Brahm Goldstein

International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics*

Objective: Although general definitions of the sepsis continuum have been published for adults, no such work has been done for the pediatric population. Physiologic and laboratory variables used to define the systemic inflammatory response syndrome (SIRS) and organ dysfunction require modification for the developmental stages of children. An international panel of 20 experts in sepsis and clinical research from five countries (Canada, France, Netherlands, United Kingdom, and United States) was convened to modify the published adult consensus definitions of infection, sepsis, severe sepsis, septic shock, and organ dysfunction for children. Design: Consensus conference. Methods: This document describes the issues surrounding consensus on four major questions addressed at the meeting: a) How should the pediatric age groups affected by sepsis be delineated? b) What are the specific definitions of pediatric SIRS, infection, sepsis, severe sepsis, and septic shock? c) What are the specific definitions of pediatric organ failure and the validity of pediatric organ failure scores? d) What are the appropriate study populations and study end points required to successfully conduct clinical trials in pediatric sepsis? Five subgroups first met separately and then together to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiological data, and coagulation variables. All conference participants approved the final draft of the proceedings of the meeting. Results: Conference attendees modified the current criteria used to define SIRS and sepsis in adults to incorporate pediatric physiologic variables appropriate for the following subcategories of children: newborn, neonate, infant, child, and adolescent. In addition, the SIRS definition was modified so that either criteria for fever or white blood count had to be met. We also defined various organ dysfunction categories, severe sepsis, and septic shock specifically for children. Although no firm conclusion was made regarding a single appropriate study end point, a novel nonmortality end point, organ failure-free days, was considered optimal for pediatric clinical trials given the relatively low incidence of mortality in pediatric sepsis compared with adult populations. Conclusion: We modified the adult SIRS criteria for children. In addition, we revised definitions of severe sepsis and septic shock for the pediatric population. Our goal is for these first-generation pediatric definitions and criteria to facilitate the performance of successful clinical studies in children with sepsis.

Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial*

BACKGROUND Endotoxin is a primary trigger of the inflammatory processes that lead to shock, multiorgan failure, and purpura fulminans in meningococcal sepsis. Bactericidal/permeability-increasing protein (BPI) is a natural protein, stored within the neutrophil granules, that binds to and neutralises the effects of endotoxin in vitro, in laboratory animals, and in humans. To establish whether a recombinant 21-kDa modified fragment of human BPI (rBPI21), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability from meningococcal sepsis, we did a randomised, double-blind, placebo-controlled trial of rBPI21 in children with severe meningococcal sepsis. METHODS We enrolled children (2 weeks to 18 years of age) presenting to 22 centres in the UK and the USA with a clinical picture suggestive of meningococcal sepsis, and with evidence of severe disease. Children were randomly assigned rBPI21 (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (0.2 mg/mL human albumin solution) in addition to conventional medical therapy. Primary outcome variables were mortality, amputations, and change in paediatric overall performance category (POPC) from before illness to day 60. Analysis was by intention to treat. FINDINGS Of 1287 patients screened, 892 were excluded, including 57 patients who died or who met criteria for imminent death before receiving the study drug. 190 patients received rBPI21, and 203 placebo. 34 (8.7%) of 393 patients died during the study: 14 (7.4%) in the rBPI21 group and 20 (9.9%) in the placebo group (odds ratio 1.31 [95% CI 0.62-2.74], p=0.48). Compared with patients randomised to placebo, fewer patients treated with rBPI21 had multiple severe amputations (six of 190 [3.2%] vs 15 of 203 [7.4%], odds ratio 2.47 [0.94-6.51], p=0.067), and more had a functional outcome similar to that before illness (as measured by the POPC scale) at day 60 (136 of 176 [77.3%] vs 126 of 190 [66.3%], p=0.019). INTERPRETATION Because most deaths occurred in the interval between identification of patients and study drug administration, the mortality rate in the placebo group was substantially lower than predicted. The trial was therefore underpowered to detect significant differences in mortality. However, patients receiving rBPI21 had a trend towards improved outcome in all primary outcome variables. Given the excellent severity match between placebo and rBPI21 groups at study entry, the results overall indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease.

