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1.  Airway pressure release ventilation: A neonatal case series and review of current pediatric practice 
The use of airway pressure release ventilation (APRV) in very low birth weight infants is limited.
To report the authors’ institutional experience and to review the current literature regarding the use of APRV in pediatric populations.
Neonates <1500 g ventilated using APRV from 2005 to 2006 at McMaster Children’s Hospital (Hamilton, Ontario) were retrospectively reviewed. Publications describing APRV in children from 1987 to 2011 were reviewed.
Five infants, 24 to 28 weeks’ gestational age, were ventilated using APRV. Indications for APRV were refractory hypoxemia (n=3), ventilatory dyssynchrony (n=1) and minimizing sedatives (n=1). All infants appeared to tolerate APRV well with no recorded adverse events. Current pediatric evidence regarding APRV is primarily observational. Published experience reveals that APRV settings in pediatrics often approximate those used in adults, thus deviating from the original guidelines recommended in children. Clinical outcomes, such as oxygenation, ventilation and sedation requirements, are inconsistent.
APRV is primarily used as a rescue ventilation mode in children. Neonatal evidence is limited; however, the present study indicates that APRV is feasible in very low birth weight infants. There are unique considerations when applying this mode in small infants. Further research is necessary to confirm whether APRV is a safe and effective ventilation strategy in this population.
PMCID: PMC3810052  PMID: 24093118
Airway pressure release ventilation; Pediatrics; Very low birth weight infant
3.  Randomized controlled trials in pediatric critical care: a scoping review 
Critical Care  2013;17(5):R256.
Evidence 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.
We 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.
We 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.
This scoping review identified the available RCTs in pediatric critical care and made them accessible to clinicians and researchers ( 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.
PMCID: PMC4057256  PMID: 24168782
4.  Magnetic resonance imaging findings and neurodevelopmental outcomes in neonates with urea-cycle defects 
The urea-cycle functions to facilitate ammonia excretion, a disruption of which results in the accumulation of toxic metabolites. The neurological outcome of neonatal-onset urea-cycle defects (UCDs) is poor, and there are no good predictors of prognosis beyond ammonia levels at presentation. The role of neuroimaging in the prognosis of neonatal-onset UCDs is unclear. We describe the magnetic resonance imaging (MRI) findings of two patients with neonatal-onset UCDs (argininosuccinic aciduria and citrullinemia) at presentation and at 2-year follow-up, and present a review of the literature on neuroimaging in this age-group. We observed two potentially significant distinct patterns of cerebral involvement on MRI: (1) a central and focal pattern of involvement limited to the basal ganglia, perirolandic regions, and internal capsule; and (2) diffuse involvement of the cerebral cortex, internal capsule, basal ganglia, and variably thalami and brain stem. Patients with more diffuse findings tended to have higher serum glutamine peaks and worse neurological outcomes, while those with central involvement, aggressive acute management, and early liver transplantation tended to have better outcomes. We propose that MRI imaging of the brain may have prognostic value following presentation with neonatal UCDs, particularly in identifying patients at risk for poor outcome. The role and timing of follow-up neuroimaging is currently unclear. Further collaborative studies are necessary to evaluate whether patterns of MRI findings vary with specific UCD subtypes, and are predictive of clinical outcomes in neonatal UCDs.
PMCID: PMC3751504  PMID: 23983495
hyperammonemia; amino acid metabolism; inborn error; metabolism; inborn errors; infant; newborn; magnetic resonance imaging
5.  Urgent Ultrasound Guided Hemodynamic Assessments by a Pediatric Medical Emergency Team: A Pilot Study 
PLoS ONE  2013;8(6):e66951.
To determine the feasibility of using the Ultrasound Cardiac Output Monitor (USCOM) as an adjunct during hemodynamic assessments by a pediatric medical emergency team (PMET).
Pediatric in-patients at McMaster Children’s Hospital aged under 18 years requiring urgent PMET consultation, were eligible. Patients with known cardiac outflow valve defects, Pediatric Critical Care Unit in-patients, and those in cardiorespiratory arrest, were excluded. The primary outcome was feasibility, and the ease of USCOM transport and application as assessed by a self-administered user questionnaire. Secondary outcomes included the quality of USCOM measurements, and agreement in clinical versus USCOM-derived assessments.
Forty-one patients from 85 eligible PMET consultations were enrolled between March and August 2011. A total of 55 USCOM assessments were performed on 36 of 41 (87.8%) participants. USCOM could not be completed in 5 (12.2%) participants due to patient agitation (n = 4) and emergent care (n = 1). USCOM was reported as easy to transport and apply by 97.4% and 94.7% of respondents respectively, not obstructive to patient care by 94.7%, and yielded timely measurements by 84.2% respondents. USCOM tracings were of good quality in 41 (75.9%) assessments. Agreement between clinical and USCOM-derived hemodynamic assessments by two independent raters was poor (Rater 1: κ = 0.094; Rater 2: κ = 0.146).
