True Rate of Allergy among Pediatric Inpatients with Penicillin Allergy Labels (TRIAL).

Background: Penicillin allergy is a common drug allergy diagnosis in pediatric patients; however, upon appropriate allergy testing, many of these patients are found not to have a true allergy. For patients with a reported allergy, alternative antibiotics are prescribed, which are less effective, more toxic, or more expensive. There is a lack of data evaluating allergies in hospitalized children and comparing allergy assessments conducted by pediatric allergists and pharmacists. Objective: To estimate the percentage of pediatric patients admitted with reported penicillin allergy who did not have a true penicillin allergy. Methods: This single-centre prospective cohort study included inpatients between 6 months and 17 years of age, with a documented penicillin allergy, who were admitted to the general pediatric and oncology units of a tertiary care children's hospital between November 2019 and March 2023. The allergy history, evaluation, and risk categorization were performed by pharmacists. The history was reviewed with the allergist, and the patient was then referred, underwent skin testing, or received oral amoxicillin challenge with monitoring for 1 hour. Results: Thirty patients were included, of whom 29 (97%) had delabelling of their penicillin allergy. Four patients (13%) had delabelling on the basis of history alone, without risk assessment. Twenty-five (83%) of the patients were assessed as having low risk; 24 of these had delabelling following oral challenge, and 1 did not complete the oral challenge because of transfer to another hospital. One patient (3%) was assessed as having moderate risk, with delabelling on the basis of results of skin testing and oral challenge. The pharmacist's and allergist's risk assessments were in agreement in 29 (97%) of the 30 cases. Conclusions: Pediatric patients, including those with oncologic malignancies, are often mislabelled as having a penicillin allergy. Pharmacists are able to accurately determine true allergy risk and delabel penicillin allergies for pediatric patients in the hospital setting.

Contexte: L'allergie à la pénicilline est un diagnostic d'allergie médicamenteuse courant chez les patients pédiatriques; cependant, après des tests d'allergie appropriés, bon nombre de ces patients ne présentent pas de véritable allergie. Pour ceux présentant une allergie signalée, des antibiotiques alternatifs sont prescrits, moins efficaces, plus toxiques ou plus coûteux. Peu de données permettent d'évaluer les allergies chez les enfants hospitalisés et de comparer les évaluations des allergies réalisées par les allergologues pédiatriques et les pharmaciens. Objectif: Estimer le pourcentage de patients pédiatriques admis avec une allergie à la pénicilline signalée, mais qui n'avaient pas de véritable allergie à la pénicilline. Méthodologie: Cette étude de cohorte prospective monocentrique comprenait des patients hospitalisés âgés de 6 mois à 17 ans, présentant une allergie documentée à la pénicilline, qui ont été admis dans les unités de pédiatrie générale et d'oncologie d'un hôpital pour enfants de soins tertiaires entre novembre 2019 et mars 2023. Les antécédents, l'évaluation et la catégorisation des risques de l'allergie ont été renseignés par les pharmaciens. L'anamnèse a été revue avec l'allergologue, et le patient a ensuite été référé, a subi un test cutané ou a reçu une provocation orale à l'amoxicilline avec surveillance pendant 1 heure. Résultats: Sur 30 patients inclus, 29 (97 %) ont vu un désétiquetage de leur allergie à la pénicilline. Quatre patients (13 %) ont bénéficié d'un désétiquetage sur la seule base de leurs antécédents, sans évaluation des risques. Vingt-cinq (83 %) patients ont été évalués comme présentant un faible risque; 24 d'entre eux ont bénéficié d'un désétiquetage à la suite d'une provocation orale, et 1 n'a pas terminé la provocation orale en raison d'un transfert vers un autre hôpital. Un patient (3 %) a été évalué comme présentant un risque modéré, avec un désétiquetage basé sur les résultats des tests cutanés et de la provocation orale. Les évaluations des risques par le pharmacien et l'allergologue concordaient dans 29 (97 %) des 30 cas. Conclusions: Les patients pédiatriques, y compris ceux atteints de cancers malins, sont souvent étiquetés à tort comme ayant une allergie à la pénicilline. Les pharmaciens sont en mesure de déterminer avec précision le risque réel d'allergie et de désétiqueter les allergies à la pénicilline chez les patients pédiatriques en milieu hospitalier.

Describing Intravenous Extravasation Injuries in Children (DIVE2 Study).

