Single-dose pharmacokinetics of sotalol in a pediatric population with supraventricular and/or ventricular tachyarrhythmia.

The pharmacokinetics (PK) of the antiarrhythmic sotalol, which elicits Class III and beta-blocking activity, has not been adequately defined in a pediatric population with tachyarrhythmias. The goal of this single-dose study with administration of sotalol HCl at a dose level of 30 mg/m2 body surface area (BSA) was to define the PK of the drug in the following four age groups: neonates (0-30 days), infants (1 month to 2 years), younger children (> 2 to < 7 years), and older children (7-12 years) with tachyarrhythmias of either supraventricular or ventricular origin. The drug was administered in an extemporaneously compounded syrup formulation prepared from the tablets containing sotalol HCl. For safety, vital signs and adverse events were recorded and the QTc interval and heart rate telemetrically monitored. Scheduled blood samples were taken over a 36-hour time interval following dose administration. The drug concentrations in plasma were measured by a sensitive and specific LC/MS/MS assay. Standard compartment model-independent methods were applied to compute the salient PK parameters of sotalol. Twenty-four clinical sites enrolled 34 patients. Thirty-three had analyzable data. Sotalol was rapidly absorbed, with mean peak concentrations occurring 2 to 3 hours after administration. The elimination of sotalol was characterized by an average half-life of between 7.4 and 9.2 hours in the four age groups. There existed statistically significant linear relationships between apparent total clearance (CL/f) or apparent volume of distribution (V lambda z/f) after oral administration and the covariates BSA, creatinine clearance (CLcr), body weight (BW), or age. The best predictors for CL/f were CLcr and BSA, whereas BW best predicted the V lambda z/f. The total area under the drug concentration-time curve in the smallest children with a BSA < 0.33 m2 was significantly greater than that in the larger children. This finding indicated that the BSA-based dose adjustment used in this study led to a larger exposure in the smallest children, whereas the exposure to the drug was similar in the larger children. The dose of 30 mg/m2 was tolerated well. No serious drug-related adverse events were reported. It can be concluded that the PK of sotalol in the pediatric patients depended only on body size, except for the neonates and smallest infants in whom the disposition of sotalol was determined by both body size and maturation of eliminatory processes.

Late onset of accessory pathway conduction in a patient with complete AV block.

This case report discusses a patient with complete AV block in early childhood. The patient required a permanent pacemaker. At 6 years of age, intermittent preexcited beats were noted on telephonic transmissions. At 7 years of age, 1:1 preexcitation was noted in sinus rhythm. Therefore, late onset of antegrade accessory pathway function is demonstrated. This case provides evidence of developmental changes in accessory pathways. This may explain age related differences in the onset of narrow complex tachycardia in the school age years.

Blade and balloon atrial septostomy for left heart decompression in patients with severe ventricular dysfunction on extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is used as circulatory support or bridge to transplantation in patients with severe left ventricular (LV) dysfunction. Left heart decompression is needed to reduce pulmonary edema, prevent pulmonary hemorrhage, and reduce ventricular distention that may aid in recovery of function. We reviewed our experience from November 1993 to December 1997 with 10 patients having severe LV dysfunction (7 myocarditis, 3 dilated cardiomyopathy) who required circulatory support with ECMO and who underwent left heart decompression with blade and balloon atrial septostomy (BBAS). Patients ranged in age from 1 to 24 years (median, 3 years). Indications for BBAS included left atrial/left ventricular distension (10), pulmonary edema/hemorrhage (9), or severe mitral regurgitation (2). BBAS was performed electively in eight patients and urgently in two patients. BBAS was performed while on ECMO in seven patients and pre-ECMO in three. A femoral venous approach was used in all patients. ECMO patients were fully heparinized. Transseptal puncture was required in nine patients while one patient had a patent foramen ovale. Blade septostomy was performed in all patients. Enlargement of the defect was then performed by stationary balloon dilation in nine and Rashkind balloon atrial septostomy in one. Balloon diameters ranged from 10 to 20 mm. Sequential balloon inflations were performed in some patients. Adequacy of the atrial septal defect (ASD) was confirmed by pressure measurement and echocardiography. Adequate left heart decompression was achieved in all patients. Pulmonary edema improved in nine of nine patients. Left atrial mean pressure fell from a mean of 30.5 mm Hg, (range, 12-50 mm Hg) to 16 mm Hg (range, 9-24 mm Hg). Left atrial to right atrial pressure gradient fell from a mean of 20 mm Hg pre-BBAS to 3 mm Hg post-BBAS. ASDs ranged in size from 2.5 to 8 mm (mean, 5.9 mm). Complications included needle perforation of the left atrium without hemodynamic compromise (one), ventricular fibrillation requiring defibrillation (one), and hypotension following BBAS which responded to volume infusion (two). Duration of ECMO ranged from 41 hr to 704 hr (mean, 294 hr). Seven patients survived and four patients had recovery of normal LV function. Of those who recovered, two had no ASD at follow-up while two ASDs are patent 14 days and 3 months post-BBAS. Three patients underwent successful cardiac transplantation. Three patients died, all of whom had multisystem organ failure with or without sepsis. A patent ASD was noted at transplant (three) or autopsy (two). No patient required a second BBAS. BBAS alleviates severe left atrial hypertension and pulmonary edema. In addition, BBAS avoids the potential bleeding complications of surgical left heart decompression. Stationary balloon dilation of the atrial septum is an effective alternative to Rashkind balloon septostomy in older patients. BBAS achieves left heart decompression that may permit recovery of LV function or allow extended ECMO support as a bridge to transplant.

