Simon Milstein

Adenosine for Paroxysmal Supraventricular Tachycardia: Dose Ranging and Comparison with Verapamil: Assessment in Placebo-Controlled, Multicenter Trials

OBJECTIVE To assess the safety and efficacy of intravenous adenosine in terminating acute episodes of paroxysmal supraventricular tachycardia. DESIGN Two prospective, double-blind, randomized, placebo-controlled trials to evaluate dose response in patients receiving adenosine and to compare the effects of adenosine with those of verapamil. PATIENTS A total of 359 patients with a tachycardia electrocardiographically consistent with paroxysmal supraventricular tachycardia were entered into the two protocols. Patients subsequently found to have arrhythmias other than paroxysmal supraventricular tachycardia were excluded from the efficacy analysis. INTERVENTIONS The first protocol compared sequential intravenous bolus doses of 3, 6, 9, and 12 mg of adenosine to equal volumes of saline. In the second protocol, patients received either 6 mg and, if necessary, 12 mg of adenosine or 5 mg and, if necessary, 7.5 mg of verapamil. MEASUREMENTS AND MAIN RESULTS When data are expressed in terms of cumulative response in eligible patients, intravenous adenosine terminated acute episodes of paroxysmal supraventricular tachycardia in 35.2%, 62.3%, 80.2%, and 91.4% of patients who received maximum doses of 3, 6, 9, and 12 mg, respectively, in a four-dose sequence, whereas 8.9%, 10.7%, 14.3%, and 16.1% of patients responded to four sequential placebo doses (P less than 0.0001). In the second trial, cumulative response rates after 6 mg followed, if necessary, by 12 mg of adenosine were 57.4% and 93.4%, and after 5 mg followed, if necessary, by 7.5 mg of verapamil were 81.3% and 91.4%. The average time after injection to termination of tachycardia by adenosine was 30 seconds. Adenosine caused adverse effects in 36% of patients, but they lasted less than 1 minute and were usually mild. CONCLUSIONS Adenosine in graded doses up to 12 mg rapidly and effectively terminates acute episodes of paroxysmal supraventricular tachycardia in which the atrioventricular node is an integral part of the re-entrant circuit. The overall efficacy of adenosine is similar to that of verapamil, but its onset of action is more rapid. Adverse reactions to adenosine are common but are minor and brief.

Demonstration of macroreentry and feasibility of operative therapy in the common type of atrial flutter.

Two patients are described who had recurrent and long-standing atrial flutter of the common type and were referred for electrophysiologic testing and surgical management. In both patients, atrial flutter could be initiated and terminated by programmed stimulation. Atrial endocardial mapping showed earliest activation during flutter at the orifice of the coronary sinus, with activity proceeding to the low atrial septum, high lateral right atrium and low right atrium, respectively. Programmed atrial extrasystoles from the high right atrium at a time when the atrial septal region was refractory advanced atrial flutter in proportion to prematurity of the extrastimulus, while maintaining the low to high activation sequence. Intraoperatively, epicardial atrial mapping revealed a large right atrial reentrant circuit beginning in the posteroseptal region and proceeding superiorly and laterally through the right atrial free wall before returning to its starting point. The narrowest part of the circuit and that showing relatively slow conduction during atrial flutter was observed in the low right atrial tissue between the tricuspid valve ring and the orifices of the inferior vena cava and proximal coronary sinus, respectively. Cryosurgical ablation around the orifice of the coronary sinus and surrounding atrial wall has prevented recurrent atrial flutter over short term follow-up in both patients, although 1 of the patients has required antiarrhythmic therapy for postoperative atrial fibrillation.

Usefulness of disopyramide for prevention of upright tilt-induced hypotension-bradycardia

Susceptibility to transient hypotension-bradycardia of neurally mediated origin has been attributed in part to accentuated afferent neural traffic arising from cardiopulmonary mechanoreceptors, and consequently, may be diminished by agents with anticholinergic and negative inotropic effects, such as disopyramide phosphate. This study assessed electrocardiographic and hemodynamic responses to upright tilt testing (alone or during isoproterenol infusion) before and after disopyramide therapy in 10 patients (age range 16 to 74 years) with recurrent syncopal episodes of neurally mediated origin. Untreated, syncope occurred at less than or equal to 7 minutes of tilt alone (6 patients) or tilt plus isoproterenol at less than or equal to 3 micrograms/min (4 patients) and was associated with hypotension (mean arterial pressure, 40 +/- 16 mm Hg vs baseline 76 +/- 10 mm Hg, p less than 0.001) and inappropriate heart rate slowing (mean heart rate, 59 +/- 39 beats/min vs baseline 88 +/- 18 beats/min, p less than 0.005). After oral disopyramide 150 mg 3 times daily (mean plasma level, 3.0 +/- 0.64 micrograms/ml), all patients tolerated 10 minutes of both tilt and tilt plus isoproterenol (maximum dose, 3 micrograms/min) without symptoms, hypotension (mean arterial pressure; tilt 1 min, 79 +/- 7 mm Hg vs tilt 10 min, 77 +/- 8 mm Hg, difference not significant) or bradycardia (mean heart rate; tilt 1 min, 81 +/- 12 beats/min vs tilt 10 min, 83 +/- 11 beats/min, difference not significant). Furthermore, during subsequent 20 +/- 5 months of disopyramide therapy, all but 1 patient remain asymptomatic. Thus, oral disopyramide may be effective for preventing inducible and spontaneous neurally mediated syncope.