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

Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis

BACKGROUND Meningococcal sepsis remains an important cause of morbidity and mortality. We hypothesised that children with severe meningococcaemia might benefit from inhibition of the inflammatory processes thought responsible for fulminant disease. rBPI21 is a recombinant, N-terminal fragment of human bactericidal/permeability-increasing protein, which kills meningococci and binds to and clears bacterial endotoxin, these being the primary inducers of the systemic inflammation. The aim of this study was to determine the safety and kinetics of rBPI21 in children with severe meningococcaemia and to make a preliminary assessment of clinical outcome. METHODS In this open-label, dose-escalation, phase I/II trial in severe meningococcaemia (Glasgow meningococcal prognostic septicaemia score [GMSPS] > or = 8), 26 patients aged 1-18 years, who had received their first dose of antibiotics no more than 8 hours earlier were given rBPI21 by infusion at total doses of 1.0, 2.0, and 4.0 mg/kg. FINDINGS The patients had significantly raised plasma concentrations of bacterial endotoxin and cytokines. Peak and steady state BPI concentrations were comparable with pharmacokinetic data in healthy adults. All complications were compatible with the expected pattern for severe meningococcal sepsis. Only one patient died. This outcome was found to compare favourably with a predicted mortality of > or = 30% by GMSPS, > or = 15% by plasma endotoxin values, > or = 28% by plasma interleukin-6 concentrations, 29-49% by severity of coagulopathy, and 20% (11/54) by comparison with recent historical patients consecutively treated in participating centres before this study. INTERPRETATION This, the first clinical trial or rBPI21, shows that rBPI21 can be safely administered to children with severe meningococcaemia and that the pharmacokinetics are consistent with patterns seen in healthy adults. Predicted mortality, on the basis of GMSPS, laboratory indices of inflammation and coagulopathy, and historical controls, was for between four and eight deaths. These findings have prompted a phase III randomised trial.

Anemia, Blood Loss, and Blood Transfusions in North American Children in the Intensive Care Unit

RATIONALE Minimizing exposure of children to blood products is desirable. OBJECTIVES We aimed to understand anemia development, blood loss, and red blood cell (RBC) transfusions in the pediatric intensive care unit (PICU). METHODS Prospective, multicenter, 6-month observational study in 30 PICUs. Data were collected on consecutive children (<18 yr old) in the PICU for 48 hours or more. MEASUREMENTS AND MAIN RESULTS Anemia development, blood loss, and RBC transfusions were measured. A total of 977 children were enrolled. Most (74%) children were anemic in the PICU (33% on admission, 41% developed anemia). Blood draws accounted for 73% of daily blood loss; median loss was 5.0 ml/day. Forty-nine percent of children received transfusions; 74% of first transfusions were on Days 1-2. After adjusting for age and illness severity, compared with nontransfused children, children who underwent transfusion had significantly longer days of mechanical ventilation (2.1 d, P < 0.001) and PICU stay (1.8 d, P = 0.03), and had increased mortality (odds ratio [OR], 11.6; 95% confidence interval [CI], 1.43-90.9; P = 0.02), nosocomial infections (OR, 1.9; 95% CI, 1.2-3.0; P = 0.004), and cardiorespiratory dysfunction (OR, 2.1; 95% CI, 1.5-3.0; P < 0.001). High blood loss per kilogram body weight from blood draws (OR, 1.11; 95% CI, 1.03-1.2; P = 0.01) was associated with RBC transfusion more than 48 hours after admission. The most common indication for transfusion was low hemoglobin (42%). Pretransfusion hemoglobin values varied greatly (mean, 9.7 +/- 2.7 g/dl). CONCLUSIONS Critically ill children are at significant risk for developing anemia and receiving blood transfusions. Transfusion in the PICU was associated with worse outcomes. It is imperative to minimize blood loss from blood draws and to set clear transfusion thresholds.

decomplexification in critical illness and injury: Relationship between heart rate variability, severity of illness, and outcome

