Br. J. clin. Pharmac. (1979), 8, 95S-100S
EFFECT OF LABETALOL IN HYPERTENSION DURING EXERCISE AND POSTURAL CHANGES V. BALASUBRAMANIAN, S. MANN, M.W. MILLAR-CRAIG
&
E.B. RAFTERY
Department of Cardiology, Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex HAl 3UJ, UK
1 Fourteen hypertensive patients were studied by intra-arterial BP monitoring to quantify the effects of standardized physiological stresses: Valsalva manoeuvre, isometric, treadmill and bicycle exercise, and 600 tilting before and after labetalol treatment. 2 The dose of labetalol ranged from 100-600 mg three times daily and the response was judged on outpatient clinic recordings. 3 The drug produced a sustained reduction of BP and heart rate responses during dynamic exercise and the Valsalva manoeuvre, but the degree of change from the lowered baseline were not changed by labetalol. The fall in BP on cessation of exercise was decreased rather than increased. 4 The response to controlled isometric muscle contraction was affected in a similar fashion. 5 Tilting produced a fall in BP after treatment, and this was most marked in those patients on the highest doses. However, compensatory increases in diastolic BP were observed.
Introduction ASSESSMENT of the efficacy of antihypertensive drugs usually depends upon one-off recordings of outpatient BPs by indirect sphygmomanometry, a method which does not allow consideration of the effects of varying physical and mental stress throughout the patients' daily activities. It is now known what parameters of BP are primarily responsible for damage to the arterial wall, but it is clearly important to understand the range of BPs and their variability in each individual, and the effects of drugs. It is well known that BP increases on static and dynamic exercise, and that it may vary considerably with posture (Astrand & Rodahl, 1970; Henschel et al., 1954; Lind, 1970; Sime et al., 1975). Failure to recognize that resting BPs do not reflect BPs at other times may lead to erroneous conclusions about drug efficacy (Goldberg & Raftery 1976; Stoker et al., 1979). Assessment of the efficacy of a hypotensive drug should therefore take into account the effects of the drug on the physiological components of the normal response to physical exertion. This can only be done in the context of carefully designed and standardized test protocols with known reproducibility which will allow the observation of drug effects. This study was planned to determine the changes in hypertensive patients on labetalol treatment, with 0306-5251/79/170095-06 $01.00
specific reference to standardized test protocols using continuous intra-arterial BP monitoring. Methods Patients
Fourteen patients (11 male, 3 female, mean age 47 yr) with mild to moderately severe hypertension were selected from the Harrow Hypertension Clinic for detailed study. All were screened in detail to exclude secondary hypertension and any other associated disorders such as ischaemic heart disease. None had ever had any anti-hypertensive treatment.
Ambulatory monitoring BP was monitored continuously by an indwelling intra-arterial cannula connected to a transducerperfusion unit and an Oxford Medilog Mark 1 multichannel tape recorder. The technical details and validation have already been reported (Millar-Craig et al., 1978b). The patients came to the hospital between 0900 and 1100 and all cannulations were completed by 1100. The non-dominant arm's brachial artery was cannulated under local anaesthesia using the
0 Macmillan Joumals Ltd 1979
96S
V. BALASUBRAMANIAN, S. MANN, M.W. MILLAR-CRAIG & E.B. RAFTERY
Seldinger technique and a small Telflon cannula was left in situ connected to a transducer-perfusion unit. This perfused the cannula with heparinized saline at 2.0 ml/h and recorded the arterial pulse on the tape recorder. Stepwise calibrations of 50 mmHg between 0 and 300 mmHg were also recorded at the beginning of the experiment and 2 h later. Recordings were made for 36-48 h continuously, and the physiological protocols were carried out in the first 2 h after cannulation. Informed consent was obtained from each patient and the project as a whole was approved by the hospital ethical committee. Valsalve manoeuvres
Patients were asked to blow into a mouthpiece-with a controlled leak attached to a mercury column which was maintained at 40 mmHg for 10 seconds. The test was repeated three times at intervals of 2 minutes. Supine rest
Patients were asked to lie supine on a horizontal tilt table and rest undisturbed in a quiet darkened room for 20 minutes. Postural tilt
At the end of the supine rest period the table was tilted head-up to 600 and kept at that inclination for 3 min, when it was returned to the horizontal. The tiltup and return were completed in under 5 seconds. Exercise