Atrial fibrillation in patients with Wolff-Parkinson-White syndrome: incidence after surgical ablation of the accessory pathway.

The effect of surgical ablation of ablation of atrioventricular accessory pathways on the incidence of atrial fibrillation in patients with Wolff-Parkinson-White syndrome was examined and the results of preoperative electrophysiologic testing were studied to determine factors predictive of outcome. Among 50 consecutive surgical cases, 19 patients were identified with a past history of at least one episode of spontaneous atrial fibrillation documented by electrocardiogram before surgery. The mean number of episodes of atrial fibrillation was 1.97/patient/year during a mean symptomatic period of 6.9 years before surgery. These patients were compared with 19 consecutive patients undergoing surgery during the same time period who had a history of only reciprocating tachycardia. Patients with atrial fibrillation had a significantly shorter antegrade accessory pathway effective refractory period (270 +/- 39 vs 330 +/- 107 msec; p less than .05) and much faster ventricular rates during induced atrial fibrillation (shortest RR interval 219 +/- 73 vs 294 +/- 60 msec, p less than .005; average RR interval 324 +/- 109 vs 405 +/- 127 msec, p less than .01). Patients with atrial fibrillation also had longer PA intervals (47 +/- 13 vs 37 +/- 7 msec; p less than .02). At preoperative electrophysiologic testing, 18 patients with atrial fibrillation had atrial fibrillation induced and 14 sustained the arrhythmia for longer than 10 min. In contrast, atrial fibrillation, although induced in 14 of 19 patients with reciprocating tachycardia, was not sustained in any. Thus electrophysiologic testing suggested that both accessory pathway properties and atrial vulnerability may predispose to atrial fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Anatomical Mechanisms Explaining Damage to Pacemaker Leads, Defibrillator Leads, and Failure of Central Venous Catheters Adjacent to the Sternoclavicular Joint

The literature suggests that approximately 93% of all pacemaker lead fractures occur in the segment of the lead lateral to the venous entry, and costoclavicular compression has been implicated. While blood vessels can be compressed by movements of the clavicle, our research suggests that lead and catheter damage in that region is caused by soft tissue entrapment rather than bony contact. Dissection of eight cadavers with ten leads revealed that two entered the cephalic vein, and were not included in the study. Of the other eight leads, four passed through the subclavius muscle, two through the costoclavicular ligament, and two through both these structures before entering the subclavian, internal jugular, or brachiocephalic vein. Anatomical studies demonstrated that entrapment by the subclavius muscle or the costoclavicular ligament could cause repeated flexing of leads during movements of the pectoral girdle. Cineradiology of patients with position dependent catheter occlusion confirmed entrapment by the subclavius muscle. Soft tissue entrapment imposes a static load upon leads and catheters, and repeated flexure about the point of entrapment may be responsible for damage previously ottributed to cyclic costoclavicular compression.

An Algorithm for the Electrocardiographic Localization of Accessory Pathways in the Wolff‐Parkinson‐White Syndrome

Accessory pathway location in the Wolff‐Parkinson‐White syndrome influences the success and morbidity of nonpharmacological therapies, so that an estimate of accessory pathway location is relevant to the practicing physician. We derived an algorithm for accessory pathway localization based on the surface electrocardiogram; we tested it in a population of 141 patients with the Wolff‐Parkinson‐White syndrome in whom accessory pathway localization was made by electrophysiological and/or intraoperative mapping. The goal of the algorithm was to localize the accessory pathway to one of four anatomic regions, namely, left free wall, posteroseptal, anteroseptal or right free wall by using a simple, easy‐to‐appiy scheme. Each of two observers, blinded to the results of mapping, correctly identified the anatomic location of 91% and 90% of pathways, respectively. We conclude that a simple algorithm utilizing the 12‐lead electrocardiogram can provide a valuable first approximation of accessory pathway location in the Wolff‐Parkinson‐White syndrome.

Cardiac asystole: a manifestation of neurally mediated hypotension-bradycardia

It has been proposed that prolonged cardiac asystole mimicking an episode of sudden cardiac death may occur as a manifestation of neurally mediated hypotension-bradycardia syndrome. To assess this possibility, electrocardiographic and hemodynamic findings during upright tilt testing were evaluated in six survivors of suspected asystolic sudden cardiac arrest with normal conventional electrophysiologic evaluation (Group I). These observations were compared with findings in two control groups: six patients with syncope but without evident asystole and with normal conventional electrophysiologic evaluation but demonstrable neurally mediated hypotension-bradycardia (Group II), and six patients with syncope in whom conventional electrophysiologic evaluation provided a presumptive diagnosis (Group III). Patients in all three groups ranged in age from 16 to 59 years. During head-up tilt testing (either alone or with isoproterenol infusion), patients in both Groups I and II developed syncope in less than or equal to 5 min, whereas patients in Group III remained asymptomatic. Patients in Groups I and II exhibited a similar tilt-induced decrease in mean arterial pressure (-46 +/- 9 and -40 +/- 9 mm Hg, respectively, p = NS) and heart rate (-44 +/- 28 and -49 +/- 12 beats/min, respectively, p = NS). In contrast, patients in Group III manifested only a moderate decrease in mean arterial pressure (-14 +/- 5 mm Hg) and had an increase in heart rate (+14 +/- 8 beats/min). Both mean arterial pressure and heart rate changes in Group I and Group II patients differed significantly (p less than 0.001) from values in Group III patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproducibility of head-up tilt-table testing for eliciting susceptibility to neurally mediated syncope in patients without structural heart disease