Background: Extravasation is the erroneous delivery of IV medication or fluid into the extravascular space. Complications ranging from mild injury to amputation can result, depending on the physical and pharmacologic properties of the infusate. Children are at increased risk for extravasation injuries. There is a paucity of data on the treatment and outcomes of extravasation injuries, particularly in terms of the role of pharmacologic antidotes. Objectives: To describe the incidence of extravasation at a tertiary pediatric care centre (as an update to a previous study), to identify the agents most commonly involved in extravasation injuries, to describe the antidotes used for management of injuries and their related adverse drug effects, and to describe complications related to injuries. Methods: The medical records of pediatric patients who experienced an extravasation injury at the BC Children's and BC Women's Hospitals, between September 1, 2008, and September 30, 2020, were reviewed. Data regarding management (adherence with institutional protocol) and outcomes of injuries were collected. Results: The 242 charts included in the analysis noted a total of 245 extravasation injuries, for an extravasation incidence of 0.04% per patient-day. Of the 242 patients, 110 were excluded from secondary outcome analysis due to lack of data detailing the extravasation event. Of the remaining 132 patients, the majority were neonates (n = 54, 40.9%), infants (n = 33, 25.0%), and children (n = 34, 25.8%), and more than a third were treated on general pediatric wards (n = 50, 37.9%). The medications most frequently involved were total parenteral nutrition with lipids (36/132, 27.3%), vancomycin (36/132, 27.3%), and IV fluids (35/132, 26.5%). Most of the patients had mild outcomes and recovered without complications. No adverse drug events from antidotes were reported. Conclusions: The incidence of extravasation at the study institution remained low, with the medications involved being similar to those reported in the literature and the majority of patients having mild outcomes. Additional prospective studies are needed to assess the efficacy and safety of antidotes administered for extravasation injuries.

Contexte: L'extravasation est l'administration erronée de médicaments ou de liquides IV dans l'espace extravasculaire. Des complications allant d'une blessure légère à l'amputation peuvent en résulter, en fonction des propriétés physiques et pharmacologiques de la perfusion. Les enfants courent un risque accru de blessures par extravasation. Il existe peu de données sur le traitement et les conséquences des blessures par extravasation, notamment en ce qui concerne le rôle des antidotes pharmacologiques. Objectifs: Décrire l'incidence des extravasations dans un centre de soins pédiatriques tertiaires (en tant que mise à jour d'une étude précédente), recenser les agents les plus couramment impliqués dans les blessures par extravasation, décrire les antidotes utilisés pour la gestion des blessures et leurs effets indésirables liés aux médicaments et décrire les complications liées aux blessures. Méthodologie: Les dossiers médicaux des patients pédiatriques ayant subi une blessure par extravasation entre le 1er septembre 2008 et le 30 septembre 2020 aux hôpitaux BC Children's Hospital et BC Women's Hospital ont été examinés. Des données concernant la prise en charge (c'est-à-dire le respect du protocole de l'établissement) et les conséquences des blessures ont été recueillies. Résultats: Les 242 dossiers inclus dans l'analyse indiquaient un total de 245 blessures par extravasation, pour une incidence d'extravasation de 0,04 % par jour-patient. Parmi les 242 patients, 110 ont été exclus de l'analyse secondaire des conséquences en raison d'un manque de données concernant les détails de l'extravasation. Sur les 132 patients restants, la majorité était des nouveau-nés (n = 54, 40,9 %), des nourrissons (n = 33, 25,0 %) et des enfants (n = 34, 25,8 %) et plus du tiers ont reçu des soins dans un service de pédiatrie générale (n = 50, 37,9 %). Les médicaments les plus fréquemment impliqués étaient la nutrition parentérale totale avec des lipides (36/132, 27,3 %), la vancomycine (36/132, 27,3 %) et des liquides IV (35/132, 26,5 %). Les conséquences sur la plupart des patients étaient bénignes et ils se sont rétablis sans complications. Aucun effet indésirable lié aux antidotes n'a été signalé. Conclusions: L'incidence des extravasations dans l'établissement à l'étude est restée faible, les médicaments impliqués étant similaires à ceux rapportés dans la littérature et les conséquences pour la majorité des patients étaient bénignes. Des études prospectives supplémentaires sont nécessaires pour évaluer l'efficacité et la sécurité des antidotes administrés pour les blessures par extravasation.

Effectiveness of Alprostadil for Ductal Patency.

OBJECTIVES: This study aims to describe the effectiveness of low initial alprostadil dosages to maintain a patent ductus arteriosus (PDA) in infants with ductal-dependent congenital heart disease (DDCHD). Secondary objectives were to describe any adverse drug events, describe prescribing trends, describe ductus arteriosus diameter changes, and compare the safety and efficacy of very low and low initial alprostadil dosage regimens. METHODS: This retrospective observational cohort study at the British Columbia's Women's and Children's Hospital neonatal intensive care unit and pediatric intensive care unit examined neonates admitted with DDCHD who received alprostadil to maintain ductal patency. Very low-dose alprostadil (less than 0.01 mcg/kg/min) versus low-dose alprostadil (equal to or greater than 0.01 mcg/kg/min) was examined. Effectiveness was defined as survival and infants not requiring a resuscitation event (cardiac arrest, cardiogenic shock, code blue, extracorporeal life support, requirement for emergent cardiac surgery, and respiratory acidosis). Adverse drug events with a Naranjo score of 3 or more were included. RESULTS: Alprostadil was effective for 88% of patients, with no difference between the very low-dose and low-dose groups. Of the 75 patients included, 25 received very low-dose alprostadil. Adverse drug events were common (51%) with neonates in the low-dose group experiencing more apnea and pyrexia than neonates in the very low-dose group. CONCLUSIONS: Alprostadil therapy was effective in maintaining the PDA in neonates with DDCHD with low-dosage regimens. Adverse drug events were common with both dosage regimens; however, the very low dosage appeared to have less apnea and pyrexia.

Pharmacologic Management of Agitation and Aggression in a Pediatric Emergency Department - A Retrospective Cohort Study.

