Sandra S. Garner

Esmolol for the management of pediatric hypertension after cardiac operations

OBJECTIVE Hypertension frequently occurs during the immediate postoperative period in children after repair of aortic coarctation but may also occur after repair of other congenital heart defects. Nitroprusside has often been used to control blood pressure in this setting. Because hypertension after coarctation repair is frequently associated with elevations in catecholamines, esmolol, a short-acting beta-blocking agent, may be an effective alternative. Therefore we undertook the first systematic investigation to determine the efficacy and disposition of esmolol in pediatric patients with acute hypertension after cardiac operations. METHODS Twenty patients aged 1 month to 12 years (median 25.6 months) with acute hypertension after cardiac operations received esmolol in an opened-labeled trial. Esmolol was titrated to a blood pressure less than or equal to the 90th percentile for age. RESULTS Ten patients had coarctation repair and the remaining patients underwent repair of other congenital heart defects. On final esmolol dose (mean +/- standard deviation dosage 700 +/- 232 microg/kg/min) there was a significant percent decrease in heart rate and systolic and diastolic blood pressures from postoperative values. Esmolol dose was significantly associated with percent reduction in systolic blood pressure. Final esmolol dose and total body clearance were significantly higher in patients after coarctation repair. There were significant associations between esmolol dose and esmolol blood concentrations at steady state. CONCLUSIONS The dosage required to control hypertension in patients after repair of aortic coarctation was higher than patients who underwent repair of other congenital heart defects. Esmolol was effective in controlling blood pressure in 19 of 20 patients without adverse effects.

Effect of Helium-Oxygen on Delivery of Albuterol in a Pediatric, Volume-Cycled, Ventilated Lung Model

Pulmonary delivery of inhaled bronchodilators in mechanically ventilated patients is inefficient whether administered by metered‐dose inhaler (MDI) or small‐volume nebulizer. One of the factors that causes inefficient aerosol delivery is turbulent gas. Heliox (He:O2) is a blend of helium and oxygen that is less dense than air, making turbulent flow less likely. We assessed the effect of 70% He:O2 on albuterol delivery in a mechanically ventilated pediatric lung model. Albuterol was administered by MDI with spacer, collected on a filter proximal to a test lung, and measured by high‐performance liquid chromatography. Mean amount and percentage albuterol delivered were significantly (p<0.05) greater for 70% He:O2 (395 ± 29 μg, 20 ± 3.2%) than for 70% nitrogen:30% oxygen (241 ± 29 μg, 12 ± 1.7%). Thus 70% He:O2 can increase the amount of albuterol delivered at the end of the endotracheal tube, suggesting a potential role for it in the care of critically ill ventilated patients.

Albuterol Delivery by Metered-Dose Inhaler With a Pediatric Mechanical Ventilatory Circuit Model

Study Objective. To determine albuterol delivery by metered‐dose inhaler (MDI) in an in vitro pediatric mechanical ventilatory circuit model. The influence of a spacing device, endotracheal tube (ETT) diameter and length, and air humidity was also investigated.

Pharmacokinetics of esmolol in children

The pharmacokinetics and concentration‐response relationships of intravenous esmolol were investigated in 20 children undergoing indicated cardiac electrophysiologic testing. A loading dose of 600 μg/kg was infused for 2 minutes. An infusion of esmolol was initiated and dosage was titrated until β‐blockade occurred. Serial esmolol blood samples were obtained for pharmacokinetic analysis. Noncompartmental pharmacokinetic analysis of the data revealed the following parameter estimates (mean ± SD): volume of distribution at steady state, 2.0 ± 1.4 L/kg; total body clearance, 321.2 ± 238.8 ml/kg/min; and terminal elimination half‐life, 4.5 ±2.1 minutes. There was a significant correlation between mean esmolol concentrations and mean percentage of reductions of mean arterial pressures and heart rates at each sample time (p < 0.001). The doses of esmolol required for β‐blockade (mean ± SD, 535 ± 180 μg/kg/min) in children were considerably higher than those typically used in adults. Esmolol should prove useful in children in the acute management of cardiac arrhythmias and hypertension.

