Two administration methods for inhaled salbutamol in intubated patients.

AIMS: To compare serum concentrations and effects on respiratory mechanics and haemodynamics of salbutamol administered by small volume nebuliser (SVN) and metered dose inhaler (MDI) plus spacer. METHODS: Blinded, randomised, crossover study in 12 intubated infants and children (mean age 17.8 months) receiving inhaled salbutamol therapy. Subjects received salbutamol as 0.15 mg/kg by SVN and four puffs (400 microg) by MDI plus spacer at a four hour interval in random order. Passive respiratory mechanics were measured by a single breath/single occlusion technique, and serum salbutamol concentrations by liquid chromatography-mass spectrometry at 30 minutes, 1, 2, and 4 hours after each dose. Haemodynamics (heart rate and blood pressure) were recorded at each measurement time. RESULTS: There was no difference in percentage change in respiratory mechanics or haemodynamics between the two methods of administration. Mean area under the curve (AUC(0-4)) was 5.86 for MDI plus spacer versus 4.93 ng/ml x h for SVN. CONCLUSIONS: Serum concentrations and effects on respiratory mechanics and haemodynamics of salbutamol were comparable with the two administration methods under the conditions studied. Future studies are needed to determine the most effective and safe combination of dose and administration method of inhaled salbutamol in mechanically ventilated infants and children.

Albuterol delivery by metered-dose inhaler in a pediatric high-frequency oscillatory ventilation model.

OBJECTIVES: To assess albuterol delivery by metered-dose inhaler (MDI) in a pediatric lung model ventilated by high-frequency oscillatory ventilation (HFOV). The percentage albuterol dose lost in the circuit's expiratory limb and the effects of operating frequency, inspiratory time, and use of a spacer were also determined. DESIGN: Prospective in vitro laboratory study. SETTING: Research laboratory. INTERVENTIONS: A model consisting of a HFOV and circuit, 4.5-mm endotracheal tube, and lung simulator was assembled. Ventilator settings were the following: humidified FIO2 of 1.0; mean airway pressure of 28 cm H2O; operating frequency of 10 Hz; pressure amplitude of 55 cm H2O; bias gas flow to maintain mean airway pressure; 30% inspiratory time; and temperature of 35 degrees C (95 degrees F). Lung simulator compliance and resistance values were consistent with pediatric patients with pulmonary disease. A total of ten MDI canisters were used to administer 2000 microg of albuterol with a spacer. Circuit filters placed proximal to the lung simulator and in the circuit's expiratory limb collected albuterol exiting the endotracheal tube and any albuterol lost, respectively. Filters were rinsed with water and albuterol concentrations determined by high performance liquid chromatography. Albuterol administration was repeated at operating frequencies of 5 and 15 Hz, inspiratory times of 40% and 50%, and with an actuator instead of a spacer. Each test condition was repeated ten times. Analysis of variance or Student's t-test was used to determine significant differences in albuterol delivered or lost among the operating frequencies and inspiratory times, and between the spacer and actuator. MEASUREMENTS AND MAIN RESULTS: Albuterol delivery to the lung simulator was <1% of the administered dose regardless of the operating frequency, inspiratory time, or use of a spacer or actuator. Albuterol lost in the expiratory limb ranged from 3.28% to 14.89% of the administered dose. CONCLUSIONS: These in vitro results suggest albuterol delivery by MDI in a pediatric model of HFOV is negligible, regardless of the operating frequency, inspiratory time, or use of a spacer or actuator.

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.

Albuterol delivery by metered-dose inhaler in a mechanically ventilated pediatric lung model.

