Advancing Nutrition Education, Training, and Research for Medical Students, Residents, Fellows, Attending Physicians, and Other Clinicians: Building Competencies and Interdisciplinary Coordination.

Nutrition plays an important role in health promotion and disease prevention and treatment across the lifespan. Physicians and other healthcare professionals are expected to counsel patients about nutrition, but recent surveys report minimal to no improvements in medical nutrition education in US medical schools. A workshop sponsored by the National Heart, Lung, and Blood Institute addressed this gap in knowledge by convening experts in clinical and academic health professional schools. Representatives from the National Board of Medical Examiners, the Accreditation Council for Graduate Medical Education, the Liaison Committee on Medical Education, and the American Society for Nutrition provided relevant presentations. Reported is an overview of lessons learned from nutrition education efforts in medical schools and health professional schools including interprofessional domains and competency-based nutrition education. Proposed is a framework for coordinating activities of various entities using a public-private partnership platform. Recommendations for nutrition research and accreditation are provided.

The Collaborative Role of North American Departments of Pediatrics in Global Child Health.

Appeals for health equity call for departments of pediatrics to improve the health of all children including those from underserved communities in North America and around the world. Consequently, North American (NA) departments of pediatrics have a role in global child health (GCH) which focuses on providing health care to underserved children worldwide. In this review, we describe how NA departments of pediatrics can collaboratively engage in GCH education, clinical practice, research, and advocacy and summarize best practices, challenges, and next steps for engaging in GCH in each of these areas. For GCH in low- and middle-income countries (LMICs), best practices start with the establishment of ethical, equitable, and collaborative partnerships with LMIC communities, organizations, and institutions engaged in GCH who are responsible for the vast majority of work done in GCH. Other best practices include adequate preparation of trainees and clinicians for GCH experiences; alignment with local clinical and research priorities; contributions to local professional development and ongoing monitoring and evaluation. Challenges for departments include generating funding for GCH activities; recruitment and retention of GCH-focused faculty members; and challenges meeting best practices, particularly adequate preparation of trainees and clinicians and ensuring mutual benefit and reciprocity in NA-LMIC collaborations. We provide examples of how departments have overcome these challenges and suggest next steps for development of the role of NA departments of pediatrics in GCH. Collaborative implementation of best practices in GCH by LMIC-NA partnerships can contribute to reductions of child mortality and morbidity globally.

Optimal dosing of intravenous ketamine for procedural sedation in children in the ED-a randomized controlled trial.

OBJECTIVE: The objective of the study is to compare need for redosing, sedation efficacy, duration, and adverse events between 3 commonly administered doses of parenteral ketamine in the emergency department (ED). METHODS: We conducted a prospective, double-blind, randomized controlled trial on a convenience sample of children 3 to 18years who received intravenous ketamine for procedural sedation. Children from each age group (3-6, 7-12, and 13-18years) were assigned in equal numbers to 3 dosing groups (1, 1.5, and 2mg/kg) using random permuted blocks. The primary outcome measure was need for ketamine redosing to ensure adequate sedation. Secondary outcome measures were sedation efficacy, sedation duration, and sedation-related adverse events. RESULTS: A total of 171 children were enrolled of whom 125 (1mg/kg, 50; 1.5mg/kg, 35; 2mg/kg, 40) received the randomized dose and were analyzed. The need for ketamine redosing was higher in the 1mg/kg group (8/50; 16.0% vs 1/35; 2.9% vs 2/40; 5.0%). There was no significant difference in the median Ramsay sedation scores (5.5 [interquartile range {IQR}, 4-6] vs 6 [IQR, 4-6] vs 6 [IQR, 5-6]), FACES-R score (0 [IQR, 0-4] vs 0 [IQR, 0-0] vs 0 [IQR, 0-0]), sedation duration in minutes (23 [IQR, 19-38] vs 24.5 [IQR, 17.5-34.5] vs 23 [IQR, 19-29]), and adverse events (10.0% vs 14.3% vs 10.0%) between the 3 dosing groups. Physician satisfaction was lower in the 1mg/kg group (79.6% vs 94.1% vs 97.3%). CONCLUSIONS: Adequate sedation was achieved with all 3 doses of ketamine. Higher doses did not increase the risk of adverse events or prolong sedation. Ketamine administered at 1.5 or 2.0mg/kg intravenous required less redosing and resulted in greater physician satisfaction.