Gabapentin Therapy for Pain and Irritability in a Neurologically Impaired Infant

Gabapentin is a γ‐aminobutyric acid analog used for numerous neurologic conditions, including neuropathic pain and epilepsy. We describe a 39‐week gestational age, male infant with hypotonicity, functional short gut, and microduplication of chromosome 22 who was treated with gabapentin to control pain and irritability. During his hospitalization, the infant experienced multiple complications including respiratory distress, persistent pulmonary hypertension of the newborn, hypocalcemia, hypoglycemia, hyperbilirubinemia, gastroesophageal reflux, necrotizing enterocolitis, and cholestatic jaundice. Pain associated with related invasive procedures and surgeries was treated with intermittent and scheduled morphine. In addition to postoperative and procedural pain, the infant continued to experience pain and irritability attributed to neurologic impairment, presumably secondary to his chromosomal abnormality. Trials of scheduled lorazepam along with intermittent morphine and phenobarbital were unsuccessful in managing these symptoms. After failure of nonpharmacologic treatment and continued trials of sedatives and analgesics, gabapentin 5 mg/kg at bedtime was started on day of life 98. Improvement in the infants tone and disposition was noted by numerous health care professionals and the infants mother. In addition, the infants pain scores, using the Pain Assessment in Neonates Scale, showed marked improvement. The infant continued to receive gabapentin; the dosage was increased to 10 mg/kg at bedtime after 6 days, then to 5 mg/kg in the morning and 10 mg/kg at bedtime 10 days later. When the infant was 7 months old, his mother requested that gabapentin be discontinued. He was slowly weaned, and the drug was discontinued when he was 11 months old. The infant tolerated gabapentin well except for experiencing nystagmus, which was noted 31 days after starting the drug and resolved after drug discontinuation. Clinicians should be aware of gabapentin as an alternative treatment for pain and irritability in neurologically impaired infants. Further study is needed, however, to verify the drugs safety and efficacy in neonates and infants. Standardized pain scales along with close patient monitoring will help to guide clinicians in dosage titration to optimize therapy.

Effect of Heliox on Albuterol Delivery by Metered‐Dose Inhaler in Pediatric In Vitro Models of Mechanical Ventilation

Study Objective. To determine the effect of varying concentrations of heliox, a mixture of helium and oxygen, on albuterol delivery administered by metered‐dose inhaler (MDI) in pediatric mechanically ventilated models.

Antibiotic timing in neonates with suspected hospital-acquired infections.

There exists general agreement within neonatology that antibiotics should be administered promptly to neonates with possible bacterial sepsis and meningitis. We initiated a series of quality improvement cycles designed to reduce delays in the initiation of antibiotic therapy to less than 2 hours when hospital-acquired infection (HAI) was suspected. All infants in this study were in neonatal intensive care (level II or III) who were started on antibiotics for a suspected HAI (defined as an infection that occurred 72 hours after admission to the NICU) were audited. Through a series of quality improvement cycles, we analyzed sources of delays in the initiation of antibiotic therapy from the time the order was written through administration. In subsequent cycles, we intervened to reduce delays through education, standardize the evaluation process, and develop an online ordering system that streamlined the workflow patterns in the nurseries and pharmacy. Using a prospective cohort design, we compared antibiotic delivery times after each process improvement cycle. Antibiotic delivery time was reduced from a median of 137.5 minutes to 75 minutes and variation of practice was reduced in terms of standard deviation and range (P < .001). The use of computerized physician order entry significantly improved the writing of STAT orders (P < .0001). A systematic analysis of workflow patterns and efficiencies, coupled with improvement cycles targeting delays and development of a computerized physician order entry system, allowed us to improve antibiotic delivery time in neonates with suspected HAI in an intensive care nursery system.

