Mild-to-severe traumatic brain injury in children: altered cytokines reflect severity.

BACKGROUND: Paediatric traumatic brain injury (TBI) is recognised to have significant longer-term neurocognitive effects. Childhood is a time of high risk for head injury. Functional recovery is variable with a combination of any or all of physical, cognitive and emotional impairment. Immune activation and alteration in cytokine levels are present following TBI which may differ from adults. METHODS: Pro- and anti-inflammatory cytokines including Interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-17A, Tumor Necrosis Factor (TNF)-α and Interferon (IFN)-γ were examined at baseline and following in vitro treatment with endotoxin of whole blood, in the following children: severe TBI (sTBI: initial Glasgow coma scale(GCS) ≤ 8), mild TBI (mTBI; GCS 14/15) at 0-4d and at 10-14d post-TBI and compared to healthy age-matched controls. RESULTS: The study enrolled 208 children, including 110 with TBI cohort (n = 104 mild; 6 severe) and controls (n = 98). At baseline all children with TBI had increased IL-6. The mTBI group had significantly increased IFN-γ versus controls. In sTBI at baseline, IFN-γ was decreased compared to controls. At baseline IL-8, IL-10, IL-17A, and TNF-α were decreased in mTBI compared to controls. This persisted at 2 week post-mTBI. The AUC for detecting mTBI was 0.801 CI (0.73-086) using IL6/IL10 ratio. mTBI showed a greater fold change in IL-8 and TNF-α in response to endotoxin stimulation, a response that persisted at 2 weeks. Children with sTBI did not have a significant IL-6 response to endotoxin, but did show an increase in IL-17A. CONCLUSION: Children with all TBI including mTBI show altered cytokine profiles and altered endotoxin responses. Although cytokines increased in sTBI especially in response to endotoxin, suppressed responses were found in mTBI coupled with persistent immune dysfunction post-injury.

The Effectiveness of α2 Agonists As Sedatives in Pediatric Critical Care: A Propensity Score-Matched Cohort Study.

OBJECTIVES: There is limited evidence supporting the widespread use of α2 agonists (clonidine and dexmedetomidine) in pediatric critical care sedation. This study sought to test the association between the use of α2 agonists and enhanced sedation. DESIGN: A retrospective observational cohort study was conducted. Noninferiority of time adequately sedated (COMFORT Behavior Score 11-16) while mechanically ventilated was assessed. Secondarily, dosing of opioids and benzodiazepines was examined. SETTING: Two tertiary PICUs. PATIENTS: Children were classified into an exposed group, who received an α2 agonist as part of their sedation regimen, and an unexposed group. Groups were matched using propensity score analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One-thousand eighty-five patients were included. The exposed group were adequately sedated 74% (95% CI, 72-75%) of the study time compared with the unexposed group at 70% (95% CI, 67-72%) giving a ratio of 1.06 (95% CI, 1.02-1.10) and a noninferior time adequately sedated. A decrease in time oversedated was observed with 8.1% (95% CI, 4.3-11.9%) less time classified as oversedated in the exposed group. Reduction in morphine use of 0.25 µg/kg/hr (95% CI, -0.68 to 1.18 µg/kg/hr) was not statistically significant. Midazolam use did not decrease and was statistically higher. CONCLUSIONS: Use of α2 agonists was associated with similar time adequately sedated as a matched unexposed group although no reduction in morphine or benzodiazepine coadministration was observed. There was a shift toward lighter sedation with α2 agonist use.

Optimizing clonidine dosage for sedation in mechanically ventilated children: A pharmacokinetic simulation study.

