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Objective:To describe the pharmacology, efficacy, and safety of stiripentol in the treatment of refractory seizures in patients with Dravet syndrome. Data Sources:A search of the English language literature was conducted using PubMed and MEDLINE (1978 to April 2019) with the search terms stiripentol, Dravet syndrome, and refractory epilepsy. Other resources included article bibliographies, prescribing information, and relevant trials at https://clinicaltrials.gov/. Study Selection and Data Extraction:All phase 1, 2, or 3 trials; observational studies; and retrospective studies were analyzed. Data Synthesis: In controlled studies, stiripentol has been shown to reduce seizure frequency by 50% or more in 40% to 70% of patients with Dravet syndrome. Reductions in seizure duration and episodes of status epilepticus have also been documented. Common adverse effects include somnolence and anorexia. Stiripentol inhibits the metabolism of clobazam and valproate, often requiring dose adjustment. Relevance to Patient Care and Clinical Practice:Stiripentol, a direct allosteric modulator of GABAAreceptors, offers a novel approach to treatment in patients with Dravet syndrome, both with and without pathogenic variants of the sodium channel α-1 subunit gene, and potentially other refractory seizures. Although available outside the United States for a decade, it was only recently approved by the Food and Drug Administration for patients 2 years of age and older with Dravet syndrome taking clobazam. Conclusions:Stiripentol is an effective adjunctive therapy for reducing the frequency and duration of refractory seizures in patients with Dravet syndrome. Its role in the treatment of other refractory epilepsies requires further study.

Objective: To review and assess the available literature on the use of intraosseous (IO) drug administration during cardiopulmonary resuscitation, addressing the benefits and risks of using this method of drug delivery in children and adults.Data Sources: The MEDLINE (1950–July 2007) database was searched for pertinent abstracts, using the key term intraosseous infusions. Additional references were obtained from the bibliographies of the articles reviewed. Manufacturer Web sites were used to obtain information about IO insertion devices.Study Selection and Data Extraction: All available English-language clinical trials, retrospective studies, and review articles describing IO drug administration were reviewed. Studies conducted in animal models to evaluate the effectiveness and safety of IO drug administration were also included.Data Synthesis: IO access uses the highly vascularized bone marrow to deliver fluids and medications during cardiopulmonary resuscitation. This route, developed in the 1940s, has been revived In the past decade as a means of achieving rapid vascular access when intravenous access cannot be obtained. The primary advantage of IO access is the high success rate (approximately 80%). Most trained providers can place an IO line within 1–2 minutes. A number of small-scale studies and retrospective reviews have established the usefulness of this route for the delivery of many commonly used resuscitation drugs. In addition, animal models have demonstrated rapid drug delivery to the systemic circulation. While all resuscitation drugs can be given by the IO route, administration of ceftriaxone, chloramphenicol, Phenytoin, tobramycin, and vancomycin may result in lower peak serum concentrations. The most common adverse effect seen with IO use, extravasation, has been reported in 12% of patients. Compartment syndrome, osteomyelitis, and tibial fracture are rare, but have also been reported.Conclusions: IO administration is a safe and effective method for delivering drugs during cardiopulmonary resuscitation. It should be considered whenever intravenous access cannot be rapidly obtained.

BACKGROUND: In 2003, the Food and Drug Administration placed spironolactone on its list of drugs needing pediatric studies.OBJECTIVE: To describe the use of spironolactone in a large group of children and evaluate its safety, focusing on its effects on potassium.METHODS: A prospective observational study was conducted. Patient demographic information was collected, as well as dosing regimens, use of other medications, and potassium concentrations. Patients were grouped by diagnosis. Comparisons were made with unpaired t-tests.RESULTS: One hundred consecutive patients were evaluated. The average age was 20.8 months and weight was 9.5 kg. Sixty-two patients had heart disease (HD), 29 had chronic lung disease (CLD), and 9 had other conditions. The initial dose was 1.8 ± 0.7 mg/kg/day. Patients with CLD received a higher dose than those with HD (2 ± 0.8 vs 1.7 ± 0.5 mg/kg/day; p = 0.04). Sixty-six patients received furosemide and 37 received thiazides (12 received both). The average potassium concentration after initiation was 4.3 ± 0.8 mEq/L, with higher values in patients with CLD versus HD (4.7 ± 0.7 vs 4.2 ± 0.7 mEq/L; p = 0.007). Twenty-six patients required potassium supplementation, including 16 with CLD and 8 with HD; no other adverse effects were noted. Average length of treatment was 16 days, with a length of stay of 38 days. Of the 92 patients surviving to discharge, 66 continued on spironolactone.CONCLUSIONS: This sample demonstrates that spironolactone is a common component of diuretic regimens in pediatric patients. The only adverse effects were alterations in potassium. While hyperkalemia was more common initially, hypokalemia was more frequent with long-term use. Potassium concentrations should be carefully monitored, particularly in children receiving multiple diuretics. Additional research is needed to define the pharmacokinetics and optimal dosing interval of spironolactone, as well as determine its long-term effects on potassium.