Low thiamine levels in children with type 1 diabetes and diabetic ketoacidosis: a pilot study.

OBJECTIVE: Thiamine deficiency has been documented in adults with diabetes and in a single report of reversible encephalopathy in a child with diabetic ketoacidosis. In children who present with severe diabetic ketoacidosis, one of the most serious complications is cerebral edema of which the primary symptom may be encephalopathy. Thiamine deficiency in other disease states has been clearly linked with acute encephalopathy, but there are no data on thiamine status in children with diabetic ketoacidosis. This study describes the prevalence of thiamine deficiency in children with type 1 diabetes mellitus who present with diabetic ketoacidosis and are admitted to the ICU. DESIGN: A prospective observational pilot study. SETTING: PICU in a tertiary care children's hospital. PATIENTS: Children 2-18 years admitted to the ICU for treatment of diabetic ketoacidosis. INTERVENTIONS: Treatment of diabetic ketoacidosis. MEASUREMENTS AND MAIN RESULTS: Twenty-two patients were enrolled. The mean age was 13.7 ± 3.6 years. Five of 21 patients (23.8%) had thiamine deficiency prior to insulin administration. After 8 hours of insulin therapy, seven of 20 patients (35%) had thiamine deficiency, and four of these seven patients also had thiamine deficiency at presentation. Sixty-eight percent of patients had a decrease in thiamine levels after 8 hours of insulin therapy, with a mean fall of 20 ± 31.4 nmol/L. CONCLUSIONS: Thiamine deficiency is common in children with diabetic ketoacidosis, and this deficiency may be worsened by treatment. When metabolic acidosis persists despite appropriate treatment of diabetic ketoacidosis, other factors such as thiamine deficiency should be considered.

Quality improvement skills for pediatric residents: from lecture to implementation and sustainability.

Quality improvement (QI) skills are relevant to efforts to improve the health care system. The Accreditation Council for Graduate Medical Education (ACGME) program requirements call for resident participation in local and institutional QI efforts, and the move to outcomes-based accreditation is resulting in greater focus on the resulting learning and clinical outcomes. Many programs have enhanced practice-based learning and improvement (PBLI) and systems based practice (SBP) curricula, although efforts to actively involve residents in QI activities appear to be lagging. Using information from the extensive experience of Cincinnati Children's Hospital Medical Center, we offer recommendations for how to create meaningful QI experiences for residents meet ACGME requirements and the expectations of the Clinical Learning Environment Review (CLER) process. Resident involvement in QI requires a multipronged approach that overcomes barriers and limitations that have frustrated earlier efforts to move this education from lectures to immersion experiences at the bedside and in the clinic. We present 5 dimensions of effective programs that facilitate active resident participation in improvement work and enhance their QI skills: 1) providing curricula and education models that ground residents in QI principles; 2) ensuring faculty development to prepare physicians for their role in teaching QI and demonstrating it in day-to-day practice; 3) ensuring all residents receive meaningful QI education and practical exposure to improvement projects; 4) overcoming time and other constraints to allow residents to apply their newly developed QI skills; and 5) assessing the effect of exposure to QI on resident competence and project outcomes.

Incidence and costs of adverse drug reactions in a tertiary care pediatric intensive care unit.

Adverse drug reactions (ADRs) increase morbidity, mortality, and hospital costs in children treated in the Pediatric Intensive Care Unit (PICU). Few studies have reported the incidence and risk factors of ADRs in PICU. Our study aimed to evaluate incidence, risk factors, and economic burden of ADRs in PICU. An intensive ADR surveillance was conducted at the PICU of Children's Hospital of Michigan between November 1, 2010 and May 31, 2011. A trigger list was used to screen for suspected ADR cases. Of the 697 consecutive PICU admissions reviewed, 13.1% experienced at least one episode of ADR. The ADR incidence was 22% in patients with cardiovascular (CV) surgery and 11.5% in other patients. The most frequently detected ADR was electrolyte imbalance associated with diuretic exposure. Mean age at admission was 4 years (interquartile range: 9 months-13 years). Risk factors for ADR included young age (<1 year), Pediatric Risk of Mortality (PRISM) score upon admission ≥3, and administration of ≥16 medications. ADRs increased total ICU costs by 3.5-fold and length of ICU stay by 3.8-fold. Increased ADR surveillance of high risk patients in conjunction with early intervention may reduce drug related morbidity and costs in the PICU.