USCOM can be applied by a PMET during urgent hemodynamic assessments in children. While USCOM has been validated in stable children, its role in guiding hemodynamic resuscitation and informing therapeutic goals in a hemodynamically unstable pediatric population requires further investigation.
PMCID: PMC3692535  PMID: 23825593
6.  Clinical Meaningfulness of the Changes in Muscle Performance and Physical Function Associated With Testosterone Administration in Older Men With Mobility Limitation 
Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial’s Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant’s perception of change.
Men aged 65 years and older, with mobility limitation, total testosterone 100–350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared.
Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change.
Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.
PMCID: PMC3202898  PMID: 21697501
Testosterone; Minimally important difference; Mobility limitation; Older men; Function promoting therapies
7.  Adverse Events Associated with Testosterone Administration 
The New England journal of medicine  2010;363(2):109-122.
Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied.
Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group.
A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load.
In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy.
PMCID: PMC3440621  PMID: 20592293
8.  Influence of Sex and Hormone Status on Circulating Natriuretic Peptides 
To assess the relationship between sex hormones and natriuretic peptide levels in community-based adults
Women have higher circulating natriuretic peptide concentrations than men, but the mechanisms for these sex-related differences and the impact of hormone therapy are unclear. Experimental studies suggest that androgens may suppress natriuretic peptide secretion.
We measured plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), total testosterone, and sex hormone binding globulin (SHBG) in 4,056 men and women (mean age 40±9 years) from the Framingham Heart Study Third Generation cohort. Sex/hormone status was grouped as: 1) men, 2) postmenopausal women not receiving hormone replacement therapy, 3) premenopausal women not receiving hormonal contraceptives, 4) postmenopausal women receiving hormone replacement therapy and 5) premenopausal women receiving hormonal contraceptives.
Circulating NT-proBNP was associated with sex/hormone status (overall P<0.0001). Men had lower NT-proBNP than women of all menopause or hormone groups, and women receiving hormonal contraceptives had higher NT-proBNP than women who were not receiving hormone therapy (all P<0.0001). These relationships remained significant after adjusting for age, body mass index, and cardiovascular risk factors. Across sex/hormone status groups, FT decreased and SHBG increased in tandem with increasing NT-proBNP. In sex-specific analyses, NT-proBNP decreased across increasing quartiles of free testosterone in men (P for trend<0.01) and in women (P for trend<0.0001). Adjustment for FT markedly attenuated the association between sex/hormone status and NT-proBNP concentrations.
These findings suggest that lower circulating androgens and the potentiating effect of exogenous female hormone therapy contribute to the higher circulating NT-proBNP concentrations in women.
PMCID: PMC3170816  PMID: 21798425
natriuretic peptides; sex; hormones
9.  Habitual Physical Activity Levels are Associated with Performance in Measures of Physical Function and Mobility in Older Men 
To determine whether objectively measured physical activity levels are associated with physical function and mobility in older men.
Academic research center.
Eighty-two community-dwelling men ≥ 65 years of age with self-reported mobility limitations were divided into a low activity and a high activity group based on the median average daily physical activity counts of the whole sample.
Physical activity by triaxial accelerometers; physical function and mobility by the Short Physical Performance Battery (SPPB), gait speed, stair climb time, and a lift and lower task; aerobic capacity by maximum oxygen consumption (VO2max); and leg press and chest press maximal strength and peak power.
Older men with higher compared to lower physical activity levels demonstrated a > 1.4 point higher mean SPPB score and a 0.35 m/s faster walking speed. They also climbed a standard flight of stairs 1.85 sec faster and completed 60% more shelves in a lift and lower task (all p < 0.01). Muscle strength and power measures, however, were not significantly different between the low and high activity group. Correlation analyses and multiple linear regression models showed that physical activity is positively associated with all physical function and mobility measures, leg press strength, and VO2max.
Older men with higher physical activity levels demonstrate better physical function and mobility than less active peers. Moreover, in older men physical activity levels are predictive of performance in measures of physical function and mobility. Future work is needed to determine whether modifications in physical activity levels can improve or preserve physical performance in later-life.
