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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.

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.

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.

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.

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.

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.

Highly branched, functionalized polymers have potential to act as efficient drug carrier systems. Dendrimers are ideal candidates among model hyperbranched polymers because of their well-defined structure and high density of functional groups. Using ibuprofen as a model drug, we studied the interaction between the drug and Polyamidoamine (PAMAM) dendrimers (generations 3 and 4 with --NH2 functionality) and Perstrop Polyol (generation 5, hyperbranched polyester with --OH functionality). FTIR and NMR studies suggest that ibuprofen predominantly forms a complex with PAMAM dendrimers because of the ionic interaction between the --NH2 end groups and the carboxyl group of ibuprofen. On an average, up to 78 molecules of ibuprofen could be incorporated into one molecule of PAMAM-G4-NH2 with 64 end groups. This complex is stable in deionized water and methanol. The in vitro release of ibuprofen from drug-dendrimer complex is appreciably slower compared to pure ibuprofen. The complexed drug enters A549 cells much more rapidly than pure drug suggesting that dendrimers may be able to carry the complexed drug inside cells efficiently. Hyperbranched Polyol (with 128 --OH end groups) appears to encapsulate approximately 24 drug molecules. Perhaps the lack of strong interactions between the --OH end groups and the drugs prevents complex formation.

Objectives: To evaluate the efficacy of a single dose of ketorolac compared with morphine for the relief of pain in children, and to determine the safety of ketorolac. Setting: Tertiary pediatric intensive care unit in a university-affiliated hospital. Design: Prospective, randomized, double-blind, parallel, single-dose, positive control study. Patients: Children admitted to the intensive care unit with postoperative pain. Interventions: Patients received a single dose of either morphine or ketorolac as the first postoperative analgesic when the pain score indicated significant pain. Blood pressure, heart rate, and urine output were recorded, as well as blood urea nitrogen, creatinine, bleeding time, hematuria or proteinuria, and aspartate aminotransferase. Side effects such as nausea and vomiting were noted. Morphine was used for rescue treatment if the patient continued to have significant pain ≥30 mins after study drug administration. Measurements and Main Results: Of the 102 children studied, 48 received morphine and 54 received ketorolac. The percentage of patients reporting pain relief in the first and second hours after drug administration was not different between groups. Likewise, the proportion of patients who met the criteria for pain relief during the entire evaluation period was not different between groups. There was a trend toward fewer patients who received ketorolac requiring remedication in the first 4 hrs compared with those who received morphine, but this trend did not reach statistical significance. More patients in the morphine group failed to achieve pain relief at any time after the dose compared with those who received ketorolac. There were no differences between the two groups in physiologic or laboratory variables. Vomiting was more common in patients who received ketorolac. Conclusion: Ketorolac is comparable to morphine in relief of postoperative pain in children. A single dose of ketorolac does not result in abnormal postoperative bleeding or alter renal function. However, ketorolac may cause nausea and vomiting in some patients.

The present investigation studied the speech production and phonological skills of 6 children between the ages of 2;8 and 6;8 (years;months) who had undergone tracheostomy before age 8 months. Each child's speech was analyzed for size and composition of phonetic inventory, use of phonological processes, production of vowels, and production of the voicing contrast for stops. Analyses were completed once consistent air support for vocalization was established for each child and 3 months after that date. This study highlights the slow development of sound acquisition, vowel production, and the distinction between voiced and voiceless stops for some, but not all, children with a history of tracheostomy. Each child exhibited his or her own pattern of speech production difficulties on four tasks. Excessive use of inappropriate phonological processes relative to age was the most prevalent speech production problem. Five of 6 subjects exhibited clinically significant use of Stridency Deletion, Liquid Deviation, and/or Cluster Reduction. Adjustments were noted in the speech of all subjects during a 3-month period.

