Douglas D. Fraser

Vasopressin in pediatric vasodilatory shock: a multicenter randomized controlled trial.

RATIONALE Vasopressin has been proposed as a potent vasoactive agent in the treatment of vasodilatory shock in adults and children. The objective of this trial was to evaluate the efficacy and safety of vasopressin as an adjunctive agent in pediatric vasodilatory shock. METHODS In this multicenter, double-blind trial, children with vasodilatory shock were randomized to receive low-dose vasopressin (0.0005-0.002 U/kg/min) or placebo in addition to open-label vasoactive agents. Vasoactive infusions were titrated to clinical endpoints of adequate perfusion. The primary outcome was time to vasoactive-free hemodynamic stability. Secondary outcomes included mortality, organ-failure-free days, length of critical care unit stay, and adverse events. MEASUREMENTS AND MAIN RESULTS Sixty-five of 69 children (94%) who were randomized received the study drug (33 vasopressin, 32 placebo) and were included in the analysis. There was no significant difference in the primary outcome between the vasopressin and placebo groups (49.7 vs. 47.1 hours; P = 0.85). There were 10 deaths (30%) in the vasopressin group and five (15.6%) in the placebo group (relative risk, 1.94; 95% confidence interval, 0.75-5.05; P = 0.24). There were no significant differences with respect to organ failure-free days (22 vs. 25.5 days; P = 0.11), ventilator-free days (16.5 23 days; P = 0.15), length of stay (8 vs. 8.5 days; P = 0.93), or adverse event rate ratios (12.0%; 95% confidence interval, -2.6 to 26.7; P = 0.15). CONCLUSIONS Low-dose vasopressin did not demonstrate any beneficial effects in this pediatric trial. Although not statistically significant, there was a concerning trend toward increased mortality. Clinical trial registered with www.controlled-trials.com (ISRCTN11597444).

External ventricular drains in pediatric patients.

Objective: To determine the indications and complications of external ventricular drain (EVD) placement in pediatric patients. Design: Retrospective chart review. Setting: University associated, tertiary–level Children’s Hospital. Patients: Sixty-six [median age, 10.1 years (interquartile range, 5.9)] patients between 1994 and 2006 with 96 EVDs. Measurements and Results: Clinical indications for EVD insertion include traumatic brain injury (TBI; 36%), acute hydrocephalus (35%), and ventriculoperitoneal shunt failure (29%). Of the 96 EVDs, 65% were inserted at the bedside in the pediatric critical care unit (PCCU) and 33% in the operating room (OR). Median duration of EVD insertion was 7.0 days (interquartile range, 8.8). Complications occurred with 26% of EVD insertions and included infection (9.4%), misplacement (6.3%), hemorrhage (4.2%), obstruction (3.1%), and malfunction (3.1%). The primary infectious etiology was coagulase-negative Staphylococcus (67% of infections). Despite patients with TBI having significantly smaller lateral ventricles than hydrocephalus patients (p < 0.05), EVD complications were similar (risk ratios 1.41; 95% confidence interval 0.68–2.72). Furthermore, the complication rate was the same for EVDs inserted in either the PCCU or OR (risk ratios 1.10; 95% confidence interval 0.55–2.29). Conclusion: EVDs were placed for TBI, ventriculoperitoneal shunt failure and new-onset hydrocephalus. The overall complication rate was 26%. Complication rates were similar in TBI and hydrocephalus patients, and with EVDs inserted in either the PCCU or OR. Prophylactic antibiotics or antimicrobial-impregnated catheters directed against coagulase-negative Staphylococcus may reduce EVD infections.

Have changes in ventilation practice improved outcome in children with acute lung injury

Objectives: To describe the changes that have occurred in mechanical ventilation in children with acute lung injury in our institution over the last 10–15 yrs and to examine the impact of these changes, in particular of the delivered tidal volume on mortality. Design: Retrospective study. Setting: University-affiliated childrens hospital. Patients: The management of mechanical ventilation between 1988 and 1992 (past group, n = 79) was compared with the management between 2000 and 2004 (recent group, n = 85). Interventions: None. Measurements and Main Results: The past group patients were ventilated with a significantly higher mean tidal volume (10.2 ± 1.7 vs. 8.1 ± 1.4 mL·kg−1 actual body weight, p < .001), lower levels of positive end-expiratory pressure (6.1 ± 2.7 vs. 7.1 ± 2.4 cm H2O, p = .007), and higher mean peak inspiratory pressure (31.5 ± 7.3 vs. 27.8 ± 4.2 cm H2O, p < .001) than the recent group patients. The recent group had a lower mortality (21% vs. 35%, p = .04) and a greater number of ventilator-free days (16.0 ± 9.0 vs. 12.6 ± 9.9 days, p = .03) than the past group. A higher tidal volume was independently associated with increased mortality (odds ratio 1.59; 95% confidence interval 1.20, 2.10, p < .001) and reduction in ventilation-free days (95% confidence interval −1.24, −0.77, p < .001). Conclusions: The changes in the clinical practice of mechanical ventilation in children in our institution reflect those reported for adults. In our experience, mortality among children with acute lung injury was reduced by 40%, and tidal volume was independently associated with reduced mortality and an increase in ventilation-free days.