OBJECTIVE: To report a case of anaphylaxis due to propofol in a child with allergies to egg and peanut oil.CASE SUMMARY: A 14-month-old boy with a history of reactive airway disease was hospitalized for treatment of respiratory symptoms. The patient had documented allergies to egg, peanut oil, and mold. Within the first few hours after admission, acute respiratory decompensation occurred, and arrangements were made to transfer the patient to our tertiary-care hospital. Prior to transfer, he was emergently intubated under sedation and paralysis with propofol and rocuronium. When emergency air transport arrived, the patient was hypotensive and tachycardic. His symptoms of anaphylaxis were managed throughout the flight and, upon arrival at our institution, the patient was admitted to the Pediatric Intensive Care Unit. He improved over a 5-day hospital course, and his caregivers were instructed to avoid propofol in the future. The patient's anaphylactic reaction following propofol was rated as a possible adverse drug reaction using the Naranjo probability scale.DISCUSSION: The use of propofol in pediatric patients for procedural sedation has gained increased favor. Since the propofol formulation contains both egg lecithin and soybean oil, its use is contraindicated in patients with hypersensitivities to these components. Several other drugs have a food component, resulting in contraindications and warnings in product labeling.CONCLUSIONS: Propofol should be avoided in patients with allergies to egg and/or soybean oil, if possible. Clinicians should consider the potential for adverse drug events in patients with select food allergies.

OBJECTIVE: To describe the dosing and pharmacokinetics of phenobarbital in a neonate receiving extracorporeal membrane oxygenation (ECMO).CASE SUMMARY: The treatment of a 2.6 kg, 38-week gestational age boy with congenital diaphragmatic hernia who developed seizures while receiving ECMO support is described. A loading dose of 20 mg/kg resulted in concentrations of 16.4 and 12.9 μg/mL at 3 and 24 hours, respectively. A maintenance dose of 5 mg/kg/d provided a peak concentration of 19.7 μg/mL and trough concentration of 16.7 μg/mL after four doses. The calculated volume of distribution was 1.2 L/kg and the estimated elimination half-life was 92 hours. Serum concentrations decreased after circuit changes unless the new circuit was redosed.DISCUSSION: The reported incidence of seizures in neonates while receiving ECMO support is 18%. Despite this frequency, there are no clinical reports describing anticonvulsant use in this population. This case demonstrates the use of standard phenobarbital doses to achieve low, but therapeutic, serum concentrations. Pharmacokinetic analysis revealed a volume of distribution slightly larger than expected in neonates and an elimination half-life similar to published values. Altering circulating blood volumes resulted in significant reductions in serum concentrations.CONCLUSIONS: Neonates on ECMO may have a larger volume of distribution than neonates not receiving ECMO and may require larger phenobarbital doses to achieve desired serum concentrations. This may result from the presence of large exogenous blood volumes for priming, as well as loss of drug during circuit changes, extraction by the circuit, or hemofiltration. Further work is needed to better define the pharmacokinetics and pharmacodynamics of phenobarbital in the neonatal ECMO population.

OBJECTIVE: To review the literature and provide recommendations for the development and dissemination of written medication information to patients and their care providers.DATA SOURCES: A MEDLINE search (1966–1997) of the English-language literature was performed to identify articles pertaining to the development or use of written medication information. A search of the Internet was conducted by using Yahoo as the guide and “medication information” as the search term. Additional resources were obtained through texts, bibliographies, and catalogs from medical publishers.DATA EXTRACTION: Reports documenting the creation and use of written medication information systems were reviewed, as well as studies of readability and reading skills assessment. Examples of materials available for purchase by laypeople and healthcare providers were also examined.DATA SYNTHESIS: Current statistics support the widespread availability of written medication information for patients and care providers. The goal set forth by the Food and Drug Administration of having 75% of patients receive written information by the year 2000 appears achievable. However, there are still many issues to address. Content is not standardized, and materials are frequently written at reading levels higher than that of the average patient. The development and use of resources requiring only minimal reading skills and an increase in the availability of materials written in Spanish are needed.CONCLUSIONS: Written medication information provides a useful addition to counseling by healthcare professionals. A wide variety of prepared materials is available, as well as resources for those interested in developing tools for a specific patient, population, or setting. Healthcare professionals should be aware of the limitations of some resources. Content and readability must be appropriate for the intended audience for these tools to serve a useful role in patient education.