To characterize and compare acid suppression (pharmacodynamics) and pharmacokinetics of IV famotidine and ranitidine in critically ill children at risk for stress gastritis. Single-blind, randomized study in PICU patients 6 months to 18 years requiring mechanical ventilation with continuous gastric pH monitoring, randomized to IV famotidine 12 mg/m(2) or ranitidine 60 mg/m(2) when gastric pH 4.01 hour with serial blood sampling following first dose. Twenty-four children randomized to either famotidine (n = 12) or ranitidine (n = 12). Sixteen out of twenty-four completed both PK and PD study arms (7/12 famotidine; 4.7 ± 3.4 years; 9/12 ranitidine; 6.6 ± 4.7 years; p = 0.38). Time to gastric pH 4.0 and total time pH above 4.0 similar with no difference in pH at 6 and 12 hours (p 0.2). No difference between drugs in clearance, volume of distribution and half-life (p 0.05). Ratio of AUC pH to AUC drug concentration 0-12 hours after first dose was significantly greater for famotidine (0.06849 ± 0.01460 SD) than ranitidine (0.02453 ± 0.01448; p 0.001) demonstrating greater potency of famotidine. pH lowering efficacy of both drugs is similar. Greater potency of famotidine may offer clinical advantage due to lower drug exposure and less frequent dosing to achieve same pH lowering effect.

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.

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.

In spite of modern technological advances, ARDS continues to be an important cause of morbidity and mortality from a diverse group of disorders such as sepsis, trauma, and aspiration. ARDS represents a target organ injury resulting from activation of the host's inflammatory cells and uncontrolled liberation of inflammatory mediators. In most instances, therefore, ARDS is a localized manifestation of a widespread onslaught characteristic of SIRS. At this time, there are no proven interventions to prevent ARDS, and the management is mainly supportive. Modulation of the host's inflammatory response seems to hold the most promise for prevention and treatment of ARDS. Such strategies need to be explored with well-controlled clinical trials.

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.

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.Prospective observational study.Pediatric intensive care unit at a tertiary care university hospital.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.Blood samples were collected before cardiopulmonary bypass and 4, 24, and 48 hrs after cardiopulmonary bypass for measurement of plasma arginine vasopressin concentration.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.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.

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.

Disulfiram is used worldwide to treat alcoholism. The presence of this drug in the home makes it a potential agent encountered in accidental poisoning. We report a child who ingested disulfiram and subsequently had unusual and prolonged neurologic manifestations of dystonia, complete loss of developmental milestones, and spastic tetraparesis. A 5-year-old girl was seen at the referring hospital for upper respiratory tract infection for 7 days and vomiting for 2 days. She was incoherent and unresponsive, with significant dehydration and cold clammy extremities on the day of admission. A bedside glucose test indicated low blood sugar. Two doses of 25% dextrose (2 mL/kg) and 0.1 mg/kg naloxone were administered. Laboratory data obtained before the above intervention included serum sodium, 141 mEq/L; potassium, 6.0 mEq/L; chlorides, 106 mEq/L; carbon dioxide content, 5 mEq/L; blood urea nitrogen, 90 mg/dL; creatinine, 1.4 mg/dL; glucose, 359 mg/dL; lactic acid, 1.3 mmol/L; and osmolality, 340 mOsm/kg. Capillary blood gas measurement showed a pH of 7.12, Pco2 of 18 mm Hg, Po2 of 98 mm Hg, and serum bicarbonate of 5.5 mEq/L. A complete blood count and spinal fluid showed no abnormalities. Subsequently, a diagnosis of diabetic ketoacidosis was made. Intravascular volume expansion was carried out using 300 mL of lactated Ringer's solution. She was transferred to the Children's Hospital of Michigan. At arrival to the intensive care unit, the physical examination revealed the following: temperature, 36.6°C (rectal); heart rate, 132 beats/min; Kussmaul breathing at a rate of 36 breaths/min; and blood pressure, 122/76 mm Hg. She had cold, clammy extremities. She remained comatose, with occasional spontaneous, nonpurposeful movements. No focal neurologic deficits were noted. Serum glucose was 551 mg/dL. A comprehensive toxicologic screen including an alcohol panel did not reveal the presence of any drugs or toxins in the urine or serum. Continuous infusions …

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.

