tients were receiving drugs, such as quinidine, that are capable of interfering with encainide metabolism.6 These data also confirm previous findings with flecainide, another potent class IC antiarrhythmic agent, in which conduction slowing was enhanced by exercise-induced sinus tachycardia or by ventricular pacing.’ In the flecainide study, the physiologic increase in heart rate associated with exercise was the major determinant of conduction slowing, and other factors associated with exercise were apparently not contributory. In addition, flecainide’s effect on QRS prolongation at rest predicted further QRS prolongation with exercise. The encainide metabolites, ODE and MODE, play an important role in drug effects at rest.8 However, what effect rate-dependent prolongation of intraventricular conduction by ODE and MODE has on either antiarrhythmic efficacy or proarrhythmia has still not been fully elucidated. Rate-dependent conduction slowing by flecainide has been implicated as an arrhythmogenic mechanism in predisposed patients. Ranger et al7 speculated that in patients with preexisting areas of abnormal conduction, rate-dependent conduction slowing by flecainide could so alter conduction that sustained reentry in a potentially arrhythmogenic region could develop. Encainide can produce a proarrhythmic effect in predisposed patients, both with exercise9 and at rest. lo Conceivably, the mechanism of proarrhythmia may involve rate-dependent conduction slowing by encainide metabolites, ODE and MODE. If so, then blunting rate-dependent conduction slowing may prevent proarrhythmia from developing. Recent evidence suggests that the proarrhythmic effects of encainide and flecainide may be reversed by ,&adrenergic b1ockade.l’ This is of particular interest in light of recent evidence from the Cardiac Arrhythmia Suppression Trial, which indicates that encainide can be deleterious in patients with asymptomatic postinfarction ventricular ectopy.12

Effects of Noninvasive on Blood Pressure

Ambulatory

Geoffrey Brigden, MRCP, Paul Broadhurst,

MRCP, Peter

does not decrease with repeated measurement, and is worse in the presence of a doctor than in the presence of a nurse.2 This suggests that the major component of the reaction is not discomfort from inflation of the cuff, and this is supported by the fact that BP usually increases before the cuff is applied. These observations have led to the assumption that ambulatory cuff BP devices do not From the Cardiology Department, Northwick Park Hospital & Clinical Research Centre, Watford Road, Harrow, Middlesex, HA1 3UJ, United Kingdom. Manuscript received April 4, 1990; revised manuscript received and accepted July 17, 1990. THE AMERICAN

JOURNAL

OF CARDIOLOGY

1. Woosley RL, Roden DM, Dai G, Wang T, Altenbern D. Oates J, Wilkinson GR. Co-inheritance of the polymorphic metabolism of encainide and debrisoquin. Clin Pharmacol Ther 1986;39:282-287. 2. Wang T, Roden DM, Wolfenden HT, Woosley RL, Wood AJJ, Wilkinson GR. Influence of genetic polymorphism on the metabolism and disposition of encainide in man. J Pharmacol Exp Ther 1984;228:605-611. 3. Carmeliet E. Electrophysiological effects of encainide on isolated cardiac muscle and Purkinje fibers and on the Langendorff-perfused guinea pig heart. Eur J Pharmacol 1980;61:241-262. 4. Dresel PE. Effect of encainide and its two major metabolites on cardiac conduction. J Pharmacol Exp Ther I984;228: 180-I 86. 5. Bartek MJ, Mayo1 RF, Boarman MP, Gammans RE, Gal10 DG. Analysis of encainide and metabolites in plasma and urine by high-performance liquid chromatography. Ther Drug Monit 1988;10:446-452. 6. Funck-Brentano C, Turgeon J, Woosley RL, Roden DM. Effect of low dose quinidine on encainide pharmacokinetics and pharmacodynamics. Influence of genetic polymorphism. J Pharmncol Exp Ther 1989;249:134-142. 7. Ranger S, Talajic M, Lemery R, Roy D, Nattel S. Amplification of flecainideinduced ventricxdar conduction slowing by exercise. A potentially significant clinical consequence of use-dependent sodium channel blockade. Circulation 1989; 79:1000-1006. 8. Barbey JT, Thompson KA, Echt DS, Woosley RL, Roden DM. Antiarrhythmic activity, electrocardiographic effects and pharmacokinetics of the encainide metabolites 0-desmethyl encainide and 3-methoxy-0-desmethyl encainide in man. Circulation 1988;77:380-391. 9. DiBianco R, Fletcher RD. Cohen AI, Gottdiener JS, Singh SN, Katz RJ, Bates HR, Sauerbrunn B. Treatment offrequent ventricular arrhythmia with encainide: asswment using serial ambulatory electrocardiograms, intracardiac electrophysiologic studies, treadmill exercise tests, and radionuclide cineangiographic studies. Circulation 1982;65:1 J34-1147. 10. Tordjman T, Podrid PJ, Raeder E, Low B. Safety and efficacy of encainide for malignant ventricular arrhythmias. Am J Cwdiol I986;58:87C-95C. 11. Myerburg RJ, Kessler KM, Cox MM, Muikuri H, Terracall E, Interian A, Fernandez P, Castellanos A. Reversal of proarrhythmic effects of flecainide acetate and encainide hydrochloride by propranolol. Circulation 1989;80:15711519. 12. The Cardiac Arrhythmic Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321: 406-412.