OBJECTIVE: TO provide a comprehensive review of warfarin use in infants and children, including recommendations for appropriate dosage and monitoring parameters.DATA SOURCES: A MEDLINE search (1966-1995) was used to identify pertinent English-language articles in the medical literature. The key search term was warfarin. Additional material was obtained from references cited in articles retrieved through MEDLINE.STUDY SELECTION: All articles involving children younger than 18 years were evaluated. In addition, articles on the pharmacokinetics and pharmacodynamics in adults, adverse effects, and drug interactions were included.DATA EXTRACTION: Material selected for review included clinical trials, case reports, and surveys of practice.DATA SYNTHESIS: Warfarin has been used as prophylactic therapy in children with prosthetic cardiac valves as well as for prevention of thromboembolic complications associated with autoimmune disorders and protein C or protein S deficiency. Warfarin also has been used to prevent embolization in children with deep-vein thrombosis or clots in central venous catheters. According to the literature, an initial dosage of 0.1 mg/kg/d should provide anticoagulation without significant adverse effects. As in adults, dosing should be adjusted to achieve a target international normalized ratio (INR). Although the target range in children is not well established, INR values of 1.5–3 are recommended for most patients. Higher values have been used in children with prosthetic cardiac valves and hereditary clotting disorders.CONCLUSIONS: Due to its infrequent use, there is limited information on the effects of warfarin in children. Basic guidelines for initiating and monitoring warfarin were developed by using data gathered from clinical trials, retrospective reviews, case series, and surveys of practice.

A two-month-old white girl presented to our facility with increasing lethargy and new onset apnea and bradycardia following a week of upper respiratory tract infection symptoms. The patient had been receiving a cough syrup containing promethazine hydrochloride during the previous five days, which was temporally correlated with the onset of lethargy and apneic episodes. Upon further investigation, it was discovered that the patient's older sibling also may have experienced phenothiazine-associated apnea after receiving a combination of meperidine hydrochloride, promethazine hydrochloride, and chlorpromazine as a premedication prior to an endoscopic examination. In addition to the presentation of these cases, the literature pertaining to phenothiazine-associated apnea is reviewed.

OBJECTIVE: To describe the use of parenteral ketorolac in a large population of children, focusing on dosing patterns, efficacy, and safety.DESIGN: Observational, prospective study conducted over a four-month period.SETTING: A 122-bed children's medical center located within an academic medical center hospital.PARTICIPANTS: Children receiving ketorolac during their hospitalization.MAIN OUTCOME PARAMETERS: Indications for treatment, dose, dosing interval, use of a loading dose, length of therapy, efficacy (subjective response and use of concomitant therapy), and adverse effects (bleeding, gastrointestinal ulceration or vomiting, and renal dysfunction).RESULTS: Of 112 children evaluated, 110 received ketorolac for analgesia, and 2 were given ketorolac as an antipyretic. The children ranged in age from 6 months to 19 years. Doses of 0.5 mg/kg q6h were used for most children (range 0.17–1.0). The average length of therapy was 3.4 days (range 1–12). The most frequent reason for discontinuing ketorolac therapy was a change to oral therapy. Therapy was discontinued because of a lack of efficacy in only 2 children. Adverse reactions were unusual, with only 2 patients having bleeding potentially associated with ketorolac use.CONCLUSIONS: Ketorolac appears to be a safe and effective therapy for children when given in appropriate doses for a limited duration.

Prostaglandin E1(PGE1) is used to maintain the patency of the ductus arteriosus in neonates when it is necessary to circumvent a defect in the heart or aorta in order to provide adequate peripheral perfusion. It has recently been recommended that medical stabilization with PGE1be done as soon as a ductus-dependent cardiac defect is suspected, preferably prior to transport of the infant to a tertiary care center for surgical repair of the defect. To accomplish this, hospitals providing obstetric services will need to maintain a supply of PGE1. This commentary provides guidelines for determining the need to stock PGE1and presents a brief review of the physiology of the ductus arteriosus and the pharmacology and adverse effects of PGE1therapy.

OBJECTIVE: To report the occurrence of vesicular lesions on the skin of a child receiving intravenous acyclovir therapy.CASE SUMMARY: A 12-year-old boy with presumed herpes simplex encephalitis developed cutaneous vesicular lesions following intravenous acyclovir administration. The lesions were initially thought to be herpetic. Further evaluation of the vesicle fluid and the temporal relationship of the development of the lesions with acyclovir administration led to the conclusion that the reaction was drug induced.DISCUSSION: Although inflammation and phlebitis are fairly common after acyclovir infusion, the development of vesicular lesions appears to be rare. Only two cases, both in adults, have been published in the medical literature. Although several theories have been proposed, including hypersensitivity, local drug toxicity, and tissue damage associated with extravasation, the mechanism of this reaction remains unclear.CONCLUSIONS: Vesicular eruption is a rare adverse reaction in patients receiving acyclovir. Careful evaluation is necessary to differentiate this reaction from herpetic lesions.