BACKGROUND: Clonidine is in widespread off-label use as a sedative in mechanically ventilated children, despite limited evidence of efficacy. A variety of dosage regimens have been utilized in clinical practice and in research studies. Within these studies, clonidine has inconsistently shown useful sedation properties. One of the reasons attributed to the inconsistent signs of efficacy is suboptimal clonidine dosing. AIMS: This study aims to propose a target plasma concentration and simulate clonidine pharmacokinetics (PK) in a cohort of mechanically ventilated children to evaluate the adequacy of clonidine dosage regimens used in clinical practice and research studies. METHODS: A literature search was undertaken to identify a clonidine pharmaockinetic-pharmacodynamics (PKPD) model, from which a target concentration for sedation was defined. Using a previously published PK model, the projected plasma concentrations of 692 mechanically ventilated children (demographics taken from a recent study) were generated. Doses from recently published clinical studies were investigated. Adequacy of each regimen to attain therapeutic clonidine plasma concentrations was assessed. RESULTS: A target plasma concentration of above 2 µg/L was proposed. Nine dosage regimens (four intravenous boluses, four intravenous infusions, and one nasogastric route boluses) were evaluated ranging from 1 µg/kg eight hourly intravenous boluses to a regimen up to 3 µg/kg/hr continuous intravenous infusion. Regimens with a loading dose of 2 µg/kg followed by variable continuous infusion of up to 2 µg/kg/hr titrated according to sedation score appear most suitable. Doses should be halved in neonates. CONCLUSION: The variety of dosage regimens in the previous studies of clonidine along with difficulties in the conduct of interventional studies may have contributed to the lack of efficacy data to support its use. Simulations of clonidine plasma concentrations based on known population pharmacokinetic parameters suggest a loading dose followed by higher than current practice maintenance dose infusion is required to achieve adequate steady-state concentrations early in treatment. Further PKPD studies will aid in the determination of the optimal clonidine dosage regimen.

Calcitriol trend following pediatric cardiac surgery and association with clinical outcome.

BACKGROUND: Consistent with accepted practice in stable ambulatory populations, the majority of ICU research has evaluated vitamin D status using a single blood 25-hydroxyvitamin D (25(OH)D) level. Only a limited number of ICU studies have measured the active hormone, 1,25-dihydroxyvitamin D (calcitriol) and none have used change in calcitriol levels to evaluate axis functioning. The objective of this study was to describe the impact of Congenital Heart Disease (CHD) surgery on calcitriol levels and evaluate the relationship between change in postoperative levels and clinical course. METHODS: Secondary analysis of a prospective cohort study of 56 children undergoing surgery for CHD. RESULTS: Mean calcitriol levels dropped from 122.3 ± 69.1 pmol/L preoperatively to 65.3 ± 36.5 pmol/L (p < 0.0001) at PICU admission. The majority (61%, n = 34) were unable to increase calcitriol levels in the 48 h immediately following surgery. Post operative trend in calcitriol was inversely related to cardiovascular dysfunction, fluid requirements, ventilatory support and PICU length of stay (p < 0.01). CONCLUSION: CHD patients had significant dysfunction of the vitamin D axis immediately postoperatively, demonstrated by both a significant intraoperative decline in calcitriol and inability to increase levels. Interventional research will be required to determine whether the use of calcitriol, in addition to cholecalciferol, reduces postoperative illness severity.

Efficacy of α2-Agonists for Sedation in Pediatric Critical Care: A Systematic Review.

OBJECTIVE: Children in PICUs normally require analgesics and sedatives to maintain comfort, safety, and cooperation with interventions. α2-agonists (clonidine and dexmedetomidine) have been described as adjunctive (or alternative) sedative agents alongside opioids and benzodiazepines. This systematic review aimed to determine whether α2-agonists were effective in maintaining patients at a target sedation score over time compared with a comparator group. We also aimed to determine whether concurrent use of α2-agonists provided opioid-sparing effects. DATA SOURCES: A systematic search was performed using the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, CINAHL, and LILACS. STUDY SELECTION: We included randomized controlled trials of children in PICU treated with clonidine or dexmedetomidine for the indication of sedation. DATA EXTRACTION: Two authors independently screened articles for inclusion. DATA SYNTHESIS: Six randomized controlled trials with sufficient data were identified and critically appraised. Three clonidine trials (two vs placebo and one vs midazolam) and three dexmedetomidine trials (two vs fentanyl, one vs midazolam) were included. Due to study heterogeneity it was not possible to pool studies. A narrative synthesis is provided. CONCLUSIONS: Reporting of study results using the outcome "time maintained at target sedation score' for clonidine or dexmedetomidine was poor. Only one trial compared clonidine with midazolam using a sedation score outcome. This study was underpowered to demonstrate equivalence to midazolam as a sedative. The adjunctive use of clonidine demonstrated significant decreases in opioid use in neonates but not in older groups. Clonidine dose was inconsistent between studies. Dexmedetomidine demonstrated an opioid-sparing effect in two small trials. Further studies, including dose-finding studies and studies with sedation score-based outcomes, are needed.