Abstract Objectives: To determine if decomplexification of heart rate dynamics occurs in critically ill and injured pediatric patients. We hypothesized that heart rate power spectra, a measure of heart rate dynamics, would inversely correlate with measures of severity of illness and outcome. Design: A prospective clinical study. Setting: A 12‐bed pediatric intensive care unit (ICU) in a tertiary care childrens hospital. Patients: One hundred thirty‐five consecutive pediatric ICU admissions. Interventions: None. Measurements and Main Results: We compared heart rate power spectra with the Pediatric Risk of Mortality (PRISM) score, the Pediatric Cerebral Performance Category (PCPC), and the Pediatric Overall Performance Category (POPC). We found significant negative correlations between minimum low‐frequency and high‐frequency heart rate power spectral values recorded during ICU stay and the maximum PRISM score (log low‐frequency heart rate power vs. PRISM, r2 = .293, p < .001; and log high‐frequency heart rate power vs. PRISM, r2 = .243, p < .001) and outcome at ICU discharge (log low‐frequency heart rate power vs. POPC or PCPC, r2 = .429, p < .001; and log high‐frequency heart rate power vs. POPC or PCPC, r2 = .271, p < .001). Conclusions: Our data support the hypothesis that measures of heart rate power spectra are inversely related and negatively correlated to severity of illness and outcome in critically ill and injured children. The phenomenon of decomplexification of physiologic dynamics may have important clinical implications in critical illness and injury. (Crit Care Med 1998; 26:352‐357) For years, physicians have believed that physiologic systems existed in a so‐called “steady” or “homeostatic” state and that these systems exhibited a linear response when stimulated. It is now clear that physiologic systems exist in a nonlinear, dynamic state [1‐4]. In other words, physiologic systems constantly change over time and respond to stimuli in a nonlinear manner. Furthermore, healthy physiologic systems exhibit marked signal variability, while aging or diseased systems show a loss of variability [2,5]. This decreased variability, or increased regularity, in physiologic dynamics has been termed “decomplexification” [1]. Commonly monitored physiologic signals, including mean heart rate, blood pressure, and cardiac output, correlate poorly with survival in both experimental models of circulatory shock and in critically ill patients [6]. These first‐order linear measures do not adequately describe dynamic changes. Power spectral analysis of heart rate variability, a second‐order linear measure, allows for quantification in the frequency domain of dynamic changes in beat‐to‐beat heart rate oscillations [1,5‐10]. Power spectral analysis of heart rate variability has been used to quantify physiologic changes in many diseases, including hypovolemia, congestive heart failure, hypertension, diabetes mellitus, renal failure, cardiac transplantation, traumatic quadriplegia, and sepsis [10‐19]. We hypothesized that decomplexification of heart rate dynamics would occur over a broad range of critical illness and injury, and would inversely correlate with disease severity and outcome in a pediatric population. To test this hypothesis, we prospectively studied 135 consecutive admissions to the Strong Childrens Critical Care Center. We compared heart rate power spectra with a previously validated measure of severity of illness, the Pediatric Risk of Mortality (PRISM) score [20], and with validated measures of outcome from pediatric intensive care, the Pediatric Overall Performance Category (POPC) [21] and Pediatric Cerebral Performance Category (PCPC) [21] scores.

An automatic beat detection algorithm for pressure signals

Beat detection algorithms have many clinical applications including pulse oximetry, cardiac arrhythmia detection, and cardiac output monitoring. Most of these algorithms have been developed by medical device companies and are proprietary. Thus, researchers who wish to investigate pulse contour analysis must rely on manual annotations or develop their own algorithms. We designed an automatic detection algorithm for pressure signals that locates the first peak following each heart beat. This is called the percussion peak in intracranial pressure (ICP) signals and the systolic peak in arterial blood pressure (ABP) and pulse oximetry (SpO/sub 2/) signals. The algorithm incorporates a filter bank with variable cutoff frequencies, spectral estimates of the heart rate, rank-order nonlinear filters, and decision logic. We prospectively measured the performance of the algorithm compared to expert annotations of ICP, ABP, and SpO/sub 2/ signals acquired from pediatric intensive care unit patients. The algorithm achieved a sensitivity of 99.36% and positive predictivity of 98.43% on a dataset consisting of 42,539 beats.