Dynamic exercise
Dynamic exercise was carried out on a bicycle ergometer in six and a treadmill in eight patients, respectively. The protocols used are shown in Table 1. The electrocardiogram was continuously monitored during and after exercise using a computerassisted system. (CASE, Marquette). Each test was terminated at the point of fatigue. Each patient was returned to the sitting posture after exercise for 5 min to monitor the post-exercise changes in BP. Each protocol was repeated at the second study after satisfactory control of clinic BP had been achieved by administration of labetalol three times daily. Data analysis
Calibrations and the arterial BP waveform were written out using an ultraviolet recorder at a suitable speed to identify individual complexes. Systolic and diastolic BPs were then measured manually in reference to standard calibration markings. Statistical analysis was carried out using Student's paired t test. Results Supine and standing BPs (Figure 1) Mean supine BP at the end of 20 min of quiet rest for the group before treatment was 165/91 mmHg (s.e.m. + 6/3) which was reduced to 146/81 ( ± 5/3) mmHg, but only the systolic change was statistically significant. Mean standing BP before treatment was 180/105 ( ± 8/4) mmHg. This was reduced after treatment to
A hand grip dynamometer (Quinton) was used to produce isometric forearm muscle contraction. Each patient's initial maximal grip was determined, and after returning to the basal state each was asked to keep the dynamometer needle at 50% of maximum for 2 minutes. The arm was supported on a pillow, and breath-holding during the test was avoided by asking the patient to count out loud.
140/81 (± 7/3) mmHg (P
EFFECT OF LABETALOL IN HYPERTENSION DURING EXERCISE AND POSTURAL CHANGES V. BALASUBRAMANIAN, S. MANN, M.W. MILLAR-CRAIG
&
E.B. RAFTERY
Department of Cardiology, Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex HAl 3UJ, UK
1 Fourteen hypertensive patients were studied by intra-arterial BP monitoring to quantify the effects of standardized physiological stresses: Valsalva manoeuvre, isometric, treadmill and bicycle exercise, and 600 tilting before and after labetalol treatment. 2 The dose of labetalol ranged from 100-600 mg three times daily and the response was judged on outpatient clinic recordings. 3 The drug produced a sustained reduction of BP and heart rate responses during dynamic exercise and the Valsalva manoeuvre, but the degree of change from the lowered baseline were not changed by labetalol. The fall in BP on cessation of exercise was decreased rather than increased. 4 The response to controlled isometric muscle contraction was affected in a similar fashion. 5 Tilting produced a fall in BP after treatment, and this was most marked in those patients on the highest doses. However, compensatory increases in diastolic BP were observed.
Introduction ASSESSMENT of the efficacy of antihypertensive drugs usually depends upon one-off recordings of outpatient BPs by indirect sphygmomanometry, a method which does not allow consideration of the effects of varying physical and mental stress throughout the patients' daily activities. It is now known what parameters of BP are primarily responsible for damage to the arterial wall, but it is clearly important to understand the range of BPs and their variability in each individual, and the effects of drugs. It is well known that BP increases on static and dynamic exercise, and that it may vary considerably with posture (Astrand & Rodahl, 1970; Henschel et al., 1954; Lind, 1970; Sime et al., 1975). Failure to recognize that resting BPs do not reflect BPs at other times may lead to erroneous conclusions about drug efficacy (Goldberg & Raftery 1976; Stoker et al., 1979). Assessment of the efficacy of a hypotensive drug should therefore take into account the effects of the drug on the physiological components of the normal response to physical exertion. This can only be done in the context of carefully designed and standardized test protocols with known reproducibility which will allow the observation of drug effects. This study was planned to determine the changes in hypertensive patients on labetalol treatment, with 0306-5251/79/170095-06 $01.00
specific reference to standardized test protocols using continuous intra-arterial BP monitoring. Methods Patients
Fourteen patients (11 male, 3 female, mean age 47 yr) with mild to moderately severe hypertension were selected from the Harrow Hypertension Clinic for detailed study. All were screened in detail to exclude secondary hypertension and any other associated disorders such as ischaemic heart disease. None had ever had any anti-hypertensive treatment.