BACKGROUND: Benzodiazepine and antipsychotic use for acute management of agitation and aggression in the pediatric emergency department (ED) setting has not been well described. OBJECTIVES: To describe medication utilization in the management of agitation and aggression in a pediatric ED and to assess the safety of their use. METHODS: This was a retrospective observational study. Patients less than 20 years of age who presented to our pediatric ED and had agitation or aggression as part of their chief complaint were included if they received at least 1 dose of benzodiazepine or antipsychotic. Outcomes included frequency of benzodiazepine and antipsychotic use, dosing of medications, and reported adverse events. RESULTS: During the 5-year study period, there were 128 visits of 120 patients who met the inclusion criteria. Lorazepam was most commonly given (70%), followed by chlorpromazine (20%). Most patients (82%) required a single dose of medication. Intoxication was associated with needing more than 1 dose of medication. Patients with autism or Asperger syndrome were more likely to receive an antipsychotic medication compared to not having these conditions (75% vs. 28%, respectively). Adverse events were documented in 6 visits: oxygen desaturation (n = 1), dizziness and nausea (n = 2), dizziness (n = 1), and paradoxical excitation (n = 2). The Naranjo Score indicated a probable adverse drug reaction for the cases of paradoxical excitation. CONCLUSIONS: Benzodiazepine and antipsychotic drug therapy for acute agitation and aggression in children appears to be safe and well tolerated when used as a single agent and at the recommended doses in this setting.

Pediatric Obesity: Pharmacokinetics and Implications for Drug Dosing.

PURPOSE: Clinicians are increasingly likely to have under their care obese children with diseases requiring pharmacotherapy. Optimal drug dosing for this population is unclear. Excess weight likely leads to alterations in pharmacokinetics. The purpose of this article was to describe the pharmacokinetics and pharmacodynamics in overweight and obese children and, where possible, provide recommendations for drug dosing. METHODS: EMBASE (1980-May 2015), MEDLINE (1950-May 2015), and International Pharmaceutical Abstracts (1970-May 2015) databases were searched by using the following terms: obesity, morbid obesity, overweight, pharmacokinetics, pharmacodynamics, drug, dose, drug levels, pediatric, and child. The search was limited to English-language articles. References of relevant articles were searched to identify additional studies. FINDINGS: Total body weight (TBW) is an appropriate size descriptor for dosing antineoplastic agents, succinylcholine, and cefazolin. Obese children seem to require less heparin, enoxaparin, and warfarin per kilogram TBW than normal-weight children; providing standard adult doses may be insufficient, however. Obese children may also require less vancomycin and aminoglycosides per kilogram TBW than normal-weight children. For these medications, an alternate size descriptor in children has not been described, and initial dosing based on TBW and monitoring serum concentrations (vancomycin and aminoglycosides) or coagulation parameters (heparin, enoxaparin, and warfarin) is warranted. Obese children require less propofol than normal-weight children; however, there is limited information about the dosing of other anesthetics or opioids. IMPLICATIONS: Limitations to the available data include the inherent design constraints to case reports and retrospective cohort studies, as well as the small numbers of children in some of the studies. Use of normal-weight historical control subjects for obese children in the context of a pharmacokinetic study is not ideal. Although more information is becoming available, our understanding of the pharmacokinetics in obese children is still limited. When dosing information is not available for obese children, it may be necessary to extrapolate from available data in obese adults, but one should consider the effects of the child's age on pharmacokinetics.

A naloxone admixture to prevent opioid-induced pruritus in children: a randomized controlled trial.

PURPOSE: Morphine administered by continuous opioid infusion (COI) or by patient-controlled analgesia (PCA) is associated with opioid-induced pruritus (OIP). Intravenous naloxone administered separately to the morphine infusion at a dose of 0.25-1.65 µg·kg(-1)·hr(-1) can provide effective prevention from OIP. Nevertheless, this strategy requires a dedicated intravenous line and an additional infusion pump. The purpose of this study was to determine whether an admixture of naloxone with morphine in normal saline administered via COI or PCA would also prevent OIP in children without attenuation of analgesia or increased opioid utilization. METHODS: In this randomized controlled trial, children meeting the inclusion criteria (aged 8-18 yr, American Society of Anesthesiologists physical status I-III, normal developmental profile and prescribed COI/PCA morphine for postoperative analgesia) were randomized to receive an infusion containing a naloxone, opioid, and saline admixture (NOSA) of 12 µg naloxone per 1 mg morphine per 1 mL normal saline or morphine only (control). The severity of opioid-induced pruritus was assessed by self-report using a modified colour analogue scale (mCAS; score 0-10). The groups were also compared for opioid utilization, pain scores, and administration of antipruritic medications, which were recorded for up to 48 hr or until the COI/PCA was discontinued. RESULTS: Ninety-two participants were enrolled in the study. The median [interquartile range] dose of naloxone administered to the NOSA participants was 0.37 [0.30-0.48] µg·kg(-1)·hr(-1). The incidence of OIP, determined by self-report and treatment, was not different between groups: 22% in the NOSA group vs 36% in the control group (mean difference, -15%; 95% confidence interval [CI], -33 to 4; P = 0.164). The severity of opioid-induced pruritus was similar in the two groups, with a median difference in the participants' mean mCAS score of -0.29 (95% CI, -0.75 to 0.26; P = 0.509). Opioid utilization did not differ between groups, with a median difference of -1.35 µg·kg(-1)·hr(-1) (95% CI, -5.85 to 7.55; P = 0.518), and pain scores did not differ, with a median difference of 0.0 (95% CI, -1.0 to 1.5; P = 0.659). CONCLUSION: This admixture of naloxone and morphine in normal saline did not decrease the incidence or severity of OIP in this sample. Separate administration of naloxone may be the more effective strategy for prevention of OIP. This trial was registered at ClinicalTrials.gov (NCT01071057).