Uncoupling of the autonomic and cardiovascular systems in acute brain injury

We hypothesized that acute brain injury results in decreased heart rate (HR) variability and baroreflex sensitivity indicative of uncoupling of the autonomic and cardiovascular systems and that the degree of uncoupling should be proportional to the degree of neurological injury. We used HR and blood pressure (BP) power spectral analysis to measure neuroautonomic regulation of HR and BP and the transfer function magnitude (TF) between BP and HR as a measure of baroreflex modulation of HR. In 24 brain-injured patients [anoxic/ischemic injury ( n = 7), multiple trauma ( n = 6), head trauma ( n = 5), central nervous system infection ( n = 4), and intracranial hemorrhage ( n = 2)], neurological injury and survival was associated with low-frequency (0.01-0.15 Hz) HR and BP power and TF. Brain-dead patients showed decreased low-frequency HR power [0.51 ± 0.36 (SE) vs. 2.54 ± 0.14 beats/min2, P = 0.03] and TF [0.61 ± 0.16 (SE) vs. 1.29 ± 0.07 beats ⋅ min-1 ⋅ mmHg-1, P = 0.05] compared with non-brain-dead patients. We conclude that 1) severity of neurological injury and outcome are inversely associated with HR and BP variability and 2) there is direct evidence for cardiovascular and autonomic uncoupling in acute brain injury with complete uncoupling during brain death.We hypothesized that acute brain injury results in decreased heart rate (HR) variability and baroreflex sensitivity indicative of uncoupling of the autonomic and cardiovascular systems and that the degree of uncoupling should be proportional to the degree of neurological injury. We used HR and blood pressure (BP) power spectral analysis to measure neuroautonomic regulation of HR and BP and the transfer function magnitude (TF) between BP and HR as a measure of baroreflex modulation of HR. In 24 brain-injured patients [anoxic/ischemic injury (n = 7), multiple trauma (n = 6), head trauma (n = 5), central nervous system infection (n = 4), and intracranial hemorrhage (n = 2)], neurological injury and survival was associated with low-frequency (0.01-0.15 Hz) HR and BP power and TF. Brain-dead patients showed decreased low-frequency HR power [0. 51 +/- 0.36 (SE) vs. 2.54 +/- 0.14 beats/min2, P = 0.03] and TF [0. 61 +/- 0.16 (SE) vs. 1.29 +/- 0.07 beats . min-1 . mmHg-1, P = 0.05] compared with non-brain-dead patients. We conclude that 1) severity of neurological injury and outcome are inversely associated with HR and BP variability and 2) there is direct evidence for cardiovascular and autonomic uncoupling in acute brain injury with complete uncoupling during brain death.

Inflicted versus accidental head injury in critically injured children

ObjectivesTo assess the frequency of inflicted head injury in critically injured children; the severity of neurologic injury; the neurologic outcome; and the historical, socioeconomic, physical, and radiologic factors associated with inflicted head injury. DesignProspective clinical study. SettingMultidisciplinary pediatric intensive care unit (ICU). PatientsConsecutive cases (n = 40) of severe head injury admitted to a pediatric ICU. InterventionsNone. Measurements and Main ResultsFourteen (35%) of 40 cases of head injury were due to inflicted head injury. Eleven (79%) of 14 inflicted head injury cases were due to child abuse and three (21%) were due to neglect. The severity of neurologic injury, as measured by the admission Glasgow Coma Scale, was worse in cases of inflicted head injury (7.1 ± 0.7 [SE] [inflicted] VS. 9.9 ± 0.8 [accidental]; p = .04). Glasgow Outcome Scores were worse after inflicted head injury (2 ± 1 [inflicted] VS. 4 ± 1 [accidental]; p = .004). In victims of child abuse, we found the combination of any two of the following three factors was associated with inflicted head injury: an inconsistent history/physical examination; retinal hemorrhages; or parental risk factors (alcohol or drug abuse, previous social service intervention within the family, or a past history of child abuse or neglect). ConclusionsThis study confirms that severity of neurologic injury and neurologic outcome in cases of inflicted head injury are worse thanin any other type of childhood head injury. We believe that a combination of any two of the above three risk factors may prove to be a reliable marker of inflicted head injury in children admitted to a pediatric ICU and will lead to an early and definitive diagnosis. (Crit Care Med 1993; 21:1328–1332)

Impact of a pediatric clinical pharmacist in the pediatric intensive care unit.

Objective To study the impact of a clinical pharmacist in a pediatric intensive care unit. The goals of the study were to determine the type and quantity of patient care interventions recommended by a clinical pharmacist and to specifically examine cost savings (or loss) that resulted from clinical pharmacist recommendations. Design A prospective case series. Setting Ten-bed pediatric intensive care unit in a university-affiliated children’s hospital. Patients All patients admitted to the pediatric intensive care unit during the study period. Interventions None. Measurements and Main Results During the 24-wk study period, the pediatric clinical pharmacist documented all interventions that occurred during her shift. She rounded with the pediatric intensive care unit team approximately two times a week and reviewed medication lists daily. Drug acquisition costs were used to calculate drug cost savings. Demographic information was collected on all the patients in the pediatric intensive care unit during the study period.There were 35 recommendations per 100 patient days. The most common interventions were dosage changes (28%), drug information (26%), and miscellaneous information (22%). The average time spent per day by the clinical pharmacist in the pediatric intensive care unit was 0.73 hrs or 0.02 full-time equivalent. The total cost direct savings for the study period was