Ambulatory monitoring BP was monitored continuously by an indwelling intra-arterial cannula connected to a transducerperfusion unit and an Oxford Medilog Mark 1 multichannel tape recorder. The technical details and validation have already been reported (Millar-Craig et al., 1978b). The patients came to the hospital between 0900 and 1100 and all cannulations were completed by 1100. The non-dominant arm's brachial artery was cannulated under local anaesthesia using the
0 Macmillan Joumals Ltd 1979
96S
V. BALASUBRAMANIAN, S. MANN, M.W. MILLAR-CRAIG & E.B. RAFTERY
Seldinger technique and a small Telflon cannula was left in situ connected to a transducer-perfusion unit. This perfused the cannula with heparinized saline at 2.0 ml/h and recorded the arterial pulse on the tape recorder. Stepwise calibrations of 50 mmHg between 0 and 300 mmHg were also recorded at the beginning of the experiment and 2 h later. Recordings were made for 36-48 h continuously, and the physiological protocols were carried out in the first 2 h after cannulation. Informed consent was obtained from each patient and the project as a whole was approved by the hospital ethical committee. Valsalve manoeuvres
Patients were asked to blow into a mouthpiece-with a controlled leak attached to a mercury column which was maintained at 40 mmHg for 10 seconds. The test was repeated three times at intervals of 2 minutes. Supine rest
Patients were asked to lie supine on a horizontal tilt table and rest undisturbed in a quiet darkened room for 20 minutes. Postural tilt
At the end of the supine rest period the table was tilted head-up to 600 and kept at that inclination for 3 min, when it was returned to the horizontal. The tiltup and return were completed in under 5 seconds. Exercise
Dynamic exercise
Dynamic exercise was carried out on a bicycle ergometer in six and a treadmill in eight patients, respectively. The protocols used are shown in Table 1. The electrocardiogram was continuously monitored during and after exercise using a computerassisted system. (CASE, Marquette). Each test was terminated at the point of fatigue. Each patient was returned to the sitting posture after exercise for 5 min to monitor the post-exercise changes in BP. Each protocol was repeated at the second study after satisfactory control of clinic BP had been achieved by administration of labetalol three times daily. Data analysis
Calibrations and the arterial BP waveform were written out using an ultraviolet recorder at a suitable speed to identify individual complexes. Systolic and diastolic BPs were then measured manually in reference to standard calibration markings. Statistical analysis was carried out using Student's paired t test. Results Supine and standing BPs (Figure 1) Mean supine BP at the end of 20 min of quiet rest for the group before treatment was 165/91 mmHg (s.e.m. + 6/3) which was reduced to 146/81 ( ± 5/3) mmHg, but only the systolic change was statistically significant. Mean standing BP before treatment was 180/105 ( ± 8/4) mmHg. This was reduced after treatment to
A hand grip dynamometer (Quinton) was used to produce isometric forearm muscle contraction. Each patient's initial maximal grip was determined, and after returning to the basal state each was asked to keep the dynamometer needle at 50% of maximum for 2 minutes. The arm was supported on a pillow, and breath-holding during the test was avoided by asking the patient to count out loud.
140/81 (± 7/3) mmHg (P
