. general hospital setting as well as those who can be safely discharged from the emergency department and managed at home. Although magnetic resonance imaging (MRI) sensitivity is understood to be superior to CT for intracranial evaluation, it is not as easily obtained acutely after injury and has not been as widely validated in large studies, particularly regarding influence on management decisions. At the current time, there is little evidence to support the use of MRI in influencing management of patients with severe TBI. It is understood that acute CT imaging is universally performed in the developed world for patients with severe TBI. Two studies (2, 3) show that children with severe TBI have a high incidence of intracranial injury on CT scan (75% and 62%, respectively). In these studies, intracranial injury included brain contusion, extracerebral hematoma, intracerebral hematoma, diffuse axonal injury, acute brain swelling, penetrating craniocerebral injury, pneumocephalus, subarachnoid hemorrhage, alterations to cisterns, midline shift, or fractures. Neither study included treatment-related outcome data related to the findings on CT scan and thus could not be used as specific evidence for this guideline. Although CT is always obtained acutely in patients with severe TBI, the use of two or more CT studies is not agreed on. Repeating a CT scan in children with severe TBI is usually considered when there is 1) no evidence of neurologic improvement; 2) persistent or increasing ICP; or 3) an inability to assess neurologic status (e.g., sedation, paralytic agents) (4). Studies have reported delayed or progressive lesions in 1% to 50% of adult/pediatric patients with TBI (5). Because epidural hematoma/subdural hematoma requiring surgical intervention can develop hours to days after the acute injury, some investigators have suggested that a follow-up CT scan be routinely acquired at 1–3 days postinjury even when clinical deterioration is not evident under the assumption that early diagnosis prompts early intervention leading to a better long-term outcome (4). However, because children with severe TBI are medically unstable and (if portable CT is not available) may further deteriorate during transport to the CT scanner (hemodynamic instability, increased ICP, oxygen desaturation), the decision to order a repeat scan is a treatment decision, weighing the knowledge gained against the risk of additional secondary brain injury. Likewise, because of the long-term effects of CT radiation exposure (lifetime risk of fatal cancer resulting from one head CT in a 1-yr-old child is as high as one in 1500), the neurosurgical decision to order a CT scan also should be considered a treatment decision, weighing the knowledge gained against the risk of long-term radiation exposure (6). This guideline addressed the issue of the value of routinely acquiring repeat CT scans in children with severe TBI.