Stability of epinephrine at standard concentrations.

BACKGROUND: To minimize medication errors, standard concentrations are recommended for medications intended for continuous infusion in pediatric patients. Premixing of epinephrine (commonly used to manage septic shock in children) would improve timeliness, safety, and cost-effectiveness. However, information about the stability of epinephrine at standard concentrations is limited. OBJECTIVES: To evaluate the stability of epinephrine in 5% dextrose in water at standard concentrations and to extend its expiration date after storage in infusion bags at 4°C and 25°C for up to 30 days. METHODS: A total of 6 infusion bags were prepared with 200 mL of epinephrine solution, 2 bags for each of 3 standard concentrations (25, 50, and 100 µg/mL). Three bags (one for each concentration) were stored under refrigeration (4°C), and the remaining 3 bags were stored at room temperature (25°C). Physical characteristics (including pH, colour, and presence of precipitate) were evaluated daily for the first 14 days and every 1 to 5 days thereafter until day 30. Three 1.5-mL samples were collected from each bag immediately after preparation (time 0), every 24 h (at 24 h, 48 h, 72 h, 96 h, etc.) for the first 14 days, and every 1 to 5 days thereafter until day 30. Each sample was analyzed by stability-indicating high-performance liquid chromatography. A solution was considered stable if it maintained at least 90% of its initial concentration. RESULTS: No notable changes in pH, colour, or precipitation were observed in any of the solutions after storage at 4°C or 25°C for up to 30 days. All formulations maintained more than 95% of the initial epinephrine concentration on day 30. In addition, the calculated lower limit of the 95% confidence interval indicated that 93% or more of the initial concentration remained on day 30. CONCLUSIONS: Preparations of epinephrine were stable for up to 30 days, with or without refrigeration. Because stability alone does not guarantee bioavailability or efficacy of a drug, future clinical studies are recommended to evaluate the pharmacokinetics and pharmacodynamics of these formulations.

CONTEXTE: Afin de réduire au maximum les erreurs de médication, il est recommandé d'utiliser des concentrations standards pour les médicaments administrés par perfusion continue aux enfants. La préparation préalable des solutions d'épinéphrine (couramment utilisée pour traiter le choc septique chez l'enfant) permettrait d'améliorer la rapidité d'action, la sécurité et le rapport coût-efficacité. Il existe malheureusement peu de données portant sur la stabilité de solutions d'épinéphrine de concentrations standards. OBJECTIFS: Évaluer la stabilité de l'épinéphrine de concentrations standards dans du dextrose à 5 % dans l'eau et augmenter la durée de conservation des solutions entreposées dans des sacs pour perfusion à 4 °C et à 25 °C jusqu'à 30 jours. MÉTHODES: Six sacs pour perfusion contenant 200 mL d'une solution d'épinéphrine ont été préparés, soit une paire de chacune des trois concentrations standards (25, 50 et 100 µg/mL). Trois sacs ont été conservés au réfrigérateur (4 °C) et les trois autres ont été entreposés à la température ambiante (25 °C). Les propriétés physiques (notamment le pH, la couleur et la présence de précipité) ont été évaluées quotidiennement les 14 premiers jours, puis à des intervalles de 1 à 5 jours jusqu'au jour 30. Trois échantillons de 1,5 mL ont été recueillis de chaque sac immédiatement après la préparation de la solution (temps 0), puis toutes les 24 heures (24 h, 48 h, 72 h, 96 h, etc.) pendant les 14 premiers jours et ensuite à des intervalles de 1 à 5 jours jusqu'à la fin de la période de 30 jours. Chaque échantillon a été analysé à l'aide d'une épreuve mesurant la stabilité par chromatographie liquide haute performance. Une solution était considérée comme stable si elle conservait au moins 90 % de sa concentration initiale. RÉSULTATS: Aucun précipité et aucun changement notable du pH ou de la couleur n'ont été observés dans l'ensemble des solutions après un entreposage à 4 °C ou à 25 °C d'une période de 30 jours. Toutes les préparations avaient conservé plus de 95 % des concentrations initiales d'épinéphrine au jour 30. De plus, la limite inférieure de l'intervalle de confiance à 95 % indiquait que les préparations avaient conservé 93 % ou plus de leurs concentrations initiales au jour 30. CONCLUSIONS: Les préparations d'épinéphrine sont demeurées stables pendant les 30 jours, qu'elles aient été réfrigérées ou non. Comme la stabilité seule ne garantit pas la biodisponibilité ou l'efficacité d'un médicament, d'autres études cliniques sont recommandées afin d'évaluer le comportement pharmacocinétique et pharmacodynamique de ces préparations. [Traduction par l'éditeur].