Blood

t is well recognized that the act of blood pressure (BP) I“cuffmeasurement may influence the level of BP.’ This response” is attributed to an alerting reaction; it

1396

Thus, in the quest for finding better ways of predicting drug efficacy, inefficacy and proarrhythmia, rate-related changes in QRS duration may be an additional means for evaluating drug effect. As indicated by these initial observations, rate-related changes in QRS duration may also be a means for recognizing subgroups of patients with different phenotypic patterns of encainide metabolism.

VOLUME

66

Pressure

Cashman,

Measuring

Devices

PhD, and Edward B. Raftery, MD

provoke such effects. This is implicit in the high reproducibility of measurements in groups of subjects that has been observed with some modern machines,3 although this could simply reflect the reproducibility of the alerting response. This issue has only been addressed in subjects confined to bed for relatively brief periods.4 No account has been taken of the possibility of effects on patients trying to sleep at night, or of the overall impact of wearing such devices. Ambulatory BP monitors are coming into wide use for the assessment of hypertensive subjects before and after treatment. This follows observations that ambulatory measurements are better prognostic indicators than casual readings.5 This study tests the hypothesis that wearing an ambulatory cuff BP monitor might, in itself, alter BP by increasing discomfort, influencing ac-

tivity or sleep patterns, or by promoting an alerting response. Thirteen patients (9 men and 4 women) undergoing ambulatory intraarterial BP monitoring for assessment of hypertension were studied. They had a mean age of 43 years (range 19 to 60). Of these subjects, 3 were taking medication: 2 were taking a slow-release preparation of nicardipine, and 1 was taking quinapril (a new angiotensin-converting enzyme inhibitor). Patients on B blockers were specifically excluded. All patients gave informed consent and the study was approved by the Harrow Health Authority Ethical Committee. Initial 24-hour ambulatory intraarterial monitoring was performed without the addition of the cuff measuring device. The intraarterial recording was then continued for a further 24 hours after a Colin 630 noninvasive ambulatory BP monitor (Nippon/Colin, Japan) was attached. The cuff of the Colin monitor was applied to the contralateral arm. This inflated 6 times per hour during the day and 3 times per hour during the night. During both monitoring periods, patients were fully ambulant outside the hospital, and were simply instructed to straighten and reduce arm movement to a minimum whenever the cuff device triggered. The pre-cuff inflation warning bleep was disabled. The device had a “retry” facility, so that if the patient moved the arm too vigorously during an inflation, a second inflation occurred. Intraarterial BP monitoring was performed using the Oxford technique, which has been fully described and validated elsewhere.6 A 3Fr gauge Teflon@ cannula was inserted into the brachial artery on the nondominant arm