An algorithm to detect adverse drug reactions in the neonatal intensive care unit.

Critically ill newborns in neonatal intensive care units (NICUs) are at greater risk of developing adverse drug reactions (ADRs). Differentiation of ADRs from reactions associated with organ dysfunction/immaturity is difficult. Current ADR algorithm scoring was established arbitrarily without validation in infants. The study objective was to develop a valid and reliable algorithm to identify ADRs in the NICU. Algorithm development began with a 24-item questionnaire for data collection on 100 previously suspected ADRs. Five pediatric pharmacologists independently rated cases as definite, probable, possible, and unlikely ADRs. Consensus "gold standard" was reached via teleconference. Logistic regression and iterative C programs were used to derive the scoring system. For validation, 50 prospectively collected ADR cases were assessed by 3 clinicians using the new algorithm and the Naranjo algorithm. Weighted kappa and intraclass correlation coefficient (ICC) were used to compare validity and reliability of algorithms. The new algorithm consists of 13 items. Kappa and ICC of the new algorithm were 0.76 and 0.62 versus 0.31 and 0.43 for the Naranjo algorithm. The new algorithm developed using actual patient data is more valid and reliable than the Naranjo algorithm for identifying ADRs in the NICU population. Because of the relatively small and nonrandom samples, further refinement and additional testing are needed.

Infants with single ventricle physiology in the emergency department: are physicians prepared?

OBJECTIVE: To assess emergency department (ED) utilization and physician preparedness for infants with single ventricle (SV) physiology between stage 1 and stage 2 surgical palliation. STUDY DESIGN: Records of infants with SV physiology discharged after stage I palliation between July 2006 and June 2009 were retrospectively reviewed. Next, a cross-sectional survey of registered ED physicians in Michigan was performed. RESULTS: Thirty-three of 42 patients (79%) required 65 ED visits, most commonly presenting with respiratory distress (35%). Six patients died in the ED; 35 other visits resulted in hospital admission, 4 requiring urgent surgery or catheterization. Median initial hospital stay in those with ED visits was significantly longer (21 days; IQR, 17-45 days) than those without (12 days; IQR, 5.5-24 days) (P = .032). Three hundred seventy-six of 915 surveyed ED physicians responded. Most (72%) were unsure of the acceptable range of arterial oxygen saturation for these infants, and 58% felt "uncomfortable" or "worried" about their treatment. Despite these concerns, 59% deemed education in SV physiology as low priority. CONCLUSIONS: Between stages I and II, infants with SV physiology utilized the ED frequently, often with high disease acuity. Most ED physicians surveyed appeared underprepared for these infants. These findings underscore the need for educational efforts aimed at increasing ED preparedness.

Relative deficiency of arginine vasopressin in children after cardiopulmonary bypass.

OBJECTIVE: To describe changes in plasma arginine vasopress in concentration in children following cardiopulmonary bypass and determine whether, in some patients, plasma arginine vasopressin remains relatively low despite hemodynamic instability. DESIGN: Prospective observational study. SETTING: Pediatric intensive care unit at a tertiary care university hospital. PATIENTS: One hundred twenty patients ≤ 18 yrs of age undergoing open heart surgery requiring cardiopulmonary bypass at Children's Hospital of Michigan between January 2008 and January 2009. INTERVENTIONS: Blood samples were collected before cardiopulmonary bypass and 4, 24, and 48 hrs after cardiopulmonary bypass for measurement of plasma arginine vasopressin concentration. MEASUREMENTS AND MAIN RESULTS: Mean plasma arginine vasopressin (pg/mL) for all patients was 21 ± 63 before cardiopulmonary bypass and 80 ± 145, 43 ± 79, and 19 ± 25 at 4, 24, and 48 hrs, respectively, after cardiopulmonary bypass. Patients with plasma arginine vasopressin below the lower quartile (< 9.2 pg/mL) at 4 hrs after cardiopulmonary bypass (n = 29), labeled group A, were examined separately and compared with the rest of the study population, labeled group B. Mean plasma arginine vasopressin was 4.9 ± 2.6 in group A at 4 hrs after cardiopulmonary bypass, statistically unchanged from its baseline mean plasma arginine vasopressin of 5.0 ± 10.4 (p = .977). Mean plasma arginine vasopressin in group B was 104 ± 160 at 4 hrs after cardiopulmonary bypass. Mean plasma arginine vasopressin of group A was also significantly lower as compared with group B before and 24 and 48 hrs after cardiopulmonary bypass. Hemodynamics, inotrope score, and serum sodium did not differ between groups at any time point. Plasma arginine vasopressin was measured immediately before exogenous arginine vasopressin administration in 10 patients; only those (n = 3) with hemodynamic instability and relatively low plasma arginine vasopressin concentration (< 9.2 pg/mL) had notable hemodynamic improvement. CONCLUSIONS: In some children undergoing open heart surgery, plasma arginine vasopressin concentration is relatively low at baseline and remains low after cardiopulmonary bypass regardless of hemodynamic stability and serum osmolality. These children are likely the optimal candidates for exogenous arginine vasopressin should hemodynamic compromise occur.

