Kusum Menon

Critically Ill Patients With 2009 Influenza A(H1N1) Infection in Canada

CONTEXT Between March and July 2009, the largest number of confirmed cases of 2009 influenza A(H1N1) infection occurred in North America. OBJECTIVE To describe characteristics, treatment, and outcomes of critically ill patients in Canada with 2009 influenza A(H1N1) infection. DESIGN, SETTING, AND PATIENTS A prospective observational study of 168 critically ill patients with 2009 influenza A(H1N1) infection in 38 adult and pediatric intensive care units (ICUs) in Canada between April 16 and August 12, 2009. MAIN OUTCOME MEASURES The primary outcome measures were 28-day and 90-day mortality. Secondary outcomes included frequency and duration of mechanical ventilation and duration of ICU stay. RESULTS Critical illness occurred in 215 patients with confirmed (n = 162), probable (n = 6), or suspected (n = 47) community-acquired 2009 influenza A(H1N1) infection. Among the 168 patients with confirmed or probable 2009 influenza A(H1N1), the mean (SD) age was 32.3 (21.4) years; 113 were female (67.3%) and 50 were children (29.8%). Overall mortality among critically ill patients at 28 days was 14.3% (95% confidence interval, 9.5%-20.7%). There were 43 patients who were aboriginal Canadians (25.6%). The median time from symptom onset to hospital admission was 4 days (interquartile range [IQR], 2-7 days) and from hospitalization to ICU admission was 1 day (IQR, 0-2 days). Shock and nonpulmonary acute organ dysfunction was common (Sequential Organ Failure Assessment mean [SD] score of 6.8 [3.6] on day 1). Neuraminidase inhibitors were administered to 152 patients (90.5%). All patients were severely hypoxemic (mean [SD] ratio of Pao(2) to fraction of inspired oxygen [Fio(2)] of 147 [128] mm Hg) at ICU admission. Mechanical ventilation was received by 136 patients (81.0%). The median duration of ventilation was 12 days (IQR, 6-20 days) and ICU stay was 12 days (IQR, 5-20 days). Lung rescue therapies included neuromuscular blockade (28% of patients), inhaled nitric oxide (13.7%), high-frequency oscillatory ventilation (11.9%), extracorporeal membrane oxygenation (4.2%), and prone positioning ventilation (3.0%). Overall mortality among critically ill patients at 90 days was 17.3% (95% confidence interval, 12.0%-24.0%; n = 29). CONCLUSION Critical illness due to 2009 influenza A(H1N1) in Canada occurred rapidly after hospital admission, often in young adults, and was associated with severe hypoxemia, multisystem organ failure, a requirement for prolonged mechanical ventilation, and the frequent use of rescue therapies.

Hypotonic versus isotonic saline in hospitalised children : a systematic review

Background: The traditional recommendations which suggest that hypotonic intravenous (IV) maintenance fluids are the solutions of choice in paediatric patients have not been rigorously tested in clinical trials, and may not be appropriate for all children. Aims: To systematically review the evidence from studies evaluating the safety of administering hypotonic versus isotonic IV maintenance fluids in hospitalised children. Methods: Data sources: Medline (1966–2006), Embase (1980–2006), the Cochrane Library, abstract proceedings, personal files, and reference lists. Studies that compared hypotonic to isotonic maintenance solutions in children were selected. Case reports and studies in neonates or patients with a pre-existing history of hyponatraemia were excluded. Results: Six studies met the selection criteria. A meta-analysis combining these studies showed that hypotonic solutions significantly increased the risk of developing acute hyponatraemia (OR 17.22; 95% CI 8.67 to 34.2), and resulted in greater patient morbidity. Conclusions: The current practice of prescribing IV maintenance fluids in children is based on limited clinical experimental evidence from poorly and differently designed studies, where bias could possibly raise doubt about the results. They do not provide evidence for optimal fluid and electrolyte homoeostasis in hospitalised children. This systematic review indicates potential harm with hypotonic solutions in children, which can be anticipated and avoided with isotonic solutions. No single fluid rate or composition is ideal for all children. However, isotonic or near-isotonic solutions may be more physiological, and therefore a safer choice in the acute phase of illness and perioperative period.

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).

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.