OBJECTIVES: To assess albuterol delivery by metered-dose inhaler in a mechanically ventilated pediatric lung model and to determine the influence of the following variables on albuterol delivery: endotracheal tube diameter; type of spacer; humidification; and pulmonary mechanics. DESIGN: Prospective, in vitro, laboratory study. SETTING: Research laboratory. INTERVENTIONS: A model, consisting of a volume-cycled ventilator, pediatric breathing circuit, 4.0- or 6.0-mm endotracheal tube, and lung simulator, was assembled. Ventilator settings were: tidal volume 250 mL; FIO2 0.5; inspiration/expiration ratio 1:3; respiratory rate 25 breaths/min; positive end-expiratory pressure 3 cm H2O; temperature 35 degrees C; and a decelerating flow pattern, using dry and humidified air. Lung simulator compliance and resistance values were consistent with those values reported for healthy childeren (20 mL/cm H2O and 40 cm H20/L/sec) and children with pulmonary disease (10 mL/cm H2O and 60 cm H2O/L/sec). Pulmonary mechanics were verified with a pulmonary function diagnostic system. Ten metered-dose inhaler canisters were used to administer 2000 micrograms of albuterol, using either a collapsible or a rigid spacer. A circuit filter placed immediately proximal to the test lung collected drug exiting the endotracheal tube. The filter was rinsed with water and albuterol concentrations were determined by high-performance liquid chromatography. Each variable was tested in triplicate. MEASUREMENTS AND MAIN RESULTS: Albuterol delivery was significantly (p < or = .05) greater for the 6.0-mm endotracheal tube, rigid spacer, dry air, and pulmonary disease mechanics by multifactor analysis of variance. Drug delivery in humidified air with pulmonary disease mechanics using the rigid chamber was 2.5 =/- 0.27% and 6.3 =/- 0.99% for the 4.0- and 6.0-mm endotracheal tubes, respectively. CONCLUSIONS: These in vitro results suggest that pulmonary disease mechanics and a 6.0-mm endotracheal tube improve albuterol delivery. Future clinical investigations in intubated pediatric patients with pulmonary disease are needed to address the clinical significance of these results.

Fetal surgical protocols in Yucatan miniature swine.

Thirty-nine Yucatan miniature swine were used in three fetal surgical experimental protocols. They involved antiarrhythmic administration, pacemaker implantation, and in-utero diagnosis of ventricular septal defect by intraoperative echocardiography. Because of problems encountered with surgical protocols in the initial stages, modifications were made to prevent fetal hypothermia and intraoperative mortality. These modifications included environmental temperature support, staple surgical techniques to reduce operative time, and development of fetal catheters designed to facilitate cannulation of small vessels. Postoperative care protocols were intensive and included antibiotics, analgesics, and supportive care designed to reduce discomfort and prevent abortion and sepsis. Thirty-seven of 39 sows survived the surgical procedures; experiments were performed on 117 fetuses. Twenty-two fetuses died either intraoperatively or postoperatively because of complications related to the experimental protocols. Modification of surgical and postsurgical protocols for these projects demonstrates the feasibility of using miniature swine as a model for fetal surgery, when their use was appropriate for anatomic and physiologic reasons.

Normal hematology, serology, and serum protein electrophoresis values in fetal Yucatan miniature swine.

We are currently developing fetal models of congenital heart disease in Yucatan miniature swine for pharmacologic, diagnostic, and interventional methods used to treat cardiac arrhythmias and ventricular septal defect. Fifty-four fetuses from 12 pregnant sows were included in this study. Eleven were fetuses between 76 and 88 days of gestation (early gestation fetuses). A second population of 43 fetuses were between 96 and 110 days of gestation (late gestation fetuses). Erythrocyte, leukocyte, serum electrolyte, enzyme, lipid, carbohydrate, and metabolite values were measured. Complete serum protein profiles were also obtained by electrophoresis. Significant differences could be shown between the sows and fetuses and between the early and late gestation fetuses in all of the categories studied, though not for every parameter. This study provides a large normal database for development of Yucatan miniature swine as an animal model in the rapidly expanding field of fetal medicine.

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. DESIGN: An albuterol MDI canister was connected to an AeroVent spacer or Airlife MDI adapter and ETT 4.0, 5.0, or 6.0 mm at commercially available and equal lengths. The ETT tip was attached to an in-line filter holder with a 1-microns type A/E glass fiber filter. Ventilator settings were fractional concentration of inspired oxygen 50%, tidal volume 250 ml, inspiratory:expiratory (I:E) ratio 1:3, rate 25 breaths/minute, temperature 35 degrees C, and a decelerating flow pattern. Ten albuterol canisters were activated two times each (total 2000 micrograms) into dry (4.0-, 5.0-, and 6.0-mm ETT) and humidified air (4.0- and 6.0-mm ETT) and repeated in triplicate. Percentage MDI output was determined by weighing the filter before and after drug administration (balance sensitivity 10 micrograms). Significant differences (p < or = 0.05) among the groups with and without a spacer and in dry and humidified air were determined by ANOVA with Scheffe's multiple comparison test. Multiple regression was used to determine significant associations between ETT diameter and length and delivery. MAIN RESULTS: With the AeroVent spacer in humidified air, delivery with the 4.0- and 6.0-mm ETT was approximately 2.3% and 5%, respectively. The spacer and dry air significantly improved delivery. CONCLUSIONS: In humidified air, the dose of albuterol by MDI with an AeroVent spacer should be doubled for children intubated with 6.0-mm ETT, and four puffs administered for every one puff desired for 4.0-mm ETT. The results of this investigation should prove useful in initial clinical trials of albuterol MDI in ventilator-dependent infants and children.