To synthesize and evaluate hyperbranched polymer (HBP)-drug conjugates with high drug payload for enhanced cellular delivery.Polyol- and polyglycerol-ibuprofen conjugates with or without imaging agent fluorescein isothiocyanate (FITC) were synthesized using dicyclohexilcarbodiimide (DCC) as a coupling agent. Drug-polymer conjugates were characterized using 13C NMR, 1H NMR, and gel permeation chromatography (GPC). Stability of the drug-conjugates was studied using free drug release through a dialysis membrane. Cellular entry of FITC-labeled HBP conjugates was studied using fluorescence activated cell sorter (FACS), and cell supernatant was analyzed by UV-visible spectrophotometer. The intracellular localization of FITC-labeled conjugates in A549 lung epithelial cells was imaged using fluorescence microscopy. Anti-inflammatory activity of the HBP-ibuprofen conjugates was estimated in vitro by measuring the concentration of prostaglandin (PGE2) using an ELISA kit.The average number of ibuprofen molecules conjugated per molecule of HBP was estimated to be 50 for polyol and 53 for polyglycerol. The HBP-drug conjugates did not release the drug up to 72 h in methanol, indicating the presence of stable ester bonds. Both the polymer-drug conjugates entered the cells rapidly. The conjugates were localized in the cell cytosol as evidenced by fluorescence microscopy. Within 30 min, the HBP-drug conjugates showed rapid suppression of PGE2 synthesis, whereas free ibuprofen did not show any activity. At later times, the conjugates showed comparable activity.For the first time, we report HBP conjugates with a high drug payload. HBP-drug conjugates entered the cells rapidly and produced the desired pharmacological action. This study demonstrates that hyperbranched polyol and polyglycerol are promising nanovehicles for achieving enhanced cellular delivery of drugs.

NSAIDs are commonly avoided by patients with aspirin-induced asthma based on the premise that there is a significant cross-reactivity between aspirin and other NSAIDs. However, ibuprofen, a NSAID sold over the counter in most countries, is commonly given to children for relief of fever and mild-to-moderate pain. Consequently, increased risk of acute bronchospasm induced by ibuprofen in children with asthma remains a persistent concern. More recently, the assumption that children with asthma are at a greater risk for exacerbations of their disease if they take ibuprofen has been questioned. There is little evidence to measurably increases morbidity in the great majority of children with asthma. In addition, recent evidence suggest that ibuprofen measurably increases morbidity in the great majority of [corrected] children with asthma. Given the infrequent occurrence of aspirin/NSAID sensitivity in children with asthma, it seems reasonable to allow the use of ibuprofen in this population unless there is a personal or family history of aspirin-induced asthma. In addition, the inflammatory pathogenesis of asthma, anti-inflammatory effect of ibuprofen, and evidence suggesting ibuprofen may reduce morbidity in children with asthma raises the intriguing possibility that ibuprofen might actually have therapeutic benefit for at least some children with asthma.

Dendrimers and hyperbranched polymers are emerging as potentially ideal drug delivery vehicles because they provide a significant amount of tailorability and a large density of functional groups. This study explores the dynamics of cellular entry of dendrimers and hyperbranched polymers alone, and in the complexed form with ibuprofen, into A549 human lung epithelial carcinoma cells using UV/Vis spectroscopy, flow cytometry and fluorescence microscopy. Both dendrimers and hyperbranched polymers appear to enter these cells rapidly. The polyamidoamine (PAMAM) dendrimers, with NH2 and OH end functionalities appear to enter cells (in approx. 1 h) faster than the hyperbranched polyol (OH functionality) (in approx. 2 h). Cellular entry of PAMAM-NH2 was detected as early as 5 min. All branched polymers and their ibuprofen complexes entered A549 lung epithelial cells rapidly when compared to the pure drug. The drug payload was about 50% by weight in the complexes formed by PAMAM-NH2 dendrimers and was about 30% in the encapsulated form for Polyol-OH and PAMAM-OH. The complexation and encapsulation of ibuprofen with the polymers appear to facilitate rapid cellular entry of ibuprofen. The anti-inflammatory effect of the polymer-complexed drug was demonstrated by more rapid suppression of COX-2 mRNA levels than that achieved by the pure drug. This suggests that these dendritic polymers can act as efficient drug carriers, delivering high 'payloads' of drug even with complexation and encapsulation.