A Prospective Multicenter Study of Adrenal Function in Critically Ill Children

RATIONALE Adrenal insufficiency is a clinical condition associated with fluid- and catecholamine-resistant hypotension. OBJECTIVES The objectives of this study were to determine the prevalence of adrenal insufficiency, risk factors and potential mechanisms for its development, and its association with clinically important outcomes in critically ill children. METHODS A prospective, cohort study was conducted from 2005 to 2008 in seven tertiary-care, pediatric intensive care units in Canada on patients up to 17 years of age with existing vascular access. Adrenocorticotropic hormone stimulation tests (1 microg) were performed and adrenocorticotropic hormone levels measured in all participants. MEASUREMENTS AND MAIN RESULTS A total of 381 patients had adrenal testing on admission. The prevalence of adrenal insufficiency was 30.2% (95% confidence interval, 25.9-35.1). Patients with adrenal insufficiency had higher baseline cortisol levels (28.6 microg/dl vs. 16.7 microg/dl, P < 0.001) and were significantly older (11.5 yr vs. 2.3 yr, P < 0.001) than those without adrenal insufficiency. Adrenal insufficiency was associated with an increased need for catecholamines (P < 0.001) and more fluid boluses (P = 0.026). The sensitivity and specificity of the low-dose adrenocorticotropic hormone stimulation test were 100% and 84%, respectively. CONCLUSIONS Adrenal insufficiency occurs in many disease conditions in critically ill children and is associated with an increased use of catecholamines and fluid boluses. It is likely multifactorial in etiology and is associated with high baseline cortisol levels. Further research is necessary to determine which of these critically ill children are truly cortisol deficient before any treatment recommendations can be made.

Critical illness in children with influenza A/pH1N1 2009 infection in Canada*

Objective: To describe characteristics, treatment, and outcomes of critically ill children with influenza A/pandemic influenza A virus (pH1N1) infection in Canada. Design: An observational study of critically ill children with influenza A/pH1N1 infection in pediatric intensive care units (PICUs). Setting: Nine Canadian PICUs. Patients: A total of 57 patients admitted to PICUs between April 16, 2009 and August 15, 2009. Interventions: None. Measurements and Main Results: Characteristics of critically ill children with influenza A/pH1N1 infection were recorded. Confirmed intensive care unit cases were compared with a national surveillance database containing all hospitalized pediatric patients with influenza A/pH1N1 infection. Risk factors were assessed with a Cox proportional hazard model. The PICU cohort and national surveillance data were compared, using chi-square tests. Fifty-seven children were admitted to the PICU for community-acquired influenza A/pH1N1 infection. One or more chronic comorbid illnesses were observed in 70.2% of patients, and 24.6% of patients were aboriginal. Mechanical ventilation was used in 68% of children, 20 children (35.1%) had acute lung injury on the first day of admission, and the median duration of ventilation was 6 days (range, 0–67 days). The PICU mortality rate was 7% (4 of 57 patients). When compared with nonintensive care unit hospitalized children, PICU children were more likely to have a chronic medical condition (relative risk, 1.73); aboriginal ethnicity was not a risk factor of intensive care unit admission. Conclusions: During the first outbreak of influenza A/pH1N1 infection, when the population was naïve to this novel virus, severe illness was common among children with underlying chronic conditions and aboriginal children. Influenza A/pH1N1-related critical illness in children was associated with severe hypoxemic respiratory failure and prolonged mechanical ventilation. However, this higher rate and severity of respiratory illness did not result in an increased mortality when compared with seasonal influenza.

Adrenal function in pediatric critical illness.

Objectives Adrenal dysfunction has been documented in critically ill adult populations and in children with septic shock and may have serious consequences if undiagnosed. However, there is no information available on adrenal function in critically ill children with various underlying conditions. Design A prospective, descriptive study was carried out to investigate the occurrence of adrenal dysfunction in pediatric critical illness. Patients Thirteen patients were consecutively recruited from a pediatric critical care unit with Pediatric Risk of Mortality Scores (PRISM; illness severity scores) ≥10 and hemodynamic instability as defined by the need for inotropes and/or >20 mL/kg fluid in a 24-hr period. Interventions Baseline cortisol and adrenocorticotropic hormone (ACTH) levels were measured followed by post-ACTH stimulation test cortisol levels to determine adrenal reserve. Measurements and Main Results Baseline cortisol levels ranged from 0.10 to 37.4 &mgr;g/dL (mean, 12.2 ± 9.6). Adrenal dysfunction as defined by a baseline cortisol level of <7 &mgr;g/dL (am cortisol) or a post-ACTH stimulation level of <18 &mgr;g/dL was observed in four of the 13 patients (31%; 95% confidence interval, 5.7%,55.9%). All three of the patients with baseline cortisol levels of <7 &mgr;g/dL had low-normal ACTH levels. There was no difference in baseline PRISM scores (14.7 ± 4.11, 12.7 ± 2.65;p = .37) or admitting diagnoses for those with and without adrenal dysfunction. Conclusions We conclude that some critically ill children do no mount adequate basal cortisol levels in the face of severe physiologic stress but do respond to external ACTH stimulation to better delineate the hypothalamic-pituitary-adrenal axis in critically ill children and to determine the clinical consequences of these biochemical abnormalities.