Stability of atenolol in an extemporaneously compounded oral liquid.

The stability of atenolol in an oral liquid stored for 40 days under various conditions was studied. A liquid preparation of atenolol 2 mg/mL was prepared by triturating 50-mg atenolol tablets with a commercially available oral diluent. Twelve 30-mL portions in vials were prepared. Three vials were refrigerated (5 degrees C) and shaken immediately before analysis, three were stored at room temperature (25 degrees C) and shaken, three were refrigerated and not shaken, and three were stored at room temperature and not shaken. One sample from each vial was assayed in duplicate on days 0, 15, 30, and 40 by stability-indicating high-performance liquid chromatography. The concentration of atenolol remained above 90% of the original concentration in each vial under each of the four sets of conditions. Microbial growth occurred in a few cultured samples, and pH changed minimally. Atenolol 2 mg/mL in an oral liquid was stable for up to 40 days when stored at 5 or 25 degrees C and shaken or at 5 or 25 degrees C and not shaken.

Stability of flecainide acetate in an extemporaneously compounded oral suspension.

The stability of flecainide acetate in an oral diluent stored for 45 days under various conditions was studied. A suspension was prepared by triturating 100-mg tablets of flecainide acetate with a commercially available oral diluent. The final theoretical drug concentration was 5 mg/mL. The suspension was poured into 12 2-oz amber glass prescription bottles for a per-bottle volume of 60 mL. Three bottles were refrigerated at 5 degrees C and shaken before analysis, three were stored at room temperature and shaken, three were refrigerated and not shaken, and three were kept at room temperature and not shaken. On days 0, 15, 30, and 45, flecainide acetate concentrations were determined by stability-indicating high-performance liquid chromatography. The concentration of flecainide acetate in the sediment in each bottle was determined on day 46. On day 45, the mean flecainide acetate concentration for each group of bottles remained above 90% of the initial concentration. Mean +/- S.D. flecainide acetate concentrations in sediment ranged from 0.53 +/- 0.30 to 1.18 +/- 0.36 mg per gram. Eight of the 12 samples contained microbial growth on at least one of the test days. Flecainide acetate 5 mg/mL oral suspension was stable for up to 45 days under the conditions investigated.

Stability of amphotericin B in four concentrations of dextrose injection.

The stability of amphotericin B in 5%, 10%, 15%, and 20% dextrose injection was investigated. The dextrose solutions were prepared in triplicate from sterile water for injection and 70% dextrose injection and placed in empty 50-mL polyvinyl chloride bags. The pH of each solution was determined before amphotericin B was added to a concentration of approximately 100 micrograms/mL. The bags were stored at 15-25 degrees C and protected from light. Three 1-mL samples were taken from each bag at various times up to 24 hours. One sample was analyzed for precipitation and color and pH changes. Two samples were analyzed in duplicate by stability-indicating high-performance liquid chromatography. No visual changes were observed, and pH did not change substantially. The mean amphotericin B concentration was greater than 90% of the initial concentration at each sampling time. However, the drug concentration in 3 of the 27 samples from the admixtures with 10% dextrose injection and 5 of the 27 samples from the admixtures with 20% dextrose injection fell below 90% of the initial concentration. Amphotericin B 100 micrograms/mL was stable in 5%, 10%, 15%, and 20% dextrose injection when stored for up to 24 hours at 15-25 degrees C and protected from light.

Cardiovascular and antiarrhythmic effects of esmolol in children.