The optimum strategy for mechanical ventilation in a child with status asthmaticus is not established. Volume-controlled ventilation continues to be the traditional approach in such children. Pressure-controlled ventilation may be theoretically more advantageous in allowing for more uniform ventilation. We describe our experience with pressure-controlled ventilation in children with severe respiratory failure from status asthmaticus.Retrospective review.Pediatric intensive care unit in a university-affiliated children's hospital.All patients who received mechanical ventilation for status asthmaticus.Pressure-controlled ventilation was used as the initial ventilatory strategy. The optimum pressure control, rate, and inspiratory and expiratory time were determined based on blood gas values, flow waveform, and exhaled tidal volume.Forty patients were admitted for 51 episodes of severe status asthmaticus requiring mechanical ventilation. Before the institution of pressure-controlled ventilation, median pH and Pco(2) were 7.21 (range, 6.65-7.39) and 65 torr (29-264 torr), respectively. Four hours after pressure-controlled ventilation, median pH increased to 7.31 (6.98-7.45, p.005), and Pco(2) decreased to 41 torr (21-118 torr, p.005). For patients with respiratory acidosis (Pco(2)45 torr) within 1 hr of starting pressure-controlled ventilation, the median length of time until Pco(2) decreased to45 torr was 5 hrs (1-51 hrs). Oxygen saturation was maintained95% in all patients. Two patients had pneumomediastinum before pressure-controlled ventilation. One patient each developed pneumothorax and subcutaneous emphysema after initiation of pressure-controlled ventilation. All patients survived without any neurologic morbidity. Median duration of mechanical ventilation was 29 hrs (4-107 hrs), intensive care stay was 56 hrs (17-183 hrs), and hospitalization was 5 days (2-20 days).Based on this retrospective study, we suggest that pressure-controlled ventilation is an effective ventilatory strategy in severe status asthmaticus in children. Pressure-controlled ventilation represents a therapeutic option in the management of such children.

Background In the evaluation of patients with acute asthma, pulsus paradoxus (PP) is an objective and noninvasive indicator of the severity of airway obstruction. However, in children PP may be difficult or impossible to measure. Indwelling arterial catheters facilitate the measurement of PP, but they are invasive and generally reserved for critically ill patients. Objective To determine the utility of the plethysmographic waveform (PP pleth ) of the pulse oximeter in measuring PP. Methods Patients from the pediatric intensive care unit, emergency department, and inpatient wards of a tertiary care pediatric hospital were eligible for the study. A total of 36 patients (mean age [SD], 11.2 [4.7] years) were enrolled in the study. Pulsus paradoxus was measured using the traditional auscultatory (PP ausc ) method with a sphygmomanometer. Pulsus paradoxus was then measured using a blood pressure cuff observing for the disappearance and reappearance of the (PP pleth ) on the pulse oximeter. Mean difference and 95% confidence intervals were calculated for each method. The 2 methods were also analyzed for correlation and agreement using the Pearson product moment correlation and a Bland and Altman plot. Results Patients with status asthmaticus had higher PP ausc and PP pleth readings compared with nonasthmatic patients. Pulsus paradoxus measured by plethysmography in patients with and without asthma was similar to PP ausc readings (mean difference, 0.6 mm Hg; 95% confidence interval, −0.6 to 2.1 mm Hg). Individual PP pleth readings showed significant correlation and agreement with PP ausc readings in patients both with and without asthma. Conclusion Measurement of PP using the pulse oximeter–pulse plethysmographic waveform offers a simple and noninvasive method for evaluating patients with airway obstruction.