Reversal of methylprednisolone effects in allergen-exposed female BALB/c mice.

A high percentage of asthma is associated with aeroallergen exposures. Glucocorticoids such as methylprednisolone represent a major method for managing chronic asthma. However, studies suggested that corticosteroid therapy might have the potential to stimulate rather than inhibit adaptive immune inflammatory reactions, raising concerns about possible adverse reactions due to excessive repeated methylprednisolone treatment. Therefore, a murine model of allergen-induced inflammation was characterized and used to investigate the effects of repeated intraperitoneal (ip) and transnasal treatments with methylprednisolone (0-20 mg/kg body weight) and cyclosporin A (20 mg/kg body weight). Sensitized BALB/c female mice were exposed daily to ovalbumin (OVA) aerosols for up to 5 d with 24-h postexposure analyses for airway responses to methacholine aerosols and inflammatory cell recoveries by bronchoalveolar lavage (BAL) and tissue collagenase dispersion. Although increased tissue neutrophils, lymphocytes, monocytes, and macrophages reached maximal levels after 2 daily OVA exposures, recoverable eosinophil numbers continued to rise over the 5-d period. Daily ip treatments with a 5-mg/kg body weight dose of methylprednisolone diminished both OVA-induced airway responses to methacholine and inflammatory-cell accumulations to levels comparable to those observed with cyclosporin A. However, treatments with higher doses of methylprednisolone reversed this anti-inflammatory effect, indicated by a return to untreated levels of OVA-induced eosinophil recovery. A similar biphasic response in eosinophil recoveries was observed using daily transnasal methylprednisolone treatments that correlated with a concomitant fall and rise in BAL interleukin-13. These results supported the hypothesis that repeated high-steroid treatments might activate rather than suppress allergen-induced immune responses.

Effects of branching architecture and linker on the activity of hyperbranched polymer-drug conjugates.

Drug release from hyperbranched polymer-drug conjugates and the subsequent activity are influenced by the branching architecture and the linker. To gain an understanding of these effects, we used hyperbranched polyol and G4-OH polyamidoamine (PAMAM) dendrimer with methyl prednisolone (MP) as the model drug. The drug was conjugated to dendrimer or polyol using a glutaric acid (GA) or a succinic acid (SA) spacer. Drug payload was the highest with polyol, while in the case of dendrimer, a higher payload was achieved with the GA than the SA spacer. Cell uptake of the polymer conjugates in A549 lung epithelial cells was higher than that of the free drug, and the conjugates largely localized in the cytosol. The anti-inflammatory activity of polymer conjugated MP, as measured by inhibition of prostaglandin synthesis, was the highest for MP-SA-dendrimer conjugate, followed by MP-GA-polyol conjugate, and then MP-GA-dendrimer conjugate. This study suggests that the branching architecture and spacer influence the drug payload and pharmacological activity of a drug-nanopolymer conjugate, which may significantly influence the in vivo efficacy of these nanodevices. This has key implications in the eventual in vivo efficacy of these nanodevices.

Synthesis, characterization, and in vitro activity of dendrimer-streptokinase conjugates.