This prospective study evaluated the cardiovascular and antiarrhythmic effects of esmolol, an intravenous beta-blocker with an extremely short half-life. Twenty patients (aged 2 to 16 years) underwent diagnostic electrophysiologic studies at rest and during beta-blockade induced with esmolol. An initial dose of 600 micrograms/kg was infused for 2 minutes and followed by an infusion of 200 micrograms/kg per minute. The dosage was increased by 50 to 100 micrograms/kg per minute every 5 to 10 minutes until a reduction of greater than 10% in either heart rate or mean blood pressure was seen. The dosage required to achieve beta-blockade ranged from 300 to 1000 micrograms/kg per minute (mean 550 micrograms/kg per minute). Electrophysiologic effects included a decrease in the rate of sinoatrial node discharge and delay in conduction through the atrioventricular node. There was no effect on His-Purkinje conduction. Atrial and ventricular effective refractory periods were unchanged. In six patients with supraventricular tachycardia, esmolol prevented induction of tachycardia in four and slowed the rate of the tachycardia in two. In four patients with ventricular tachycardia, clinical findings were improved in three and unchanged in one. Heart rate and blood pressure returned to near baseline values 10 minutes after the esmolol infusion was stopped. Adverse ventricular electrophysiologic effects were observed in two patients with biopsy evidence of myocarditis. No other adverse effects were seen. We conclude that the effects of esmolol in children are similar to those of other beta-blockers and that it is useful in the evaluation and management of pediatric tachyarrhythmias. The weight-adjusted dosage required to induce beta-blockade in children is larger than the adult dosage, and the effects of esmolol dissipate rapidly.

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 micrograms/kg was infused for 2 minutes. An infusion of esmolol was initiated and dosage was titrated until beta-blockade occurred. Serial esmolol blood samples were obtained for pharmacokinetic analysis. Non-compartmental 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 less than 0.001). The doses of esmolol required for beta-blockade (mean +/- SD, 535 +/- 180 micrograms/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.

Population pharmacokinetics of intravenous indomethacin in neonates with symptomatic patent ductus arteriosus.

The population pharmacokinetics of intravenous indomethacin were investigated with 665 indomethacin serum concentrations from 83 neonates (mean +/- SD: gestational age, 28.8 +/- 2.5 weeks; postnatal age, 5.7 +/- 4.7 days; birth weight, 1.13 +/- 0.40 kg) receiving indomethacin for symptomatic patent ductus arteriosus. A one-compartment open model was used for pharmacokinetic analysis. Hypotheses were tested to determine which developmental and demographic data influenced clearance (CL) and volume of distribution (V(area)). In the final regression equation CL and V(area) were modeled as a function of body weight and postnatal age (PNA) from 0 to 20 days. Final estimates were as follows: CL (ml/hr) = 2.63.weight (kg) + 0.244.PNA (days) and V(area) (L) = 0.28.weight (kg) + 0.0041.PNA (days). The coefficients of variation for interindividual variability in CL and V(area) were 77% and 28%, respectively. Intraindividual variability was 19%. These mean population parameter estimates should prove useful in designing dosage regimens to achieve desired indomethacin concentrations for neonates from 0 to 20 days of age with symptomatic patent ductus arteriosus.

The disposition of alfentanil in neonates with respiratory distress.

The disposition of continuous infusion alfentanil was evaluated in 13 mechanically ventilated neonates (gestational age 37.6 +/- 2.4 wks) with hyaline membrane disease (n = 7) or persistent pulmonary hypertension of the newborn (n = 6). Alfentanil was administered as a loading dose 8 micrograms/kg, followed by a variable-rate continuous infusion (maximum 10 micrograms/kg/hr; minimum 2.5 micrograms/kg/hr) for 27 hours. Serial plasma samples were obtained for pharmacokinetic analysis. Noncompartmental pharmacokinetic analysis of the data revealed the following estimates (mean +/- SD): total-body clearance 3.24 +/- 2.23 ml/kg/minute, volume of distribution 0.54 +/- 0.21 L/kg, and elimination half-life 4.14 +/- 2.58 hours. A significant effect of alfentanil plasma concentration on total-body clearance was found (r = -0.75; p = 0.02), suggesting nonlinear pharmacokinetics. No correlation was seen between total-body clearance and alfentanil dose (r = -0.37; p = 0.32). The results suggest that a larger dose-proportionality study is required to determine the linearity or nonlinearity of alfentanil pharmacokinetics in neonates.

Pharmacokinetics of ranitidine in critically ill infants.

The pharmacokinetic parameters of ranitidine were studied following administration of a single intravenous dose in 9 critically ill infants. Ranitidine disposition was best described by a biphasic elimination curve. For 8 patients, the mean values for T1/2, apparent volume of distribution, and total body clearance were 2.09 h, 1.61 l/kg, and 13.93 ml/min/kg, respectively. Based on simulated steady-state concentration profiles, a dose of 0.7 mg/kg administered intravenously every 6 h should maintain serum levels above 40 ng/ml for 4.7 h of the dosing interval with a wide degree of variability.