Proadrenomedullin NH2-terminal 20 peptide has cAMP-mediated vasodilator activity in the mesenteric vascular bed of the cat.

Responses to proadrenomedullin NH2-terminal 20 peptide (hPAMP), a truncated analogue [hPAMP(12-20)], and adrenomedullin (hADM) were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of hPAMP, hPAMP(12-20), and hADM caused dose-related decreases in mesenteric perfusion pressure. hADM was 100-fold more potent than hPAMP, and 1000-fold more potent than hPAMP(12-20). Vasodilator responses to hPAMP and hADM were not altered by adrenergic-blocking agents, were similar in innervated and denervated preparations, and were similar when tone was increased by sympathetic nerve stimulation or phenylephrine infusion. Vasodilator responses to hPAMP and hADM were increased in duration by rolipram, a cAMP phosphodiesterase inhibitor. The present data suggest that vasodilator responses to the hPAMP and hADM are mediated by an increase in cAMP and that an interaction with the adrenergic nervous system is not involved.

Emergent radiofrequency ablation of the AV node in a neonate with unstable, refractory supraventricular tachycardia.

Supraventricular tachycardia due to accessory atrioventricular connections in infants is usually well-tolerated. Rarely an infant can have supraventricular tachycardia that is incessant and refractory to medical therapy. We describe a patient with supraventricular tachycardia detected prenatally that caused severe cardiac dysfunction and hemodynamic instability after birth.

Pharmacy-managed protocol for warfarin use in orthopedic surgery patients.

A pharmacy-managed protocol for warfarin use in orthopedic surgery patients was studied. In 1990 a protocol designed to accommodate either protocol- or physician-determined dosing of warfarin for orthopedic antithrombotic prophylaxis (OAP) was implemented at a community hospital. A "protocol" group consisting of patients treated entirely under the protocol-determined dosing option was prospectively identified over a two-year period. A "physician" group consisting of patients treated by physicians in the 10 months immediately preceding implementation of the protocol was also identified. The ability of the protocol to achieve laboratory-test and clinical goals was assessed by comparing the two groups. The proportion of patients who received OAP increased from 89% for the physician group to 98% for the protocol group. Mean prothrombin times (PTs) were significantly higher in the protocol group only on postoperative day 2; 66% of all PTs beyond post-operative day 1 in the protocol group were within the targeted range, which reflected an International Normalized Ratio of 1.6-3.2. The frequencies of clinically apparent postoperative thrombotic events and bleeding episodes were low in each group and comparable to literature values. Analysis of protocol-group patients with PTs of > 20 seconds indicated that lower weight, female sex, and blood loss during surgery were associated with an elevated PT. The protocol was revised to provide for a lower initial warfarin dose in elderly women. A pharmacy-managed protocol for dosing warfarin achieved therapeutic goals and promoted nearly universal use of OAP in patients undergoing high-risk orthopedic surgery.

Lack of superiority of the vectorcardiogram over the electrocardiogram in detecting inferior wall myocardial infarction regardless of time since infarction.

Using more recent VCG and ECG criteria, the relative accuracy of these two tests in detecting inferior wall MI over time was evaluated in 38 of 236 patients undergoing elective left ventriculographic and coronary angiographic studies who had clinical plus angiographic evidence of inferior wall myocardial infarction. The overall sensitivity and specificity of the ECG criteria of the New York Heart Association and Warner did not differ from that of the VCG criteria of Starr and Takatsu. There was a trend toward decreased sensitivity in both VCG criteria and the ECG criterion of Warner in detecting inferior wall myocardial infarction greater than or equal to 18 months, although the difference did not reach statistical significance. Changing the age of infarction to greater than or equal to 3, greater than or equal to 6, greater than or equal to 12, or greater than or equal to 24 months did not yield a different result. It is concluded that VCG is not superior to ECG in the diagnosis of inferior wall MI regardless of time since occurrence of infarction.

Cervical cancer occurrence in Memphis and Shelby County, Tennessee, during 25 years of its cervical cytology screening program.

This review of the cytologic history of 430 women with histologically proved invasive cancer of the uterine cervix indicates that several significant subgroups can be defined. One major subgroup consists of 142 patients or 33% of the total group in whom invasive cancer developed within 1 to 5 years, with an average of 2.6 years, after one or more negative cytologic findings. This appears to be a significant proportion of the occurrence of invasive cervical cancer and warrants consideration in the recommendation of screening intervals. The second major subgroup, consisting of 88 patients (20.5%), had a delay in diagnosis averaging 9.9 years after the first abnormal cytologic finding. In some of these patients either the cytologic examination results reverted to negative for a period or the biopsy material did not confirm the cytologic abnormalities. The disease progressed to invasion. These findings appear to bear out the importance of close follow-up of patients with any abnormal cytologic finding in the intraepithelial neoplasia category even though intermittent cytologic studies may appear negative.