Impact of anesthesia and surgery for congenital heart disease on the vitamin d status of infants and children: a prospective longitudinal study.

BACKGROUND: Vitamin D is recognized as a pleiotropic hormone important for the functioning of organ systems, including those central to critical illness pathophysiology. Recent studies have reported associations between vitamin D status and outcome among critically ill adults and children. Preoperative vitamin D status, impact of operative techniques, and relationship between immediate postoperative vitamin D levels and clinical course have not been described in the pediatric congenital heart disease (CHD) population. The objective of this study was to describe the impact of CHD surgery on vitamin D status and relationship between postoperative levels and clinical course. METHODS: A prospective cohort study was conducted from 2009 to 2011 at a single tertiary care pediatric hospital. A total of 58 children with CHD were enrolled and blood collected preoperatively, intraoperatively, and postoperatively. Serum 25-hydroxyvitamin D (25OHD) was measured using liquid chromatography-mass spectrometry. RESULTS: The mean preoperative 25OHD was 58.0 nM (SD, 22.4), with 42% being deficient (<50 nM). Postoperatively, we identified a 40% decline in 25OHD to 34.2 nM (SD, 14.5) with 86% being deficient. Intraoperative measurements determined that initiation of cardiopulmonary bypass coincided with abrupt decline. CHD patients requiring catecholamines had lower postoperative 25OHD (38.2 vs. 26.5 nM, P=0.007), findings confirmed through multivariate logistic regression. Lower postoperative 25OHD was associated with increased fluid requirements and intubation duration. CONCLUSIONS: Most CHD patients are vitamin-D deficient postoperatively due to low preoperative levels and a significant intraoperative decline. Interventional studies will be required to determine whether prevention of postoperative vitamin D deficiency improves outcome.

Hypothermia therapy after pediatric cardiac arrest.

BACKGROUND: Hypothermia therapy improves mortality and functional outcome after cardiac arrest and birth asphyxia in adults and newborns. The effect of hypothermia therapy in infants and children with cardiac arrest is unknown. METHODS AND RESULTS: A 2-year, retrospective, 5-center study was conducted, and 222 patients with cardiac arrest were identified. Seventy-nine (35.6%) of these patients met eligibility criteria for the study (age >40 weeks postconception and <18 years, cardiac arrest >3 minutes in duration, survival for > or = 12 hours after return of circulation, and no birth asphyxia). Twenty-nine (36.7%) of these 79 patients received hypothermia therapy and were cooled to 33.7+/-1.3 degrees C for 20.8+/-11.9 hours. Hypothermia therapy was associated with higher mortality (P=0.009), greater duration of cardiac arrest (P=0.005), more resuscitative interventions (P<0.001), higher postresuscitation lactate levels (P<0.001), and use of extracorporeal membrane oxygenation (P<0.001). When adjustment was made for duration of cardiac arrest, use of extracorporeal membrane oxygenation, and propensity scores by use of a logistic regression model, no statistically significant differences in mortality were found (P=0.502) between patients treated with hypothermia therapy and those treated with normothermia. Also, no differences in hypothermia-related adverse events were found between groups. CONCLUSIONS: Hypothermia therapy was used in resuscitation scenarios that are associated with greater risk of poor outcome. In an adjusted analysis, the effectiveness of hypothermia therapy was neither supported nor refuted. A randomized controlled trial is needed to rigorously evaluate the benefits and harms of hypothermia therapy after pediatric cardiac arrest.

Off-label drug use in pediatric anesthesia and intensive care according to official and pediatric reference formularies.