Objective To compare the pharmacokinetics and metabolism of R (+)- and S (−)- ketorolac in children. Methods Children from 3 to 18 years old received 0.6 mg/kg racemic ketorolac intravenously. Serial blood samples were obtained for 12 hours, and urine was collected for 12 to 24 hours. Racemic ketorolac was measured in plasma, and racemic ketorolac, para-hydroxyketorolac, and ketorolac glucuronide were measured in urine by HPLC. S (−)- and R (+)-ketorolac were measured in plasma; S (−)- and R (+)-ketorolac and ketorolac glucuronide were measured in urine by chiral HPLC separation. Plasma pharmacokinetic parameters for racemic drug and both enantiomers were determined for each patient. Results Clearance of racemic ketorolac in children was approximately 2 times the clearance reported in adults. Clearance of the S (−) enantiomer was 4 times that of the R (+) enantiomer. Terminal half-life of S (−)-ketorolac was 40% that of the R (+) enantiomer, and the apparent volume of distribution of the S (−) enantiomer was greater than that of the R (+) form. Recovery of S (−)-ketorolac glucuronide was 2.3 times that of the R (+) enantiomer. Conclusion The higher clearance in children suggests that the weight-adjusted dose of ketorolac may have to be greater for children to achieve plasma concentrations comparable to those of adults. Because of the greater clearance and shorter half-life of S (−)-ketorolac, pharmacokinetic predictions based on racemic assays may overestimate the duration of pharmacologic effect. Enantiomeric pharmacokinetic differences are best explained by stereoselective plasma protein binding. Selective glucuronidation of the S (−) enantiomer suggests that stereoselective metabolism may also be a contributing factor. Clinical Pharmacology & Therapeutics (1999) 65, 382–388; doi

a) To determine if antidiuretic hormone (ADH) is elevated in patients undergoing spinal fusion, especially in those who have clinical evidence of syndrome of inappropriate antidiuretic hormone (SIADH); b) to evaluate the relationship between ADH secretion and the secretion of atrial natriuretic peptide (ANP).Tertiary care pediatric intensive care unit (ICU) in a university hospital.A prospective cross-sectional, observational study with factorial design.Thirty patientsor = 10 yrs of age undergoing spinal fusion admitted to the ICU for postoperative care.Patients underwent anterior, posterior, or both anterior/posterior spinal fusion. Blood was collected for serial measurements of ADH, ANP and serum electrolyte levels. Heart rate, blood pressure and central venous pressure were measured.Thirty children were studied. Nineteen had idiopathic scoliosis, nine had neuromuscular scoliosis, one had Marfan's disease, and one had congenital scoliosis. Ten (33%) children met clinical criteria of SIADH. There was no difference in duration of surgery, blood loss, volume of iv fluid administration pre- and intraoperatively, or type of scoliosis between those who developed SIADH and those who did not. Hemodynamic variables were similar in both groups. ADH levels increased in both groups immediately postoperatively and at 6 hrs after surgery, but were much more elevated in those patients with SIADH. Patients with SIADH also had significantly higher ADH levels preoperatively. In relation to serum osmolality, ADH was considerably higher in those with SIADH compared with those who did not. Although ANP values tended to be higher in the group with SIADH, this did not reach statistical significance.SIADH occurs in a subset of children who undergo spinal fusion. The diagnosis of SIADH can be made easily using clinical parameters which are well-defined. In the face of SIADH, continued volume expansion may be harmful, and should therefore be avoided.

