Donald B. Wiest

Esmolol : a review of its therapeutic efficacy and pharmacokinetic characteristics

Esmolol is an ultra short-acting intravenous cardioselective beta-antagonist. It has an extremely short elimination half-life (mean: 9 minutes; range: 4 to 16 minutes) and a total body clearance [285 ml/min/kg (17.1 L/h/kg)] approaching 3 times cardiac output and 14 times hepatic blood flow. The alpha-distribution half-life is approximately 2 minutes. When esmolol is administered as a bolus followed by a continuous infusion, onset of activity occurs within 2 minutes, with 90% of steady-state beta-blockade occurring within 5 minutes. Full recovery from beta-blockade is observed 18 to 30 minutes after terminating the infusion. Esmolol blood concentrations are undetectable 20 to 30 minutes postinfusion. The elimination of esmolol is independent of renal or hepatic function as it is metabolised by red blood cell cytosol esterases to an acid metabolite and methanol. The acid metabolite, which is renally eliminated, has 1500-fold less activity than esmolol. Methanol concentrations remain within the range of normal endogenous levels. Clinically, esmolol is used for the following: (i) situations where a brief duration of adrenergic blockade is required, such as tracheal intubation and stressful surgical stimuli; and (ii) critically ill or unstable patients in whom the dosage of esmolol is easily titrated to response and adverse effects are rapidly managed by termination of the infusion. In adults, bolus doses of 100 to 200mg are effective in attenuating the adrenergic responses associated with tracheal intubation and surgical stimuli. For the control of supraventricular arrhythmias, acute postoperative hypertension and acute ischaemic heart disease, doses of < 300 micrograms/kg/min, administered by continuous intravenous infusion, are used. The principal adverse effect of esmolol is hypotension (incidence of 0 to 50%), which is frequently accompanied with diaphoresis. The incidence of hypotension appears to increase with doses exceeding 150 micrograms/kg/min and in patients with low baseline blood pressure. Hypotension infrequently requires any intervention other than decreasing the dose or discontinuing the infusion. Symptoms generally resolve within 30 minutes after discontinuing the drug. In surgical and critical care settings where clinical conditions are rapidly changing, the pharmacokinetic profile of esmolol allows the drug to provide rapid pharmacological control and minimises the potential for serious adverse effects.

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.

Clinical Pharmacokinetics and Therapeutic Efficacy of Esmolol

Esmolol is a unique cardioselective β1-receptor blocking agent with a rapid onset and short duration of action. Since our previous review in 1995, the pharmacokinetics and efficacy of esmolol have been investigated in a number of acute care settings. Three studies investigated the pharmacokinetics and safety of esmolol in the paediatric population. The disposition of esmolol in children was found to be linear with plasma concentrations increasing in proportion to dose over the ranges studied. The pharmacokinetic estimates for esmolol showed a shorter elimination half-life (t1/2) [2.7–4.8 minutes] and a higher clearance (281 mL/kg/min) in newborns and infants than that found in children (>2 years old) and adults. Dosing requirements to achieve targeted blood pressure in post-coarctectomy patients were substantially higher (mean 700 μg/kg/min) than that used in adults. Esmolol was effective in controlling hypertension following cardiac surgery and terminating supraventricular arrhythmias in children.The efficacy of esmolol has been established in a variety of patients, including those with unstable angina, myocardial ischaemia, supraventricular arrhythmias, peri- and postoperative tachycardia and hypertension, and electroconvulsive therapy. With careful titration and monitoring, esmolol can be used effectively in patients with congestive heart failure and chronic obstructive lung disease because of its unique short t1/2 and β1-selectivity. Different dosage schedules have been developed depending on clinical setting and diagnosis. Generally, a loading dose of ≤500 μg/kg/min over 1 minute is administered followed by a continuous infusion of 25–300 μg/kg/min. Hypotension, being the primary adverse effect, can be minimized by careful dosage titration and patient monitoring.In the perioperative setting involving tracheal intubation and extubation, a number of recent studies have suggested that titration of esmolol to a haemodynamic endpoint can be safe and effective, resulting in a decreased incidence of myocardial ischaemia. The most effective regimen in attenuating the response to heart rate and blood pressure after laryngeal tracheal intubation was a loading dose of 500 μg/kg/min for 4 minutes followed by a continuous infusion of 200–300 μg/kg/min. In cardiac and non-cardiac surgical patients esmolol has been shown to decrease episodes of myocardial ischaemia and arrhythmias. In the perioperative period for non-cardiac surgery routine use of β-blockers (β-adrenoceptor antagonists) is no longer recommended. However, in patients at high risk for myocardial ischaemia or undergoing high-risk surgery where a β-blocker is indicated, esmolol is the ideal perioperative agent to minimize the risk of hypotension and bradycardia based on its pharmacodynamic and pharmacokinetic characteristics. For postoperative patients in atrial fibrillation, esmolol achieves rapid ventricular rate control. However, for the prevention of postoperative atrial fibrillation esmolol provides no advantage over oral β-blockers. In other situations where emergent β-blockade is required, such as electroconvulsive therapy, esmolol has been shown to effectively control haemodynamic response. After more than 2 decades of use esmolol continues to provide an important therapeutic option in the acute care setting.