Randomized controlled trials in pediatric critical care: a scoping review

IntroductionEvidence from randomized controlled trials (RCTs) is required to guide treatment of critically ill children, but the number of RCTs available is limited and the publications are often difficult to find. The objectives of this review were to systematically identify RCTs in pediatric critical care and describe their methods and reporting.MethodsWe searched MEDLINE, EMBASE, LILACS and CENTRAL (from inception to April 16, 2013) and reference lists of included RCTs and relevant systematic reviews. We included published RCTs administering any intervention to children in a pediatric ICU. We excluded trials conducted in neonatal ICUs, those enrolling exclusively preterm infants, and individual patient crossover trials. Pairs of reviewers independently screened studies for eligibility, assessed risk of bias, and abstracted data. Discrepancies were resolved by consensus.ResultsWe included 248 RCTs: 45 (18%) were multicentered and 14 (6%) were multinational. Trials most frequently enrolled both medical and surgical patients (43%) but postoperative cardiac surgery was the single largest population studied (19%). The most frequently evaluated types of intervention were medications (63%), devices (11%) and nutrition (8%). Laboratory or physiological measurements were the most frequent type of primary outcomes (18%). Half of these trials (50%) reported blinding. Of the 107 (43%) trials that reported an a priori sample size, 34 (32%) were stopped early. The median number of children randomized per trial was 49 and ranged from 6 to 4,947. The frequency of RCT publications increased at a mean rate of 0.7 RCTs per year (P<0.001) from 1 to 20 trials per year.ConclusionsThis scoping review identified the available RCTs in pediatric critical care and made them accessible to clinicians and researchers (http://epicc.mcmaster.ca). Most focused on medications and intermediate or surrogate outcomes, were single-centered and were conducted in North America and Western Europe. The results of this review underscore the need for trials with rigorous methodology, appropriate outcome measures, and improved quality of reporting to ensure that high quality evidence exists to support clinical decision-making in this vulnerable population.

Enrollment of intensive care unit patients into clinical studies: a trinational survey of researchers' experiences, beliefs, and practices.

Background:As critical care practice increases in scope, size, and complexity, enrollment of critically ill patients into clinical studies is increasing. Objective:To understand the experiences, beliefs, and practices of the Canadian Critical Care Trials Group and Australian and New Zealand Intensive Care Society Clinical Trials Group regarding enrollment of critically ill children and adults into clinical studies. Methods:Survey items generated by the research team were formatted in four domains: experiences, beliefs, practices, and demographics. Five research coordinators and five physicians pretested the survey, providing feedback on clarity and completeness. Intrarater reliability (16 participants, 2 wks apart) was very good. Results:The response rate was 284 of 322 (88.2%). Respondents worked in intensive care units with a mean of 20.5 (sd 10) beds, caring for adults (72.2%), pediatric (18.8%), and both groups (9%) of critically ill patients. Clinical research was considered key to the future of improved clinical care. To enhance recruitment efficiency, respondents widely endorsed the effectiveness of increasing participating centers, after-hours, and weekend enrollment (all 3 scores 7 [6–7[sqb], reflecting median [interquartile range] on 1–7 scale). Overall, the effectiveness (6 [4–7]), feasibility (5 [4–6]) and ethics (5 [4–7]) of coenrollment into more than one randomized trial was endorsed. Half of respondents have adopted coenrollment with scientific and psychosocial provisos. Alternative designs, such as factorial and cluster randomized trials, were considered when suitable. Modifications to consent approaches (deferred consent (7 [6–7]), waived consent (7 [6–7]), or consent from two physicians in the absence of a substitute decision maker (6 [5–7])) were considered effective, but beliefs about the feasibility and ethics of some of these approaches varied. Conclusions:Clinical research is highly valued by these intensive care unit communities. Strategies to increase capacity involve enhancing recruitment efficiencies, considering alternative study designs and expanding consent procedures. Thoughtfully implementing these strategies may advance the care of critically ill adults and children.

Efficacy of high-dose vitamin D in pediatric asthma: a systematic review and meta-analysis

Abstract Context: Observational studies have suggested a relationship between vitamin D status and asthma-related respiratory outcomes. The benefit of vitamin D supplementation for pulmonary function, symptoms and exacerbations is not well established. Objective: To systematically review paediatric clinical trials investigating the role of vitamin D on asthma-related respiratory outcomes. Data sources: MEDLINE, EMBASE and CENTRAL were searched until January 2014. No date or language restrictions. Study selection: Clinical trials reporting asthma-related respiratory outcomes following vitamin D administration at a dose equal or greater than 500 IU per day were included and reviewed independently by two authors for full systematic review eligibility. Data extraction: Two reviewers independently extracted and verified pre-defined data fields. Results: We identified five studies that met study eligibility and assessed final data synthesis. The median trial size was 48 participants (range 17–430) and the average daily dose of cholecalciferol ranged from 500 to 2000 IU/day. Overall study methodological quality was high, but some heterogeneity in population and vitamin D dosing regimen was evident. Meta-analysis suggested a statistically significant reduction (RR 0.41, CI 0.27–0.63) in asthma exacerbation with vitamin D therapy. Limitations: Due to variability in outcome selection and missing data, it was not possible to perform meta-analysis for pulmonary function testing and asthma symptom scores. Vitamin D-related adverse events were not considered in four of five papers. Conclusions: Available evidence from this systematic review suggests that high dose vitamin D may prevent asthma exacerbation. This should be confirmed through larger well-designed randomised controlled trials.