Early mobilization in the critical care unit: A review of adult and pediatric literature.

Early mobilization of critically ill patients is beneficial, suggesting that it should be incorporated into daily clinical practice. Early passive, active, and combined progressive mobilizations can be safely initiated in intensive care units (ICUs). Adult patients receiving early mobilization have fewer ventilator-dependent days, shorter ICU and hospital stays, and better functional outcomes. Pediatric ICU data are limited, but recent studies also suggest that early mobilization is achievable without increasing patient risk. In this review, we provide a current and comprehensive appraisal of ICU mobilization techniques in both adult and pediatric critically ill patients. Contraindications and perceived barriers to early mobilization, including cost and health care provider views, are identified. Methods of overcoming barriers to early mobilization and enhancing sustainability of mobilization programs are discussed. Optimization of patient outcomes will require further studies on mobilization timing and intensity, particularly within specific ICU populations.

Elevated plasma matrix metalloproteinases and their tissue inhibitors in patients with severe sepsis

PURPOSE Matrix metalloproteinases (MMPs) are essential for tissue remodeling. Our objectives were to determine (1) the concentrations of MMPs and their tissue inhibitors (TIMPs) in plasma obtained from patients with severe sepsis, (2) to correlate changes in MMP and TIMP levels with disease severity, and (3) to investigate recombinant activated protein C (rAPC) actions on plasma MMP2, 9 activities from severe sepsis patients. MATERIALS AND METHODS Matrix metalloproteinase and TIMP levels were quantified in plasma from patients with severe sepsis using antibody microarrays and gelatin zymography. RESULTS Plasma MMPs (3, 7, 8, 9) and TIMPs (1, 2, 4) on microarray were increased in severe sepsis on intensive care unit (ICU) day 1, with more than 3-fold increases in MMP3, MMP7, MMP8, MMP9, and TIMP4. Latent forms of MMP2, 9 on zymography were increased in plasma from patients with severe sepsis, whereas only half of severe sepsis patients showed active MMP9. Elevated MMP7 and MMP9 on ICU days 1 and 3 negatively correlated with multiple organ dysfunctions. The temporal activity patterns of MMP2, 9 during 21 ICU days were not altered in patients treated with rAPC or by the addition of exogenous rAPC to plasma. CONCLUSION Most plasma MMPs and TIMPS were elevated in patients with severe sepsis, but only a limited subset of MMPs (7, 9) negatively correlated with disease severity. Recombinant activated protein C does not appear to directly alter MMP2, 9 activities.

Cardiac Arrest Following Ketamine Administration for Rapid Sequence Intubation

Given their relative hemodynamic stability, ketamine and etomidate are commonly chosen anesthetic agents for sedation during the endotracheal intubation of critically ill patients. As the use of etomidate has come into question particularly in patients with sepsis, due to its effect of adrenal suppression, there has been a shift in practice with more reliance on ketamine. However, as ketamine relies on a secondary sympathomimetic effect for its cardiovascular stability, cardiovascular and hemodynamic compromise may occur in patients who are catecholamine depleted. We present 2 critically ill patients who experienced cardiac arrest following the administration of ketamine for rapid sequence intubation (RSI). The literature regarding the use of etomidate and ketamine for RSI in critically ill patients is reviewed and options for sedation during endotracheal intubation in this population are discussed.

An epidemiologic profile of pediatric concussions: identifying urban and rural differences.

BACKGROUND The objective of this study was to describe the epidemiology of concussions presenting to the emergency department (ED). METHODS A retrospective cohort of concussions for pediatric (age < 18 years) patients treated in the ED of a regional pediatric Level 1 trauma center from 2006 to 2011 was examined. Descriptive and geographic analyses were completed, with comparisons by age groups and residence (urban/rural). RESULTS There were a total of 2,112 treated pediatric concussions. Two thirds of the concussions occurred in males (67%), with a median age of 13 years (interquartile range [IQR], 6). Nearly half of the pediatric concussions were sports related (48%); 36% of these concussions were from hockey. Significant differences were found in the distribution of the mechanism of injury across age groups (p < 0.001). Falls were most prevalent among young children, and sports concussions, for children 10 years and older. Two fifths of concussions occurred during winter months. Discharge disposition significantly differed by age (p < 0.001), with home discharge increasing with age up to 14 years. There were a total of 387 rural (19%) and 1,687 urban (81%) concussed patients, for a mean ED concussion visit rate of 2.2 per 1,000 and 3.5 per 1,000, respectively. Rural patients were older (14 [IQR, 6] vs. 13 [IQR, 6], p = 0.019] and sustained 2.5 times more concussions from a motor vehicle crash compared with urban youth patients (p < 0.001). CONCLUSION Males in early adolescence are at highest risk for concussion, particularly from sport-related activities. Urban and rural children have differences in their etiology and severity of concussions. Concussions are predictable, and their prevention should be targeted based on epidemiologic and environmental data. LEVEL OF EVIDENCE Epidemiologic, study, level III.