a) To demonstrate the effect of high-frequency ventilation on gas exchange in children with severe acute respiratory failure unresponsive to conventional ventilation; b) to identify patients at high risk of death early after institution of high-frequency ventilation.Tertiary care pediatric intensive care unit in a university hospital.A cross-sectional, observational study with factorial design.Thirty-one patients with severe acute respiratory failure defined as a Pao2/F1o2 of150 torr (20 kPa) with a positive end-expiratory pressure ofor = 8 cm H2O and/or Paco2 of60 torr (8 kPa) with an arterial pH7.25.Patients received either high-frequency oscillation or jet ventilation if respiratory failure was unresponsive to conventional ventilation and if the underlying disease process was deemed reversible.Thirty-one children were managed with high-frequency ventilation, 11 children with jet and 20 children with oscillator. Arterial blood gases and level of ventilatory support were recorded before and at 6, 24, 48, 72, and 96 hrs after institution of high-frequency ventilation. There was an improvement in an arterial pH, Paco2, Pao2, and Pao2/FID2 6 hrs after institution of high-frequency ventilation (p.01). This improvement, along with decreased need for oxygen, was sustained through the subsequent course. Twenty-three (74%) of 31 children treated with high-frequency ventilation survived. Survivors showed an increase in an arterial pH, Pao2, Pao2/FIO2, and a decrease in Paco2 within 6 hrs, whereas nonsurvivors did not. Oxygenation index was the best predictor of outcome. A combination of an initial oxygenation index of20 and failure to decrease the oxygenation index by20% by 6 hrs after initiation of high-frequency ventilation predicted death with 88% (7/8) sensitivity and 83% (19/23) specificity, with an odds ratio of 33 (p = .0036, 95% confidence interval 3-365).In patients with potentially reversible underlying diseases resulting in severe acute respiratory failure that is unresponsive to conventional ventilation, high-frequency ventilation improves gas exchange in a rapid and sustained fashion. The magnitude of impaired oxygenation and its improvement after high-frequency ventilation can predict outcome within 6 hrs.

To study the effect of ribavirin aerosol therapy on the immediate clinical course of mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease.Prospective, randomized, double-blind, placebo-controlled study.Pediatric intensive care unit (ICU) of a university teaching hospital.Forty-one children requiring mechanical ventilation for respiratory syncytial virus lower respiratory tract disease.Patients were stratified by the presence or absence of and underlying disease and then randomized to receive aerosolized ribavirin (20 mg/mL) or saline for 18 hrs/day for 5 days or until endotracheal extubation, whichever came first.Dependent variables included the time course of the illness and the change in FIO2, ventilatory rate, PaO2/FIO2 ratio, and ventilatory-efficiency index of patients while they received aerosol therapy. Ribavirin- and placebo-treated patient groups were not significantly different in the number of ventilator days (6.4 +/- 6.9 vs. 8.2 +/- 10.1; p = .5), oxygen days (10.8 +/- 7.7 vs. 12.2 +/- 11.8; p = .9), ICU days (7.9 +/- 7.0 vs. 10.3 +/- 11.0; p = .7), or hospital days (12.9 +/- 9.7 vs. 16.2 +/- 14.0; p = .6) after the initiation of aerosol therapy. The change in FIO2, ventilatory rate, PaO2/FIO2 ratio, or ventilatory-efficiency index did not differ between the two groups. No ventilator malfunction was observed. There were six deaths caused by intractable hypoxemia in patients with underlying cardiopulmonary disease. Four of these deaths were in the placebo group and two in the ribavirin group (p = .5).Ribavirin aerosol therapy can be safely administered to mechanically ventilated children with severe respiratory syncytial virus lower respiratory tract disease. However, this therapy does not appear to affect immediate clinical outcome in such patients.

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.

The initial evaluation, stabilization, and subsequent transport of the neurologically compromised child should take into account the pathophysiologic response of the CNS to a variety of injurious factors. Little can be done to avoid neuronal damage from the primary event. Secondary insults resulting from hypoxemia, ischemia, intracranial hypertension, and fluid shifts can and must be prevented to ensure maximum neuronal salvage, however. Maintenance of an adequate airway, breathing, and circulation assume an immediate and ongoing priority. Neuroresuscitation should be directed toward reversing alterations in cerebral metabolism, autoregulation, brain water, and ICP associated with individual pathologic states.