Standard-dose versus high-dose acyclovir in children treated empirically for encephalitis: a retrospective cohort study of its use and safety.

BACKGROUND: Intravenous acyclovir is the treatment of choice for herpes simplex virus encephalitis. In 2006, the American Academy of Pediatrics updated its dosing recommendations for children aged 3 months to 12 years to receive high-dose acyclovir (60 mg/kg/day). The association between acyclovir dose and toxicity is unclear. OBJECTIVE: The purpose of our study was to review our institution's experience with standard- and high-dose acyclovir for the empiric treatment of encephalitis. STUDY DESIGN, SETTING AND PATIENTS: This retrospective cohort study included patients aged 1 month to 18 years who received acyclovir as empiric treatment for encephalitis between 2005 and 2009 at a tertiary care children's hospital. We excluded patients with baseline renal impairment and those without serum creatinine measurements prior to and during treatment. MAIN OUTCOME MEASURE: The main outcome measure of this study was to compare the occurrence of renal injury or failure between children who received the standard- versus high-dose regimen. RESULTS: Sixty-one patients were included (n = 32 standard-dose; n = 29 high-dose). There was no statistical difference in change in serum creatinine from baseline between children who received standard- versus high-dose acyclovir (0 vs. 5.1 %; p = 0.79). One child in the standard-dose group and three children in the high-dose group developed renal injury or failure during treatment (3.1 vs. 10.3 %; p = 0.34). Children with renal injury or failure were older, had a longer length of stay, and longer duration of therapy than children without. CONCLUSIONS: The incidence of renal injury or failure was similar between children who received standard-dose and high-dose acyclovir.

Compatibility and stability of morphine sulphate and naloxone hydrochloride in 0.9% sodium chloride for injection.

BACKGROUND: Naloxone may be administered in conjunction with morphine to reduce the risk of opioid-induced pruritis. Combining these drugs for coadministration may be beneficial, but little is known about their physical compatibility and stability in combined solutions. OBJECTIVE: To describe the physical compatibility and stability of morphine sulphate and naloxone hydrochloride (at various concentrations) in IV admixtures. METHODS: The physical compatibility and stability of admixtures of morphine 1000 µg/mL and naloxone 4 µg/mL, 12.5 µg/mL, and 25 µg/mL in 0.9% sodium chloride were studied. For each concentration of naloxone, one bag was stored at room temperature (22°C) for 72 h and one bag was stored under refrigeration (4°C) for 30 days. For all preparations, physical characteristics, including pH, colour, and formation of precipitate, were evaluated. The samples were also analyzed by a stability-indicating high-performance liquid chromatographic method. Stability was defined as the retention of at least 90% of the initial concentration. RESULTS: No notable changes in pH or colour and no macroprecipitation were observed in any of the preparations after storage at 22°C for up to 72 h or at 4°C for up to 30 days. All preparations maintained more than 90% of the initial concentrations of morphine and naloxone at the end of the respective study periods. The calculated lower limit of the 95% confidence interval also indicated that 90% or more of the initial concentration remained at the end of each study period. CONCLUSION: Admixtures of morphine sulphate and naloxone hydrochloride were stable for 72 h at room temperature and for 30 days with refrigeration.

CONTEXTE: La naloxone peut être administrée en concomitance avec la morphine pour réduire le risque de prurit induit par les opioïdes. L'association de ces médicaments pour leur administration concomitante peut être bénéfique, mais on ne sait que peu de choses sur leur compatibilité physique et leur stabilité dans des solutions combinées. OBJECTIF: Décrire la compatibilité physique et la stabilité du sulfate de morphine et du chlorhydrate de naloxone (à diverses concentrations) mélangés dans des solutions pour administration i.v. MÉTHODES: La compatibilité physique et la stabilité des mélanges de morphine à 1000 µg/mL et de naloxone à 4 µg/mL, 12,5 µg/mL et 25 µg/mL dans du chlorure de sodium à 0,9 % ont été étudiées. Pour chaque concentration de naloxone, on a entreposé un sac à la température ambiante (22 °C) pendant 72 heures et un autre au réfrigérateur (4 °C) pendant 30 jours. Les propriétés physiques, notamment le pH, la couleur et la formation de précipité, ont été évaluées pour toutes les préparations. Les échantillons ont aussi été analysés à l'aide d'une épreuve validée mesurant la stabilité par chromatographie liquide haute performance. La stabilité a été définie comme étant la rétention d'au moins 90 % de la concentration initiale des agents. RÉSULTATS: Aucun changement notable du pH ou de la couleur et aucune formation de macroprécipité n'ont été observés dans l'ensemble des préparations qui ont été conservées à une température de 22 °C pendant un maximum de 72 heures ou à une température de 4 °C pendant un maximum de 30 jours. Toutes les préparations ont conservé plus de 90 % de leurs concentrations initiales de morphine et de naloxone à la fin de leurs périodes d'étude respectives. La limite inférieure de l'intervalle de confiance à 95 % indiquait également que 90 % ou plus de la concentration initiale subsistait à la fin de chaque période d'étude. CONCLUSION: Les mélanges de sulfate de morphine et de chlorhydrate de naloxone sont demeurés stables pendant 72 heures à la température ambiante et pendant 30 jours lorsqu'ils étaient réfrigérés. [Traduction par l'éditeur].