Dendrimer conjugation with low molecular weight drugs has been of increasing interest recently for improving pharmacokinetics, targeting drugs to specific sites, and facilitating cellular uptake. Opportunities for increasing the performance of relatively large therapeutic proteins such as streptokinase (SK) using dendrimers are being explored in this study. Using the active ester method, a series of streptokinase-poly(amido amine) (PAMAM) G3.5 conjugates were synthesized with varying amounts of dendrimer-to-protein molar ratios. Characterization of these conjugates by GPC, IEC, and native-PAGE suggested that the conjugation reaction was successful, resulting in relatively pure SK-dendrimer conjugates. The conjugate made with an equimolar ratio of dendrimer to streptokinase (1:1) exhibited the highest enzymatic activity retention ( approximately 80% retained) that has been reported so far for conjugated streptokinase with macromolecules such as PEG or dextran. SK conjugates with higher streptokinase-to-dendrimer molar ratios (1:10 and 1:20) exhibited lower initial enzymatic activities. However, these conjugates showed sustained thrombolytic activity in plasma, perhaps due to the release of SK from the conjugate. All of the SK conjugates displayed significantly improved stability in phosphate buffer solution, compared to free SK. The high coupling reaction efficiencies and the resulting high enzymatic activity retention achieved in this study could enable a desirable way for modifying many bioactive macromolecules with dendrimers.

Preparation, cellular transport, and activity of polyamidoamine-based dendritic nanodevices with a high drug payload.

Dendrimers are emerging as a relatively new class of polymeric biomaterials with applications in drug delivery, and imaging. Achieving a high drug payload in dendrimers, and understanding the therapeutic effect of the dendrimer-drug conjugates are receiving increasing attention. A high drug payload nanodevice was obtained by covalent conjugation of ibuprofen to a polyamidoamine (PAMAM-G4-OH) dendrimer. Using DCC as a coupling agent, 58 molecules of ibuprofen were covalently conjugated to one molecule of generation 4 PAMAM-OH dendrimer. Cellular entry of the fluoroisothiocynate (FITC)-labeled dendrimer-drug conjugate was evaluated in vitro by using human lung epithelial carcinoma A549 cells by flow cytometry, confocal microscopy and UV/Visible spectroscopy. The pharmacological activity of the dendrimer-ibuprofen conjugate was compared to pure ibuprofen at various time points by measuring the suppression of prostaglandin E2. Significant amounts of the conjugate entered the cells rapidly within 15 min. Suppression of prostaglandin was noted within 30 min for the dendrimer-drug conjugates versus 1 h for the free ibuprofen. The results suggest that dendrimers with high drug payload improve the drug's efficacy by enhanced cellular delivery, and may produce a rapid pharmacological response. These dendrimer-drug conjugates can potentially be further modified by attaching antibodies and ligands for targeted drug delivery.

Synthesis, cellular transport, and activity of polyamidoamine dendrimer-methylprednisolone conjugates.

Dendrimers have emerged as promising multifunctional nanomaterials for drug delivery due to their well-defined size and tailorability. We compare two schemes to obtain methylprednisolone (MP)-polyamidoamine dendrimer (PAMAM-G4-OH) conjugate. Glutaric acid (GA) was used as a spacer to facilitate the conjugation. In scheme A, PAMAM-G4-OH was first coupled to GA and then further conjugated with MP to obtain PAMAM-G4-GA-MP conjugates. This scheme yields a lower conjugation ratio of MP, presumably because of lower reactivity and steric hindrance for the steroid at the crowded dendrimer periphery. In scheme B, this steric hindrance was overcome by first preparing the MP-GA conjugate, which was then coupled to the PAMAM-G4-OH dendrimer. The (1)H NMR spectrum of the conjugate from scheme B indicates a conjugation of 12 molecules of MP with the dendrimer, corresponding to a payload of 32 wt %. In addition, conjugates were further fluorescent-labeled with fluoroisothiocynate (FITC) to evaluate the dynamics of cellular entry. Flow cytometry and UV/visible spectroscopic analysis showed that the conjugate is rapidly taken up inside the cell. Fluorescence and confocal microscopy images on A549 human lung epithelial carcinoma cells treated with conjugates show that the conjugate is mostly localized in cytosol. MP-GA-dendrimer conjugate showed comparable pharmacological activity to free MP, as measured by inhibition of prostaglandin secretion. These conjugates can potentially be further conjugated with a targeting moiety to deliver the drugs to specific cells in vivo.