Head-up tilt testing has gained acceptance as a tool for assessing susceptibility to neurally mediated syncopal syndromes (e.g., vasovagal syncope), and is currently being evaluated as a means of testing therapeutic interventions in these conditions. To assess reproducibility of head-up tilt testing and thereby assess the potential of such testing for immediate evaluation of a planned treatment, findings during 2 sequential 80 degrees head-up tilt tests were compared in 23 patients (age range 6.5 to 74 years) undergoing evaluation of syncope of unknown origin. Upright tilt was performed initially in the absence of drugs, and repeated if necessary during pharmacologic provocation by means of isoproterenol infusions of 1 and 3 micrograms/min (tilt 1). End points were syncope, maximal tolerated isoproterenol dose, or a tilt duration of 10 minutes. The second tilt test (tilt 2) was conducted after approximately 30 minutes of supine rest using the maximal provocative conditions used in tilt 1. Fifteen of 23 patients (65%) developed syncope in either tilt 1 or 2, while 8 of 23 (35%) remained asymptomatic. Tilt testing results were concordant (i.e., positive in both tests, or negative in both tests) in 20 of 23 (87%) patients. Concordance was, however, less among tilt-positive patients (12 of 15, 80%) since 3 patients were tilt-positive in tilt 1 only.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac electrophysiologic and hemodynamic correlates of neurally mediated syncope

This study assessed the temporal relation of RR interval, AH interval and systemic blood pressure changes during induced symptomatic bradycardia-hypotension episodes in 14 patients with recurrent syncope suspected of being neurally mediated. Upright tilt with isoproterenol reproduced symptoms in 9 of 14 patients (positive response) and was negative in 5 of 14 (negative response). Isoproterenol alone shortened supine RR intervals in all patients. With tilt, however, isoproterenol prolonged RR intervals in those with positive results (supine 519 +/- 124 ms vs tilt 845 +/- 212 ms, p less than 0.005) while further shortening RR intervals among negative responders (supine 436 +/- 90 ms vs tilt 377 +/- 82 ms, p less than 0.05). Similarly, tilt with isoproterenol prolonged AH intervals in patients with positive responses despite RR prolongation, while shortening AH in negative responders. Additionally, with combined tilt and isoproterenol, systemic arterial pressure decreased significantly in patients with positive responses (systolic 99 +/- 13 vs 57 +/- 13 mm Hg, p less than 0.001, diastolic 62 +/- 17 vs 28 +/- 9 mm Hg, p less than 0.001) but not in patients with negative responses. Further, onset of hypotension (42 +/- 14 seconds after tilt) preceded onset of RR interval prolongation (52 +/- 23 seconds after tilt). Syncope (142 +/- 72 seconds after tilt) coincided closely with nadir of systemic pressure (136 +/- 74 seconds) and both tended to precede maximum RR prolongation (152 +/- 87 seconds). Thus, the bradycardia and hypotension associated with neurally mediated syncope exhibit characteristic but distinctly different time courses, with arterial pressure changes developing earlier and coinciding more closely with symptom development.

Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern

Electrophysiologic testing in patients with asymptomatic Wolff-Parkinson-White syndrome (WPW) may be useful in defining arrhythmic substrates and predictors of fatality. Forty-two patients with asymptomatic WPW, mean age 36 years, underwent electrophysiologic studies and were followed prospectively. They were compared with a matched control group of patients studied within the same period for documented tachycardia associated with the WPW syndrome. Asymptomatic patients had longer anterograde effective refractory periods of the accessory pathway, longer minimum cycle lengths maintaining 1:1 conduction over the accessory pathway, longer minimum RR intervals between consecutive preexcited beats during atrial fibrillation (AF) and longer mean RR intervals during AF than their symptomatic counterparts. Sustained reciprocating tachycardia could not be induced in most patients and induction of AF required rapid atrial pacing in all patients. Nine patients had an anterograde effective refractory period of less than 270 ms and 17% had minimum cycle length less than 250 ms during induced AF. Over a follow-up of 29 +/- 18 months, 1 patient died of noncardiac causes and the rest remained asymptomatic. Thus, patients with asymptomatic WPW have deficient electrophysiologic substrates to maintain orthodromic reciprocating tachycardia under baseline conditions and do not have atrial vulnerability. Seventeen percent of patients had potentially lethal ventricular rates during induced AF.