PURPOSE: In pediatric practice, the official drug label often does not accurately reflect the contemporary use of many drugs prescribed to children. Therefore, clinicians frequently use contemporary drug references as a source of prescribing information instead of national formularies. The objective of this study was to compare drug prescriptions between two national formularies and two commonly used contemporary pediatric reference guidelines in the operating room/postanesthetic care unit (OR/PACU), pediatric intensive care unit (PICU), and neonatal intensive care unit (NICU). METHODS: We performed a retrospective chart review of patients admitted over a one-month period to the NICU and PICU, and for one week during the same month, we reviewed charts of patients in the OR/PACU. The data collected included patients' demographic information, drugs prescribed, and dosage information. We assessed conformity with two national formularies, the Canadian Compendium of Pharmaceuticals and Specialties (CPS) and France's 2009 Dictionnaire Vidal (Vidal), and two contemporary pediatric references, the Hospital for Sick Children Handbook and Formulary and the Lexi-Comp Pediatric Dosage Handbook. RESULTS: Across the three clinical units, 59.7% (95% confidence interval [CI] 57.1-62.1%) of prescriptions were identified as being off-label, as defined by the CPS formulary. The odds of having an off-label prescription would have been substantially lower if the contemporary pediatric references (odds ratio [OR] = 0.074; 95% CI 0.065-0.084) or Vidal (OR = 0.70; 95% CI 0.63-0.77) had been used to define the label (both P < 0.001 compared with the CPS). CONCLUSION: Drugs are less likely to be off-label if prescribed according to a contemporary pediatric reference rather than according to national formularies. Methodologies used to compile contemporary references might serve as templates to inform a drug's official label.

A review of pediatric capnography.

OBJECTIVES: Capnography has become a standard of perioperative monitoring in pediatric anesthesiology. It has also begun to find application in a variety of situations outside the perioperative setting. While the use of capnography has been increasing, the dissemination and acceptability of capnography in all areas of pediatrics has been variable. The purpose of this study was to describe all the applications and interpretations of capnography that have been reported in children. METHODS: In March 2010, we completed a search of peer reviewed literature from MEDLINE (from 1950), CINAHL (from 1982) and the Cochrane Library. Final search results were limited to publications in which the primary intent was to describe the application or interpretations of capnography in children. RESULTS: This search resulted in a list of 44 applications and interpretations of capnography. We classified the applications and interpretations of capnography in children into six categories--Anesthetic Delivery Apparatus, Airway, Breathing, Circulation, Homeostasis and Non-perioperative. We discuss the four randomized controlled trials describing the use of capnography in children. Based on the available evidence, we have also assigned grades of recommendations for these applications and interpretations. CONCLUSIONS: Capnography has been proven to be a useful non-invasive perioperative monitor of the physiology and safety of the child. This list of the clinical applications and interpretations of capnography could find use in teaching and simulation in pediatrics.

Prevention of post-cardiac surgery vitamin D deficiency in children with congenital heart disease: a pilot feasibility dose evaluation randomized controlled trial.

BACKGROUND: The vast majority of children undergoing cardiac surgery have low vitamin D levels post-operative, which may contribute to greater illness severity and worse clinical outcomes. Prior to the initiation of a large phase III clinical trial focused on clinical outcomes, studies are required to evaluate the feasibility of the study protocol, including whether the proposed dosing regimen can safely prevent post-operative vitamin D deficiency in this high-risk population. METHODS: We conducted a two-arm, double-blind dose evaluation randomized controlled trial in children requiring cardiopulmonary bypass for congenital heart disease. Pre-operatively, participants were randomized to receive cholecalciferol representing usual care (< 1 year = 400 IU/day, > 1 year = 600 IU/day) or a higher dose approximating the Institute of Medicine tolerable upper intake level (< 1 year = 1600 IU/day, > 1 year = 2400 IU/day). The feasibility outcomes were post-operative vitamin D status (primary), vitamin D-related adverse events, accrual rate, study withdrawal rate, blinding, and protocol non-adherence. RESULTS: Forty-six children were randomized, and five withdrew prior to surgery, leaving 41 children (21 high dose, 20 usual care) in the final analysis. The high dose group had higher 25-hydroxyvitamin D concentrations both intraoperatively (mean difference + 25.9 nmol/L; 95% CI 8.3-43.5) and post-operatively (mean difference + 17.2 nmol/L; 95% CI 5.5-29.0). Fewer participants receiving high-dose supplementation had post-operative serum 25-hydroxyvitamin D concentrations under 50 nmol/L, compared with usual care (RR 0.31, 95% CI 0.11-0.87). Post-operative vitamin D status was associated with the treatment arm and the number of doses received. There were no cases of hypercalcemia, and no significant adverse events related to vitamin D. While only 75% of the target sample size was recruited (limited funding), the consent rate (83%), accrual rate (1.5 per site month), number of withdrawals (11%), and ability to maintain blinding support feasibility of a larger trial. CONCLUSIONS: Pre-operative daily high-dose supplementation improved vitamin D status pre-operatively and at time of pediatric ICU admission. The protocol for a more definitive trial should limit enrollment of children with at least 30 days between randomization and surgery to allow adequate duration of supplementation or consider a loading dose. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01838447. Registered on April 24, 2013.