A systematic review of the pharmacokinetics of antiepileptic drugs in neonates with refractory seizures.

BACKGROUND: Neonatal seizures are associated with neurological sequelae and an increased risk of epilepsy later in life. Phenobarbital and phenytoin remain the antiepileptic drugs (AEDs) most commonly used to treat neonatal seizures, despite their suboptimal effectiveness and safety. As a result, other AEDs, such as levetiracetam and topiramate, are often used in neonates with refractory seizures, despite limited data and off-label use. OBJECTIVES: To systematically review published pharmacokinetic data for second-line AEDs used in neonates with seizures and to provide dosing recommendations for these agents in the neonatal population. METHODS: A literature search was conducted in PubMed (1949-May 2012), Medline (1950-May 2012), and Embase (1980-May 2012). Each study was ranked according to the quality of evidence it provided, based on the classification system developed by the US Preventive Services Task Force. Information extracted from each study included study design, number of subjects, gestational and postnatal age, AED dosage regimen, pharmacokinetic parameters, pharmacokinetic model, AED serum concentrations, and sampling times. RESULTS: Nineteen relevant pharmacokinetic studies involving a total of 8 different drugs were identified. No prospective, randomized, controlled studies (level I evidence) or nonrandomized controlled studies (level II-I evidence) were identified; 2 studies were prospective, nonrandomized, uncontrolled (cohort) studies (level II-2 evidence), 11 studies obtained evidence from multiple time series (level II-3 evidence), and 6 studies were case reports or descriptive studies (level III evidence). CONCLUSIONS: There are limited pharmacokinetic data for the use of carbamazepine, levetiracetam, lidocaine, paraldehyde, topiramate, valproic acid, and vigabatrin for neonates with seizures refractory to treatment with first-line antiepileptic agents. Further research is needed to elucidate target AED serum concentrations (if any) required to optimize effectiveness and minimize dose-related adverse effects in neonates.

Canadian survey of critical care pharmacists' views and involvement in clinical research.

BACKGROUND: The involvement of Canadian critical care pharmacists in clinical research is not well documented. OBJECTIVE: To describe the clinical research experience of Canadian critical care pharmacists, describe their views about clinical research, and identify factors that facilitate their involvement in clinical research. METHODS: A cross-sectional electronic survey of Canadian critical care pharmacists was developed through an iterative process and conducted from July to October 2010. We invited 325 pharmacists from 129 hospitals across Canada to participate. Surveys with more than 30% of questions unanswered were discarded. RESULTS: Analyzable response rate was 66.2%. Overall, 33 pharmacists (15.7%) were highly involved in research, 54 (25.7%) were moderately involved, and 123 (58.6%) were minimally involved. Most respondents (97.2%) believed that critical care pharmacist involvement in research was desirable, and many (80.4%) expressed interest to be more involved in research. Nearly all respondents (99.5%) agreed that more support should be provided to pharmacists interested in conducting research. Pharmacists currently involved in research have obtained higher academic degrees (adjusted OR 11.23; p < 0.001), express a strong interest in research (adjusted OR 7.44; p < 0.001), report a higher level of training for involvement in research (adjusted OR 2.23; p = 0.047), and practice more often in a university hospital (adjusted OR 3.68; p = 0.004) within an intensive care unit where involvement in research is valued (adjusted OR 5.61; p < 0.001). Support from pharmacy departments is not related to involvement in research (adjusted OR 1.22; p = 0.633). CONCLUSIONS: Canadian critical care pharmacists are involved to varying degrees in clinical research and are very interested in initiating and supporting research activities. Opportunities are present but significant barriers exist. The value of pharmacist-initiated research needs recognition as a priority within hospital pharmacy administration.

Use of methadone for prevention of opioid withdrawal in critically ill children.

BACKGROUND: Opioids are commonly administered to critically ill children for analgesia and sedation, but many patients experience opioid withdrawal upon discontinuation. The authors' institution developed a protocol for using methadone to prevent opioid withdrawal in children who have received morphine by continuous IV infusion for 5 days or longer in the pediatric intensive care unit (PICU). OBJECTIVES: The primary objectives were to determine if opioids were tapered according to the protocol and to determine the conversion ratio for IV morphine to oral methadone that was used. Secondary objectives were to describe the methadone dosage used and the clinical outcomes, to evaluate adjustments to methadone dosing, and to report the incidence of adverse effects. METHODS: A retrospective analysis of charts was conducted for pediatric patients who had received morphine by continuous IV infusion for 5 days or longer followed by methadone in the PICU between May 2008 and August 2009. Validated scoring systems (the Withdrawal Assessment Tool and the State Behavioral Scale) were used to assess symptoms of withdrawal and degree of sedation, respectively. RESULTS: Forty-three patients were included in the study, with median age of 8 months (range 0.25-201 months). For 31 patients (72%), the protocol was not used, and there were no patients for whom the protocol was followed to completion. The median duration of weaning was 10 days (range 0-91 days). The conversion ratio for IV morphine to oral methadone was 1:0.78 for anticipated 5-day weaning and 1:0.98 for anticipated 10-day weaning. During the first 10 days of weaning, 18 patients (42%) experienced withdrawal symptoms. The methadone dose was increased for 11 (26%) of the 43 patients. Patients were sedated for a median of 1 day (range 0-9 days), were comfortable for a median of 6.5 days (range 1-64 days), and were agitated for a median of 2.5 days (range 0-23 days). Naloxone was required for 2 patients. CONCLUSIONS: The institution's methadone protocol was not followed consistently during the study period, and practices for transitioning from morphine by continuous IV infusion to methadone with tapering were also inconsistent. Further studies are needed to determine the optimal conversion ratio for morphine to methadone and the optimal tapering regimen to minimize withdrawal symptoms and adverse events.