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.

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.

DRUG THERAPY IN THE NURSING MOTHER

The benefits of breast-feeding on newborn and infant health and for the maternal-infant relationship are well established. It is a failing of health care providers that breast-feeding is too frequently interrupted because of unfounded concerns over the potential adverse effects of concurrent drug therapy in the nursing mother. An overwhelming minority of medications are contraindicated during lactation, while the vast majority are considered either safe to use or the risk versus benefit considerations clearly favor use with continuation of breast-feeding. For those drugs that may pose a potential concern to the newborn, there are practical suggestions and precautions that can be taken to minimize risk. These include such interventions as selection of alternative effective drug regimens with safer profiles in breast-feeding, timing of drug dosing to minimize accumulation in the breast milk, surveillance for newborn or infant symptomatology that may be a sign of toxicity, or even the determination of drug levels in the infants circulation. With a commitment to the advantages of breast-feeding and the information contained both herein and elsewhere regarding the interaction of medical therapy, pharmacology, and lactation, it is hoped that the health care provider will be empowered both to encourage and counsel more effectively the parturient who wishes to breast-feed but is concerned about ongoing drug therapy during lactation.

Pharmacokinetics and pharmacodynamics of atenolol in children

The pharmacokinetics and pharmacodynamics of intravenous atenolol were studied in 10 children during cardiac electrophysiologic studies. The intravenous pharmacokinetic data were best described by a two‐compartment model and revealed the following (mean ± SD): total body clearance, 0.15 ± 0.06 L/hr/kg; volume of the central compartment 0.33 ± 0.06 L/kg; volume of distribution at steady state, 0.83 ± 0.15 L/kg; distributive elimination half‐life, 0.29 ± 0.08 hour; and terminal elimination half‐life, 4.56 ± 1.05 hours. The data suggest that children have a slightly shorter terminal elimination half‐life than that of adults. Pharmacodynamic data showed a significantly (p < 0.01) increased sinus cycle length and an increase in His to ventricle conduction time (p < 0.05). Further studies are necessary to determine the optimal oral dose and dosing frequency of atenolol and to access the response of children to long‐term treatment.

Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis

Objective To evaluate the clinical safety of antenatal and postnatal N-acetylcysteine (NAC) as a neuroprotective agent in maternal chorioamnionitis in a randomized, controlled, double-blinded trial. Study design Twenty-two mothers >24 weeks gestation presenting within 4 hours of diagnosis of clinical chorioamnionitis were randomized with their 24 infants to NAC or saline treatment. Antenatal NAC (100 mg/kg/dose) or saline was given intravenously every 6 hours until delivery. Postnatally, NAC (12.5–25 mg/kg/dose, n = 12) or saline (n = 12) was given every 12 hours for 5 doses. Doppler studies of fetal umbilical and fetal and infant cerebral blood flow, cranial ultrasounds, echocardiograms, cerebral oxygenation, electroencephalograms, and serum cytokines were evaluated before and after treatment, and 12, 24, and 48 hours after birth. Magnetic resonance spectroscopy and diffusion imaging were performed at term age equivalent. Development was followed for cerebral palsy or autism to 4 years of age. Results Cardiovascular measures, cerebral blood flow velocity and vascular resistance, and cerebral oxygenation did not differ between treatment groups. Cerebrovascular coupling was disrupted in infants with chorioamnionitis treated with saline but preserved in infants treated with NAC, suggesting improved vascular regulation in the presence of neuroinflammation. Infants treated with NAC had higher serum anti-inflammatory interleukin-1 receptor antagonist and lower proinflammatory vascular endothelial growth factor over time vs controls. No adverse events related to NAC administration were noted. Conclusions In this cohort of newborns exposed to chorioamnionitis, antenatal and postnatal NAC was safe, preserved cerebrovascular regulation, and increased an anti-inflammatory neuroprotective protein. Trial registration ClinicalTrials.gov: NCT00724594.

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.