Haemodynamic effects of the antiarrhythmic quaternary ammonium compound QX-572 in man.

British Heart journal, 1975, 37, 65-73. Haemodynamic effects of the antiarrhythmic quaternary ammonium compound QX-572 in man L. Ryden, A. Hjalmarson, J. Kvasnicka,' and B. Liander From Division of Cardiology, Department of Medicine I, Sahlgren's Hospital, Goteborg, Sweden The haemodynamic effects of N,N-bis(phenyl-carbamoylmethyl) dimethylammonium chloride (QX-572) in man were studied. A controlled study was performed to rule out a possible influence of the catheterization procedure as such on the results. Ten patients with mild to moderate aortic regurgitation were studied: based on clinical data the patients were divided into 2 ggoups of .5. Randomly it was decided that one group should constitute a control group receiving saline while the second group received QX-572 8 mg/kg body weight. In both groups the administration was performed as a slow intravenous infusion during 30 minutes. Heart rate, pressures in brachial artery and right atrium, cardiac output, stroke volume, and systemic vascular resistance were determined before, during, and up to 30 minutes after completion of placebo or QX-572. These variables remained stable in the control group while QX-572 produced an increase in heart rate most pronounced at the end of the infusion period, a transient decrease in systolic and mean brachial artery pressure during the infusion, and during the same period a decrease in right atrial pressure. Cardiac output and systemic vascular resistance were unchanged by QX-572 but they were not measured during the infusion when the changes in pressures were most pronounced. QX-572 was thought to act as a peripheral vasodilator during the infusion. Left ventricular contractility was studied by means of pressure curves obtainedfrom a catheter tip manometer placed in the left ventricle. The first derivative of the isovolumic left ventricular pressure at the highest level (45 mmHg) common to all patients was used (dp/dt-45). No significant difference could be observed when comparing mean changes of dp/dt-45 for the two groups. In the control group there was a slight but significant increase in dp/dt-45 during the time of observation. In the QX-572 group the results varied between individuals. Two of the patients differedfrom all other patients in the control and the QX-572 groups showing a decrease in dp/dt-45 which, when most pronounced at the end of the infusion period, was -3I and -28 per cent of the preinfusion levels, respectively. This decrease probably reflects reduction of contractility. It was concluded that QX-572 in a dose of 8 mg/kg body weight did not have any major haemodynamic drawbacks. The lignocaine derivative, N,N-bis (phenylcarbamoylmethyl) dimethylammoniumchloride (QX572)2 has been shown to be active against ventricular tachyarrhythmias (Katz, I965; Schwartz, Stapleton, and Covino, I967). In a recent study the drug was remarkably effective in the treatment of serious, refractory ventricular tachyarrhythmias, and its duration of action was long (Ryden et al., I974a). A limitation of commonly used antiarrhythmic drugs is reduction of cardiac contractility or other unfavourable haemodynamic effects. This Received 28th May I974. 'Present address: Medical Clinic I, Fakultni nemocnice, Kfinz, Hradec Kr4lov6, Czechoslovakia. 2Manufactured by Astra. sometimes precludes the use of sufficiently high doses to suppress arrhythmia (Mason et al., 1973). QX-572 has been claimed to possess a positive inotropic effect (Katz, I963). However, it has also been found that a rapid rate of injection can produce peripheral vasodilatation and a concomitant drop in blood pressure (Schwartz et al., I967). These findings are to a large extent based on studies on dogs. No detailed haemodynamic investigations have so far been performed in man. Directional changes in cardiac performance caused by the administration of antiarrhythmic drugs are often evaluated by means of their influence on pressures and cardiac output. Peripheral effects have, however, a great influence on cardiac output, 66 Ryden, Hjalmarson, Kvasnicka, and Liander and compensatory mechanisms may mask the influence of the intervention (Sonnenblick, Parmley, and Urschel, I969). When planning the investigation of the haemodynamic effects of QX-572, it was felt that a more complete picture could be gained by adding to the measurement of flow and pressures an analysis of the contractile state of the myocardium. In the present study the pressures in the brachial artery, right atrium, and left ventricle as well as heart rate, cardiac output, and systemic vascular resistance have been studied in man. Left ventricular contractility indices have been derived from pressure curves obtained by means of a catheter tip manometer placed in the left ventricle. To rule out the possible influence of the procedure as such on the results the study has been performed in a controlled manner. Subjects and methods Observations were made on I0 patients with aortic insufficiency after informed consent had been obtained. Selected data from the patients are presented in Table On clinical grounds the degree of aortic regurgitation was considered mild in Cases 2, 3, 6, and 9. In the remaining cases it was judged as moderate. The study of QX-572 was performed as part of a routine cardiac catheterization. This was either a postoperative evaluai. tion of valvular surgery with fascia lata prosthesis (Cases I, 2, 3, 4, 6, 7, and 9) or a clinical evaluation of aortic insufficiency (Cases 5, 8, and io). None of the patients had aortic stenosis or mitral valvular disease. Before catheterization the patients were divided into two comparable groups. This division was based upon clinical history with functional classification according to the New York Heart Association (I964), physical examination performed independently on the same day by two examiners, x-ray of the chest, and electrocardiogram. Randomly, it was decided that one group of patients (Cases 1-5, Table I) should constitute a control group while the patients in the other group (Cases 6-Io, Table i) were given QX-572. All catheterizations were performed in the nonsedated, postabsorptive state, with the patients in the supine position. All drugs were withheld for at least 12 hours before the study. A polyethylene catheter (PE 205) was introduced percutaneously into a brachial artery. A flow directed 5 F Swan-Ganz catheter (Edwards Laboratories, Santa Ana, U.S.A.) was use,d for pressure recordings in the right atrium and dye injections. Right atrial pacing at double the threshold of stimulation was performed via a bipolar pacemaker electrode (USCI, C 5I, 5 F) positioned close to the sinus node. A Statham SF-i catheter tip manometer was placed in the left ventricle by transseptal catheterization via the right subclavian vein (Kvasnicka et al., 1973). This manometer had a resonance frequency of approximately 5 kHz. The fluid-filled arm of the SF-i catheter, the brachial artery catheter, and the Sw (...truncated)