Hypothermia therapy for cardiac arrest in pediatric patients.

Cardiac arrest is associated with high morbidity and mortality in children. Hypothermia therapy has theoretical benefits on brain preservation and has the potential to decrease morbidity and mortality in children following cardiac arrest. The American Heart Association guidelines recommend that it should be considered in children after cardiac arrest. Methods of inducing hypothermia include simple surface cooling techniques, intravenous boluses of cold saline, gastric lavage with ice-cold normal saline, and using the temperature control device with extracorporeal life support. We recommend further study before a strong recommendation can be made to use hypothermia therapy in children with cardiac arrest.

Effectiveness of α2agonists for sedation in paediatric critical care: study protocol for a retrospective cohort observational study.

INTRODUCTION: Mechanically ventilated children in paediatric intensive care units are commonly administered analgesics and sedative agents to minimise pain and distress and facilitate cooperation with medical interventions. Opioids and benzodiazepines are the most common analgesic and sedative agents but have safety concerns. The α2 agonists clonidine and dexmedetomidine are alternative sedatives in use despite neither having robust evidence to support their use. Studies evaluating effectiveness of α2 agonists to date have not focused on sedation-based outcomes instead focusing on opioid-sparing properties and ventilation outcomes. The aim of this study is to evaluate if an opioid-based sedation regimen, with an α2 agonist adjunct (clonidine or dexmedetomidine), produces a non-inferior proportion of time adequately sedated compared with a control group without an α2 agonist adjunct, while conferring potential additional benefits such as reduced opioid administration and less exposure to potential additional agents such as benzodiazepines. METHODS AND ANALYSIS: We will conduct a retrospective cohort study in two Irish paediatric intensive care units using clinical information on patient characteristics, sedation scores and drug use. Eligible children admitted between January 2014 and June 2016 who were mechanically ventilated and received an opioid infusion will be included. Patients will be categorised into two exposure categories (received an α2 agonist or did not receive an α2 agonist) and the time adequately sedated (measured using the COMFORT Behaviour Score) will be calculated using interpolation of nursing sedation scores at each recorded time point. At least 150 per group is planned for inclusion to ensure adequate study power. Propensity score matching will be used in analysis to account for potential confounding by indication. ETHICS AND DISSEMINATION: The study has been approved by the ethics committees of both hospitals. Dissemination will occur via local, national and international presentations for academic and healthcare audiences as well as through peer reviewed publications.

1,25-Dihydroxyvitamin D Levels in Pediatric Intensive Care Units: Risk Factors and Association With Clinical Course.

