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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.

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 (

This study detailed the sequence of recurring inflammatory events associated with episodic allergen exposures of mice resulting in airway hyperreactivity, sustained inflammation, goblet cell hyperplasia, and fibrogenesis that characterize a lung with chronic asthma. Ovalbumin (OVA)-sensitized female Balb/c mice were exposed to saline-control or OVA aerosols for 1hr per day for episodes of 3 days every week for up to 8 weeks. Lung inflammation was assessed by inflammatory cell recoveries using bronchoalveolar lavages (BAL) and tissue collagenase dispersions. Cell accumulations were observed within airway submucosal and associated perivascular spaces using immunohistochemical and tinctorial staining methods. Airway responsiveness to methacholine aerosols were elevated after 2 weeks and further enhanced to a sustained level after the 4th and 8th weeks. Although by the 8th week, diminished OVA-induced accumulations of eosinophils, neutrophils and monocyte-macrophages were observed, suggesting diminished responsiveness, the BAL recovery of lymphocytes remained elevated. Airway but not perivascular lesions persisted with a proliferating cell population, epithelial goblet cell hyperplasia and evidence of enhanced collagen deposition. Examination of lung inflammatory cell content before the onset of the 1st, 2nd and 4th OVA exposure episodes demonstrated enhancements in residual BAL lymphocyte and BAL and tissue eosinophil recoveries with each exposure episode. Although tissue monocyte-macrophage numbers returned to baseline prior to each exposure episode, the greatest level of accumulation was observed after the 4th week. These results provide the basis for establishing the inflammatory and exposure criteria by which episodic environmental exposures to allergen might result in the development of a remodeled lung in asthma.

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.

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.

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.

Extracorporeal membrane oxygenation (ECMO) for the support of children outside the newborn period who have pulmonary failure is only recently becoming accepted. It is again being applied, after earlier failures, because well-trained teams and improved equipment and techniques are available following the success of neonatal ECMO. In addition, in Europe extracorporeal CO2 removal (ECCO2R) in adults has been more successful. The use of ECMO for pulmonary failure in children does not have fixed indications and has had considerably less success than neonatal ECMO. Patients who require inspired oxygen fractions of over 0.5 and positive end-expiratory pressures of over 6 cm H2O for more than 12 h after being treated for more than 48 h should be considered candidates, given the high mortality of children with ARDS (70%). Survival averages 50% to 60%. Circuits and patient management techniques are very similar to those for newborn ECMO, but patients usually require longer times on ECMO. There are many more options for cannulation for both venoarterial and venovenous techniques than in neonatal and cardiac ECMO. The improving results indicate that ECMO will play a part in treating children with pulmonary failure. Further studies will be required to determine which patients can benefit from ECMO as well as the exact application in each case.

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 …

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

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.

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.