Pregnant Yucatan Miniature Swine as a Model for Investigating Fetal Drug Therapy

Initially it was felt that during maternal drug therapy the placenta served as a protective barrier preventing fetal exposure. This concept was invalidated as a result of the thalidomide tragedy in the early 1960s. Maternal thalidomide use in the first trimester of pregnancy resulted in approximately 7,000 limb anomalies, with or without gastrointestinal or cardiac malformations.1 As a result of this disaster, research was focused on toxicologic and teratogenic effects of drugs on the fetus. Despite 3 decades of research, approximately 20 drugs and chemicals, e.g., isotretinoin, valproic acid, phenytoin, polychlorinated biphenyls, have been confirmed to be teratogenic. Most drugs, when used appropriately, do not pose a threat to the fetus.2 In the 1970s, therapeutic benefits started to be recognized in the pharmacologic management of fetal disorders. The discovery inspiring research in this area was the observation that maternal beclomethasone administration enhanced fetal lung maturity decreasing the incidence of neonatal respiratory distress syndrome.3 Considerable data have accumulated to indicate that nearly all maternally administered drugs enter the fetal circulation and may exert pharmacologic effects on the fetus. These observations have led to the increasing use of the maternal route of drug administration to manage the compromised fetus. Pharmacologic management has extended into the treatment of fetal arrhythmias4, toxoplasmosis5, congenital adrenal hyperplasia6 and preventing vertical transmission of HIV during pregnancy.7 We will discuss factors that influence the kinetics of drug transfer to the fetus, pharmacologic management of fetal tachyarrhythmias and the application of pregnant Yucatan miniature swine as a model for investigating fetal antiarrhythmic drug therapy.

Research in Women and Special Populations

The American College of Clinical Pharmacy charged a Task Force on Research in Special Populations to review, update, and broaden its 1993 White Paper on Women as Research Subjects. Participants of the task force included pharmacy clinicians and investigators in the field. This resulting White Paper, Research in Women and Special Populations, discusses the current concepts regarding the conduct of research in women, as well as in special populations such as children, elderly, minorities, cognitively impaired, and other vulnerable populations (e.g., prisoners and refugees). For each specific population, the barriers to research participation, current guidelines and regulations, and available recommendations to address these barriers are discussed. The participation in research by these populations requires addressing special social and ethical challenges. Clinical pharmacy researchers should be cognizant of these guidelines and be an advocate for the inclusion and the rights of women and special populations in research participation.

Evaluating the Potential Severity of Look-Alike, Sound-Alike Drug Substitution Errors in Children

OBJECTIVE Look-alike, sound-alike (LASA) drug name substitution errors in children may pose potentially severe consequences. Our objective was to determine the degree of potential harm pediatricians ascribe to specific ambulatory LASA drug substitution errors. METHODS We developed a unified list of LASA pairs from published sources, removing selected drugs on the basis of preparation type (eg, injectable drugs). Using a modified Delphi method over 3 rounds, 38 practicing pediatricians estimated degree of potential harm that might occur should a patient receive the delivered drug in error and the degree of potential harm that might occur from not receiving the intended drug. RESULTS We identified 3550 published LASA drug pairs. A total of 1834 pairs were retained for the Delphi surveys, and 608 drug pairs were retained for round 3. Final scoring demonstrated that participants were able to identify pairs where the substitutions represented high risk of harm for receiving the delivered drug in error (eg, did not receive methylphenidate/received methadone), high risk of harm for not receiving the intended drug (eg, did not receive furosemide/received fosinopril), and pairs where the potential harm was high from not receiving the intended drug and from erroneously receiving the delivered drug (eg, did not receive albuterol/received labetalol). CONCLUSIONS Pediatricians have identified LASA drug substitutions that pose a high potential risk of harm to children. These results will allow future efforts to prioritize pediatric LASA errors that can be screened prospectively in outpatient pharmacies.