Pharmacokinetics and drug dosing in obese children.

OBJECTIVES: To review pharmacokinetics in obese children and to provide medication dosing recommendations. METHODS: EMBASE, MEDLINE, AND INTERNATIONAL PHARMACEUTICAL ABSTRACTS DATABASES WERE SEARCHED USING THE FOLLOWING TERMS: obesity, morbid obesity, overweight, pharmacokinetics, drug, dose, kidney function test, creatinine, pediatric, and child. RESULTS: We identified 10 studies in which the authors examined drug dosing or pharmacokinetics for obese children. No information was found for drug absorption or metabolism. Obese children have a higher percent fat mass and a lower percent lean mass compared with normal-weight children. Therefore, in obese children, the volume of distribution of lipophilic drugs is most likely higher, and that of hydrophilic drugs is most likely lower, than in normal-weight children. Serum creatinine concentrations are higher in obese than normal-weight children. Total body weight is an appropriate size descriptor for calculating doses of antineoplastics, cefazolin, and succinylcholine in obese children. Initial tobramycin doses may be determined using an adjusted body weight, although using total body weight in the context of monitoring serum tobramycin concentrations would also be an appropriate strategy. We found no information for any of the opioids; antibiotics such as penicillins, carbapenems, vancomycin, and linezolid; antifungals; cardiac drugs such as digoxin and amiodarone; corticosteroids; benzodiazepines; and anticonvulsants. In particular, we found no information about medications that are widely distributed to adipose tissue or that can accumulate there. CONCLUSIONS: The available data are limited because of the small numbers of participating children, study design, or both. The number and type of drugs that have been studied limit our understanding of the pharmacokinetics in obese children. In the absence of dosing information for obese children, it is important to consider the nature and severity of a child's illness, comorbidities, organ function, and side effects and physiochemical properties of the drug. Extrapolating from available adult data is possible, as long as practitioners consider the effects of growth and development on the pharmacokinetics relevant to the child's age.

Comparison of Continuous and Intermittent IV Infusion of Vancomycin: Systematic Review.

BACKGROUND: There is some evidence that administration of vancomycin by continuous infusion has pharmacokinetic and pharmacodynamic advantages over traditional intermittent dosing. Whether these advantages translate into clinical efficacy remains controversial. OBJECTIVE: To review the literature comparing continuous infusion of vancomycin and conventional intermittent IV dosing in terms of efficacy and safety. METHODS: A literature search was conducted in the PubMed/MEDLINE and Embase databases and the Cochrane Central Register of Controlled Trials, and by means of the Google search engine, and the reference lists of pertinent articles were searched manually. All human studies published in English or French that evaluated vancomycin given by continuous and intermittent IV infusion were reviewed. Articles that did not include a comparator arm and those that assessed continuous and intermittent intraperitoneal infusions were excluded. The level of evidence of each study was categorized according to the US Preventive Services Task Force rating scale. RESULTS: In total, 9 studies were identified: 1 in a pediatric population and 8 in adult populations. Of the 3 studies with the highest quality of evidence (level I), one demonstrated pharmacodynamic advantages with continuous infusion of vancomycin. Of the 6 studies representing a moderate level of evidence (level II), 3 also favoured continuous infusion in terms of pharmacokinetic and pharmacodynamic outcomes, but the findings in terms of clinical outcomes were mixed. CONCLUSIONS: Current evidence evaluating the pharmacokinetic and pharmacodynamic advantages and clinical efficacy of continuous versus intermittent vancomycin infusions is inconsistent and does not support the routine use of continuous infusion for the treatment of multidrug-resistant gram-positive infections.

Complementary and alternative medicine for upper-respiratory-tract infection in children.