CONTEXT: Multiple adult and some pediatric critical care studies have suggested that poor vitamin D status is associated with illness severity and outcome. The majority have evaluated vitamin D status through serum 25-hydroxyvitamin D [25(OH)D]. Critical illness-related organ dysfunction may result in impaired conversion of 25(OH)D to the active hormone 1,25-dihydroxyvitamin D [1,25(OH)2D]. Consequently 1,25(OH)2D levels could be an independent additive prognostic marker in the intensive care unit. OBJECTIVES: The distribution of 1,25(OH)2D levels, prevalence of low levels, investigation of risk factors, and tests for associations with markers of illness severity and outcome are reported. DESIGN, SETTING, AND PATIENTS: This was a secondary analysis of data and samples collected as part of a prospective cohort study in six Canadian pediatric intensive care units (PICUs). MAIN OUTCOME MEASURE: Admission blood 1,25(OH)2D concentrations were measured. RESULTS: The median cohort 1,25(OH)2D level was 93.3 pmol/L (interquartile range, 53.0-121.9) with 13% (95% confidence interval, 9-17) and 21% (95% confidence interval, 17-27) of patients having levels of <40 and <50 pmol/L, respectively. Low 1,25(OH)2D levels occurred more often in patients with low 25(OH)D and hepatic, renal, and parathyroid organ dysfunction. After adjustment for 25(OH)D, low 1,25(OH)2D levels were not associated with catecholamine or fluid administration, ventilation, PICU length of stay, or mortality. CONCLUSION: Critically ill children are at risk for low 1,25(OH)2D levels, particularly in the presence of established risk factors. However, the lack of association between the 1,25(OH)2D level and selected outcome measures, after controlling for 25(OH)D, does not suggest value in measuring this metabolite at the time of PICU admission.

The relationship between vitamin D status and adrenal insufficiency in critically ill children.

CONTEXT: Recent studies in critically ill populations have suggested both adrenal insufficiency (AI) and vitamin D deficiency to be associated with worse clinical outcome. There are multiple mechanisms through which these pleiotropic hormones might synergistically influence critical illness. OBJECTIVE: The aim of the study was to investigate potential relationships between vitamin D status, adrenal status, and cardiovascular dysfunction in critically ill children. DESIGN: We conducted a secondary analysis of data from a prospective cohort study. SETTING AND PATIENTS: The study was conducted on 319 children admitted to 6 Canadian tertiary-care pediatric intensive care units. MAIN OUTCOME MEASURES: Vitamin D status was determined through total 25-hydroxyvitamin D (25OHD) levels. AI was defined as a cortisol increment under 9 µg/dL after low-dose cosyntropin. Clinically significant cardiovascular dysfunction was defined as catecholamine requirement during pediatric intensive care unit admission. RESULTS: Using 3 different thresholds to define vitamin D deficiency, no association was found between vitamin D status and AI. Furthermore, linear regression failed to identify a relationship between 25OHD and baseline or post-cosyntropin cortisol. However, the association between AI and cardiovascular dysfunction was influenced by vitamin D status; compared to children with 25OHD above 30 nmol/L, AI in the vitamin D-deficient group was associated with significantly higher odds of catecholamine use (odds ratio, 5.29 vs 1.63; P = .046). CONCLUSIONS: We did not find evidence of a direct association between vitamin D status and critical illness-related AI. However, our results do suggest that vitamin D deficiency exacerbates the effect of AI on cardiovascular stability in critically ill children.

The association of vitamin D status with pediatric critical illness.

OBJECTIVES: Vitamin D is a pleiotropic hormone important for the proper functioning of multiple organ systems. It has been hypothesized that vitamin D deficiency could contribute to or worsen outcomes in critical illness. The study objective was to determine the prevalence of vitamin D deficiency, risk factors for its presence, and potential association with clinically relevant outcomes in critically ill children. METHODS: A prospective cohort study, conducted from 2005 to 2008 in 6 tertiary-care PICUs in Canada. Data and biological samples from 326 critically ill children up to 17 years of age were available for analysis. Total serum 25 hydroxyvitamin D or 25(OH)D was measured by using liquid chromatography-mass spectrometry. RESULTS: The prevalence of 25(OH)D <50 nmol/L was 69% (95% confidence interval, 64-74), and 23% (95% confidence interval, 19-28) for 25(OH)D between 50 to 75 nmol/L. Lower levels were associated with hypocalcemia, catecholamine utilization, and significant fluid bolus administration. Vitamin D deficiency was independently associated with a longer PICU length of stay (+1.92 days, P = .03) and increasing severity of illness as determined by the Pediatric Risk of Mortality score with every additional point increasing the likelihood of being vitamin D deficient by 8% (P = .005). CONCLUSIONS: This study provides evidence that vitamin D deficiency is both common among critically ill children and associated with greater severity of critical illness. Further research will determine whether targeted vitamin D supplementation or rapid restoration will improve outcome.