PMCID: PMC2945416  PMID: 20738436
aging; sarcopenia; muscle strength; disability; exercise
10.  Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes 
The mechanisms by which androgens regulate fat mass are poorly understood. Although testosterone has been reported to increase lipolysis and inhibit lipid uptake, androgen effects on proliferation and differentiation of human mesenchymal stem cells (hMSCs) and preadipocytes have not been studied. Here, we investigated whether dihydrotestosterone (DHT) regulates proliferation, differentiation, or functional maturation of hMSCs and human preadipocytes from different fat depots. DHT (0–30 nM) dose-dependently inhibited lipid accumulation in adipocytes differentiated from hMSCs and downregu-lated expression of aP2, PPARγ, leptin, and C/EBPα. Bicalutamide attenuated DHT's inhibitory effects on adipogenic differentiation of hMSCs. Adipocytes differentiated in presence of DHT accumulated smaller oil droplets suggesting reduced extent of maturation. DHT decreased the incorporation of labeled fatty acid into triglyceride, and downregulated acetyl CoA carboxylase and DGAT2 expression in adipocytes derived from hMSCs. DHT also inhibited lipid accumulation and downregulated aP2 and C/EBPα in human subcutaneous, mesenteric and omental preadipocytes. DHT stimulated forskolin-stimulated lipolysis in subcutaneous and mesenteric preadipocytes and inhibited incorporation of fatty acid into triglyceride in adipocytes differentiated from preadipocytes from all fat depots.
DHT inhibits adipogenic differentiation of hMSCs and human preadipocytes through an AR-mediated pathway, but it does not affect the proliferation of either hMSCs or preadipocytes. Androgen effects on fat mass represent the combined effect of decreased differentiation of fat cell precursors, increased lipolysis, and reduced lipid accumulation.
PMCID: PMC2873614  PMID: 18801408
Androgen; hMSC; Preadipocyte; Differentiation; Proliferation; Testosterone
11.  Surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis 
Critical Care  2007;11(3):R66.
Exogenous surfactant is used to treat acute respiratory failure in children, although the benefits and harms in this setting are not clear. The objective of the present systematic review is to assess the effect of exogenous pulmonary surfactant on all-cause mortality in children mechanically ventilated for acute respiratory failure.
We searched the MEDLINE, EMBASE, CINAHL and Ovid Healthstar databases, the bibliographies of included trials and review articles, conference proceedings and trial registries. We included prospective, randomized, controlled trials of pulmonary surfactant that enrolled intubated and mechanically ventilated children with acute respiratory failure. We excluded trials that exclusively enrolled neonates or patients with asthma. Two reviewers independently rated trials for inclusion, extracted data and assessed the methodologic quality. We quantitatively pooled the results of trials, where suitable, using a random effects model.
Six trials randomizing 314 patients were included. Surfactant use reduced mortality (relative risk = 0.7, 95% confidence interval = 0.4 to 0.97, P = 0.04), was associated with increased ventilator-free days (weighted mean difference = 2.5 days, 95% confidence interval = 0.3 to 4.6 days, P = 0.02) and reduced the duration of ventilation (weighted mean difference = 2.3 days, 95% confidence interval = 0.1 to 4.4 days, P = 0.04).
Surfactant use decreased mortality, was associated with more ventilator-free days and reduced the duration of ventilation. No serious adverse events were reported.
PMCID: PMC2206432  PMID: 17573963
12.  Ventilatory management in extremely low birth weight infants 
The improvement in survival in premature infants associated with the evolution of mechanical ventilation has been accompanied by an increase in ventilator induced lung injury. High frequency ventilation has been shown to reduce the incidence of ventilator induced lung injury and hence chronic lung disease in the very low birth weight infant. The evolution in understanding how to best use high frequency ventilation in this population has prompted us to ask whether similar strategies to optimize lung volumes on conventional mechanical ventilation can minimize chronic lung disease in the neonate. We retrospectively reviewed the medical charts of 51 extremely low birth weight infants born in Kingston, Ontario in two epochs, 1990 to 1991 and 1999 to 2000, for ventilatory strategy and outcome. From our review, it is clear that surfactant therapy rapidly changes lung mechanics by improving pulmonary compliance and that lung damage may result if there are not changes in the ventilatory management to reflect the altered compliance. Early ventilation strategies during the apparently stable “honeymoon period” in a patient with respiratory distress syndrome (RDS) has significant implications on long term morbidity. In the era prior to the use of surfactant, 30% of infants died and 40% developed chronic lung disease (CLD). Immediately following the use of surfactant , mortality was reduced to 18%, however, the incidence of CLD increased to 78%. In the most recent era, following 10 years of experience with surfactant and mechanical ventilation, morbidity was 17% and CLD 21%. This study demonstrates that a particularly crucial time is in the immediate period following surfactant administration. The use of lower peak inspiratory pressure (PIP) and mean airway pressure (MAP) over the first 24 hours and an increase in the use of synchronous intermittent mandatory ventilation (SIMV) was associated with an improved outcome. The challenge remaining is to determine how to best utilize a conventional mode of ventilation to best optimize lung volume and protect the immature lung.
PMCID: PMC2323525  PMID: 18523620

Results 1-12 (12)