Diabetic Ketoacidosis-Associated Stroke in Children and Youth

Diabetic ketoacidosis (DKA) is a state of severe insulin deficiency, either absolute or relative, resulting in hyperglycemia and ketonemia. Although possibly underappreciated, up to 10% of cases of intracerebral complications associated with an episode of DKA, and/or its treatment, in children and youth are due to hemorrhage or ischemic brain infarction. Systemic inflammation is present in DKA, with resultant vascular endothelial perturbation that may result in coagulopathy and increased hemorrhagic risk. Thrombotic risk during DKA is elevated by abnormalities in coagulation factors, platelet activation, blood volume and flow, and vascular reactivity. DKA-associated cerebral edema may also predispose to ischemic injury and hemorrhage, though cases of stroke without concomitant cerebral edema have been identified. We review the current literature regarding the pathogenesis of stroke during an episode of DKA in children and youth.

Dehydration in children with diabetic ketoacidosis: a prospective study

Objectives To investigate the association between the degree of patient dehydration on presentation with diabetic ketoacidosis (DKA) and clinical and laboratory parameters obtained on admission. Design Prospective descriptive study. Setting A tertiary care childrens hospital. Patients Thirty-nine paediatric patients (1 month–16 years) presenting with 42 episodes of DKA. Intervention Clinical and biochemical variables were collected on admission. Dehydration was calculated by measuring acute changes in body weight during the period of illness. All patients were treated according to a previously established protocol. Main outcome measures Magnitude of dehydration, defined as % loss of body weight (LBW), was determined by the difference in body weight obtained at presentation and at discharge. The relationship between the magnitude of dehydration and the clinical assessment and biochemical parameters was examined. Results The median (25th–75th centiles) magnitude of dehydration at presentation was 5.7% (3.8–8.3%) (mean±SD 6.8±5%). Neither the initial clinical assessment nor the comprehensive biochemical profile at admission correlated with the magnitude of dehydration. Despite considerable variation in the degree of dehydration and biochemical disequilibrium, all patients recovered from DKA within 24 h with a standardised therapeutic approach. Furthermore, the rapidity of patient recovery did not correlate with the magnitude of dehydration on presentation or the amount of fluid administered (median (25th–75th centiles) 48.8 ml/kg (38.5–60.3)) in the first 12 h. Conclusion The magnitude of dehydration in DKA is not reflected by either clinical or biochemical parameters. These findings need confirmation in larger studies.

Fatal cerebral edema from late-onset ornithine transcarbamylase deficiency in a juvenile male patient receiving valproic acid.

Objectives: The aims of this report are to 1) present a rare case of fatal cerebral edema associated with late-onset ornithine transcarbamylase (OTC) deficiency in a juvenile male patient receiving valproic acid and 2) review the neuropathologic changes associated with the hyperammonemia. Design: Case report. Setting: A community hospital and a tertiary pediatric critical care unit. Interventions: Carbohydrate administration, intravenous nitrogen excretion cocktail, and high-flux hemodialysis. Measurements and Main Results: Despite aggressive therapy for presumed late-onset OTC deficiency, the patient rapidly developed fatal cerebral edema with tonsillar herniation. A liver biopsy confirmed OTC deficiency with ∼3% of residual hepatic enzyme activity. Chromosomal analysis showed a normal male karyotype. A thorough molecular analysis of the coding region in the OTC gene Xp21.1 was completed, but mutations were not identified, suggesting an upstream or downstream abnormality. Severe brain swelling was evident on neuropathology, and histopathology showed Alzheimer type II astrocytes, neuronal cytoplasmic changes, and hypertrophy and eosinophilia of the small arterial walls. Conclusions: OTC deficiency is the most common urea cycle defect causing hyperammonemia. Late-onset presentations of OTC are infrequent, primarily affecting female patients. We present a rare case of a late-onset OTC deficiency in a juvenile male patient receiving valproic acid therapy who developed fatal cerebral edema. Valproic acid exacerbates acute elevations in ammonia and may contribute synergistically with ammonia to cerebral mitochondrial dysfunction.