PURPOSE: Evidence on the efficacy and safety of complementary and alternative medicine (CAM) for the prevention and treatment of upper-respiratory-tract infection (URTI) in children is reviewed. SUMMARY: A search of the literature to June 2005 identified six clinical trials examining the use of herbal medicines and nine trials of other CAM therapies. All articles were critically evaluated for adherence to standards of efficacy and safety research. Echinacea did not reduce the duration and severity of URTI. Andrographis paniculata or echinacea decreased nasal secretions (p < 0.01) but not URTI symptoms. A combination of echinacea, propolis, and ascorbic acid decreased the number of URTI episodes, the duration of symptoms, and the number of days of illness (p < 0.001). Echinacea was associated with a higher frequency of rash compared with placebo (p = 0.008). Neither ascorbic acid nor homeopathy was effective. The efficacy of zinc was not clear, and zinc may be associated with adverse effects in children. Osteopathic manipulation decreased episodes of acute otitis media (p = 0.04) and the need for tympanostomy tube insertion (p = 0.03) in children with recurrent acute otitis media. Stress-management therapy reduced the duration of URTI compared with relaxation therapy with guided imagery or standard care (p < 0.05). CONCLUSION: Current data are generally inadequate to support CAM for the prevention or treatment of URTI in children.

Assessing the guidelines for potassium replacement in pediatric oncology patients receiving amphotericin B.

OBJECTIVE: To examine the practice of potassium chloride (KCl) replacement in pediatric oncology patients receiving amphotericin B (amp-B). METHODS: A retrospective observational chart review was conducted of patients who received amp-B on the oncology unit between August 2000 and May 2001. A survey was distributed to pediatric oncology pharmacists at other pediatric institutions to assess KCl infusion guidelines across North America. RESULTS: Twenty hypokalemic episodes were identified within 22 patient admissions. Fifty-five percent used KCl replacement (by all combined routes) at rates exceeding the institution's guidelines. Other pediatric institutions varied with respect to the maximum rates and concentration of KCl permitted on non-intensive care units. CONCLUSIONS: Based on the data from this review, the KCl administration guidelines for our hospital were changed. We now allow a maximum peripheral line concentration of 60 mEq/L, a maximum central line concentration of 120 mEq/L and a maximum KCl infusion rate of 0.4 mEq/kg/hr without the requirement of a heart monitor. Parenteral Nutrition is now restricted to maximum potassium concentration of 80 mEq/L and fluid-restricted patients are restricted to a maximum concentration of 150 mEq/L.

Azithromycin for improving pulmonary function in cystic fibrosis.

OBJECTIVE: To review the literature concerning the use of azithromycin in the treatment of patients with cystic fibrosis (CF). DATA SOURCES: A search of MEDLINE (1966-April 2004), Embase (1980-April 2004), and International Pharmaceutical Abstracts (1971-April 2004) was performed. Search terms included cystic fibrosis, macrolide, and azithromycin. DATA SYNTHESIS: Four studies have been performed in 7-185 patients (children and adults) over a 3- to 6-month period. The azithromycin dosage ranged from 250 mg 3 times weekly to 500 mg daily. The trials reported an improvement in percent predicted forced expiratory volume ranging from 2.95% to 6.2% in patients treated with azithromycin compared with those receiving placebo. CONCLUSIONS: Azithromycin appeared to improve pulmonary function in adults and older children with CF and was well tolerated when administered for 6 months. Further research is needed to determine an optimal dosage regimen, duration of treatment, effects on quality of life, and cost-effectiveness of azithromycin therapy.

Drug disposition and therapy in adolescence: the effects of puberty.

Puberty, a part of adolescence, is a time of rapid physical, psychological, and psychosocial changes. Variability in drug absorption, distribution, metabolism and excretion occurs due to physical and hormonal changes, as well as those of body composition. Environmental factors affecting nutrition and compliance in the pubescent individual also affect success in achieving desired pharmacologic effects while minimizing toxicities. Based on available data, pharmacologic research has been relatively inadequate in providing information about drug disposition during puberty. The majority of available studies have neglected to provide staging for pubescent adolescents or have altogether excluded this population from their investigations. However, data are available that describe the effects of puberty on the pharmacokinetics of agents such as theophylline, digoxin, carbamazepine, lamotragine, vigabatrin and benzodiazepines.To date, few clinically significant changes in drug disposition have been noted during puberty. However, factors such as compliance, concomitant drug use, and the potentially rebellious nature of adolescents must be taken into consideration in the medical management of the adolescent.

Fluoxetine in the treatment of premenstrual dysphoric disorder.

OBJECTIVE: To examine the role of fluoxetine in the treatment of premenstrual dysphoric disorder (PMDD). DATA SOURCES: Search strategy included MEDLINE (1966-February 2002), Embase (1988-February 2002), HealthStar (1975-December 2000), Current Contents (1996-November 2001), and Copernic (November 2001). Search terms included fluoxetine, premenstrual dysphoric disorder, PMDD, late luteal-phase dysphoric disorder, and severe premenstrual syndrome. STUDY SELECTION: English-language human studies were selected and evaluated based on quality of evidence. DATA SYNTHESIS: Eight prospective trials (3 double-blind, placebo-controlled, crossover; 3 double-blind, randomized, controlled; 2 open-label), 1 case series, and 1 meta-analysis were identified. Although 6 of the studies involved small sample sizes (n < 50), all found fluoxetine to be effective in the treatment of PMDD. CONCLUSIONS: Despite limited data, fluoxetine 20 mg/d appears to be effective in the treatment of PMDD. However, adverse effects, particularly headaches and sexual dysfunction, are possible. Given the long half-life of fluoxetine and the short duration of PMDD symptoms per cycle, larger, well-designed clinical trials evaluating intermittent dosing for only 1 week or a few doses need to be performed.