Objective: To study the hypothesis that, in the absence of an ischemic-hypoxic state, children with severe traumatic brain injury and with unfavorable Glasgow Coma Scale scores may have good recovery. Design: Retrospective, observational, cross-sectional study with factorial design. Setting: Inpatient population in a university hospital. Patients: Seventy-nine children with traumatic brain injury admitted to the intensive care unit. Interventions: All patients received close monitoring and strict control of intracranial pressure ( 60 mm Hg). Measurements and results: Admission Glasgow Coma Scale score, survival, need for cardiopulmonary resuscitition, presence of shock, peak intracranial pressure, duration of coma, Glasgow outcome Scale score, and the results of neuropsychologic tests were analyzed. Of 79 children, 70 (89%) survived. Although the mortality rate was higher among patients with Glasgow Coma Scale scores of 3 to 5, 14 (64%) of 22 of these children survived. Nonsurvivors had a significantly higher incidence of shock and need for cardiopulmonary resuscitation. Except for two patients who had prolonged hypoxemia, all children, including those with Glasgow Coma Scale scores of 3 to 5, had a satisfactory outcome (Glasgow Outcome Scale scores of 4 or 5). Neuropsychologic outcome was not significantly different in the survivors with Glasgow Coma Scale scores of 3 to 5 and those with Glasgow Coma Scale scores of 6 or more. Conclusions: A low Glasgow Coma Scale score does not always accurately predict the outcome of severe traumatic brain injury; in the absence of hypoxic-ischemic injury, children with traumatic brain injury and Glasgow Coma Scale scores of 3 to 5 can recover independent function.

To study the value of intensive care in childhood cancer, we evaluated the clinical course and outcome of all such children admitted to our intensive care unit (ICU) (n = 183) during the five-year period from 1984-1988. Excluding those admitted for postoperative observation, there were a total of 63 admissions for complications of malignancy. Of these, admissions for sepsis, pulmonary parenchymal disease, or coma were associated with poor outcome. Thirty-six percent of patients requiring mechanical ventilation for respiratory failure and 27% requiring inotropic support survived longer than six months. Physiologic Stability Index and Therapeutic Intervention Scores were significantly greater in nonsurvivors than survivors. Of those who survived their ICU stay, 50% went home functioning at their premorbid state. The duration of ICU stay was not different in survivors and nonsurvivors, suggesting that intensive care does not excessively prolong the dying process. We conclude that many life-threatening complications of cancer are potentially reversible. The extent of functional recovery of survivors warrants aggressive intensive support in this setting.

In an effort to delineate the clinical characteristics of respiratory syncytial virus (RSV) infection in the compromised host, we compared children with bronchopulmonary dysplasia (BPD), congenital heart disease (CHD), premature birth, failure to thrive, and gastroesophageal reflux to previously healthy children. During a four-year period, 262 patients were admitted to the hospital with RSV infection diagnosed by a rapid RSV antigen detection test. Children with BPD or CHD had more hospital days and supplemental oxygen days than the previously healthy group (P less than 0.05). Patients with BPD also had more ICU days, ventilator days, and NPO days, as well as a higher physiologic stability index and therapeutic intervention score than the previously healthy group (P less than 0.05). Premature infants were more likely to present with apnea from RSV (P less than 0.001). Patients with underlying illness tended to be older, although significant difference was demonstrated only for the BPD group (7.0 +/- 5.3 vs. 3.5 +/- 3.3, P less than 0.05). Patients with BPD and CHD had more nosocomial infections than the previously healthy group (P less than 0.0001) and death occurred only in patients with underlying illness. We conclude that previously compromised patients are at risk for more severe and prolonged RSV disease. Earlier diagnosis and therapeutic intervention may be necessary in such patients to improve outcome.

Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were strictly controlled in 11 pediatric victims of near-drowning. Three outcome groups were defined: complete recovery, persistent vegetative state, and death. In the early postimmersion phase (first 72 h), CPP was consistently above 50 mm Hg in all patients. There were occasional, nonrepetitive, and easily controllable ICP spikes above 15 mm Hg in three patients from each group. Repeated ICP spikes above 15 mm Hg were observed in some patients with adverse outcome only after 72 h. Successful control of ICP and CPP did not ensure intact survival, and sustained late intracranial hypertension is more likely a sign of profound neurologic insult rather than its cause.