under local anesthetic with the Seldinger technique, and was then connected to a transducer/perfusion unit through a manometer line; the signalsfrom this and a bipolar electrocardiogram were recorded onto an Oxford Medilog 4-24 recorder, incorporating a time channel and electrical event marker. The intraarterial BP tapes were replayed using an analog chart recorder to check for gross artifact or recorder malfunction. They were then analyzed with a purpose-built system consistingof a modified Reynolds Medical CR1 1 Holter cassettedeck and a DEC MING 1l/23 digital computer. The timing was set up to align the digital clock of the Colin monitor with the intraarterial recording, and time correction was performed to account for tape speedvariation. In no instance did this vary by >I minute in 24 hours. In addition, the intraarterial BP signal was visually checked,for eachpatient, by an observer (PC), who tried to identify the points of cuff inflation from changes in intraarterial BP. For eachpatient the 30-secondmeanintraarterial BP coincident with each cuff inflation was identified and compared with their residual overall mean daytime (midday to P.M. hours) and nighttime (midnight to 6 A.M. hours) BPS.PairedStudent’s t testswereperformed

go-c a 9

+i 2 3 I

ao-

70-

60 J

180 1 s 160I g 140a, 2 2 1209 8 ioo,"

m ao-

10 12 14 16 18 2022 24 2 4 6 8 FIGURE 1. Part of an ambulatory recording of intraarterial blood pressure (BP) and heart rate (HR) with the points of cuff inflation indicated by arrows (lo-minute intervals)). The increase in BP coincided with activity and not with cuff inflation. bpm = baats/min.

Time

of day

10

12

(hours)

FIGURE 2. ~wen~f~r-her profiles of intraarterial blood pressure and heart rate before (closed bullet) and after (open bullet) applying the noninvasive monitor.

THE AMERICAN

JOURNAL

OF CARDIOLOGY

DECEMBER

1, 1990

TABLE

I Number

of Subjects

Showing

Day (Midday

a Difference

in Blood

Pressure

to 6 P.M.)

at Times

of Inflation Night (Midnight

to 6A.M.)

Increase

Decrease

No Effect

Increase

Decrease

No Effect

0

l(5.7)

12

0

l(1.7)

12

Diastolic

0

0

13

0

0

13

pressure (mm W Heart rate (beats/min)

0

l(5.9)

12

0

l(3.4)

12

Systolic pressure (mm W

Numbers of subjects showing any significant effect (i.e., no effect indicates p >0.05) on 30second mean intraarterial blood pressure at times of inflation compared with the residual mean. The only significant changes occurred in 4 d&rent subjects. The magnitudes of these changes are shown in brackets--all were decreases rather than increases.

for each patient to see if any significant changes in BP or heart rate had occurred. A 30-second mean intraarterial BP might be expected to coincide with the systolic and diastolic points of a cuff inflation, because it has been previously shown that brief (e.g., I minute) intraarterial BP means do not differ signij?cantly from randomly selected single beats from within that period.7 Pooled mean hourly intraarterial BP and heart rate for all subjects were obtained for each hour of the 24hour period before application of the Colin device. These were plotted for comparison with pooled mean hourly intraarterial BP and heart rate during the 24 hours of cuff BP monitoring to assess any overall impact of wearing the device. Significance was assessed using paired Student’s t tests. Inspection of the intraarterial BP signal as it was replayed did not reveal any recurring pattern of BP elevation that could be distinguishedfrom normal variation (Figure I ). The patients did, however, show an increase in BP coincident with returning to the hospital to see the physician in the late afternoon (Figure 2). Table I lists the numbers of subjects showing s&n>cant differences between their 30-second mean intraarterial BP at the times of cuff inflation and their residual means (each taken as a constant) for the daytime and nighttime periods. Only inflations that could be timed precisely were used (thus, failed inflations and “retries” were excluded), so that during the day these were based on a mean of 27 readings per patient and at night on a mean of 16 readings per patient. The only signif?cant changes were small decreases in systolic BP and heart rate in 4 different subjects, suggesting that there were no pressor effects at the times of inflation, and that reduced activity at the points of inflation did not influence the results. The pooled mean hourly intraarterial BP for the 2 consecutive 24-hour periods are shown in Figure 2. Overall9 it can be seen that there was little difference between them. The characteristic BP increase at 17:OO hours (5 P.M.) coincided with thepatients returning to the hospital for equipment checks by the physician. At this point, the intraarterial systolic BP was higher 0,