Br. J. clin. Pharmac. (1979), 8, 189S-193S
ACUTE MANAGEMENT OF SEVERE HYPERTENSION WITH ORAL LABETALOL R.R. GHOSE Consultant Physician, Singleton Hospital, Swansea, Wales
1 Six previously untreated emergency admissions to hospital with severe hypertension were given oral treatment with labetalol. 2 Pre-treatment diastolic BP exceeded 130 mmHg, and clinical evidence of either accelerated hypertension or encephalopathy was present. 3 Hypotensive response after treatment followed two patterns. 4 Quick-responders (n = 3) showed a sharp fall in BP to normal levels within 2 h, which was subsequently sustained for 10 or more hours. The daily dose of labetalol eventually required to achieve good BP control in this group was relatively low: 600-1200 mg. 5 Slow-responders (n = 3) showed a gradual, less marked fall in BP, which was sustained for many hours. These patients required further doses of labetalol to reduce BP to normal. The eventual daily dose of labetalol that ensured good BP control was high: 1200-2400 mg. 6 Heart rate was little changed by treatment. 7 Complications or side-effects were not observed.
Introduction
LABETALOL is rapidly absorbed from the gut in normal man. Peak plasma levels of labetalol occur within 2 h of taking an oral dose (Martin et al., 1976). The hypotensive action of labetalol after oral administration of 100, 200 and 400 mg doses is doserelated and occurs maximally over the first 3 h in mild-to-moderate hypertension, and is sustained for a period of 8 h (Serlin et al., 1979). A prompt hypotensive response has been observed within 2 h of treatment with 300 or 400 mg in severe hypertension (Ghose & Sampson, 1977) and an oral regime of labetalol has been shown capable of treating hypertensive emergencies such as accelerated hyper-
tension, or hypertensive encephalopathy (Ghose et al., 1978). Further clinical experience is presented which suggests that an oral regimen may be useful in the general medical ward for the acute management of severe hypertension with complications.
of characteristic neuro-retinitis on fundoscopic examination. Encephalopathy was suspected clinically by characteristic symptoms which disappeared after BP reduction was achieved by treatment. All patients were treated in bed in the supine position. BP was recorded at set intervals using a Roche Arteriosonde ultrasound device for automated measurement; heart rate was assessed by counting the radial pulse. The dose of labetalol to be used in the patients was calculated by a simple arbitrary formula using the diastolic BP (DBP). The first digit of the DBP is omitted, and zero is added to the last two digits, giving a figure representing the size of the proposed dose. For example, if the DBP is 130 mmHg (the lowest dose figure acceptable for entry to the study) then (1) 30 + 0 = 300 mg dose. The maximum dose recommended is 400 mg. The second dose was given at 6 hours. No further doses were administered if the DBP fell to 100 mmHg or below.
Methods Results
Previously untreated patients with severe hypertension complicated by either accelerated-phase or encephalopathy, were treated by oral labetalol. Accelerated hypertension was diagnosed on the basis 0306-5251/79/170189-05 $01.00
Clinical details and responses of the patients are shown in Table 1. Subsequent investigations showed that all patients had essential hypertension. BP and © Macmillan Journals Ltd 1979
190S
R.R. GHOSE 220
o,180-
E 160 E 140 120
'~100 CL
o0
mn
80-
6040-
200
3 4 pm
5 6
7 8 9 10 11 12 1
2
3 4 5 6 7 8 9
am
Time Figure 1 Quick response to labetalol 200 mg orally (at arrow) with a prompt fall in BP within 1 h (patient 1, male, 50 yr) Reduced BP level sustained for approximately 12 h with this dose.
240 220 200 E
E
~'180160140-
120) (D
C'a
o co
8
120 80
6040-
20 6
7
PM
8 9
10 11 12 1 am
2
3
4
5 6
7
8
9 10 11 12
Time Figure 2 This patient (no. 2, female, 32 yr) showed a relatively slow fall over 5 h, with subsequent variability, after labetalol 400 mg orally (at arrows). The dose was sustained over a period of 10 hours. Lower solid line, pulse rate. Table 1 Type of patient treated and effect of labetalol treatment in six severely hypertensive patients Patient
Sex/Age
Diagnosis
Serum creatinine
Pmol/l 160 88 355 i11
AH 1 M/50 AH 2 F/32 AH 3 M/38 AH 4 M/49 87 AH 5 F/38 HE 110 6 M/48 AH, Accelerated hypertension; HE, hypertensive encephalopathy.
Blood pressure (mmHg) Pretreatment
210/140 228/150 210/164 190/140 230/150 230/140
24 hour post-treatment
120/70 180/110 170/110 150/100 150/90 140/80
ACUTE MANAGEMENT OF SEVERE HYPERTENSION
191S
220 r 200-
1801160140 130 120 Cn cn 100 a) 0. -o0 80 0 60 40
I
E E
-
0
*
*
i
11 12
2 3
1
4
5
6
nm pill
7
I
* L.
8
9
*
10 11 12 1 am
2
3
4
5
Time
Figure 3 Initial rapid fall in BP over 2 h, with sustained BP for 10 h, after labetalol 400 mg orally (at arrow), remained at moderate-grade hypertension. A further 400 mg oral dose (at arrow) produced a slight decline in BP. Lower solid line, pulse rate. 220 200 180 I 160 E 140 E 120 en 100 80 60 40120 0..
0
0
0
2 3
4
5 6 7
8 9 10 11 12 1
pm
2
3
4
5
6
7
8
am
Time h and sustained for 12 hours. (Patient 4, male, 49 yr). Lower maximal 3 fall in BP was A 4 by prompt Figure solid line, pulse rate.
pulse rate are recorded against time in Figures 1-6. There were three quick-responders (Nos. 1, 4 and 6) who eventually required labetalol 600, 900 and 1200 mg daily, respectively; and three slowresponders (Nos. 2, 3 and 5), requiring doses of 2400, 1500 and 2100 mg, respectively. All cases responded to oral labetalol therapy by a reduction in BP to satisfactory levels 24 h after commencement, and no complications or side-effects were noted. Discussion The two patterns of hypotensive response noted after oral labetalol presumably represent two ends of a
spectrum of activity. Separation into two groups, quick-responders and slow-responders, may be useful clinically, as recognition of these patterns is helpful to bedside management. The quick-responder does not require a second dose for 10012 h, but the slowresponders need further doses at 6 or 8 h intervals. The differences between the groups could relate to their different metabolic or pharmacokinetic characteristics in the handling of labetalol; or to different haemodynamic, volume or humoral characteristics of the underlying hypertensive process. The immediate fall in BP after oral labetalol is predominantly related to haemodynamic consequences of a-adrenoceptor blockade. Individual sensitivity of resistance to the action of labetalol is poorly
192S
R.R. GHOSE 240 220 200x 180-
E
T)a v00 .2 co
160 140 120 100
80604020-
0L 2 3
4
5 6 7
pm
8 9 10 11 12 1 2 am
3
4
5
6 7
8 9 10
Time Figure 5 Slow response to 400 mg oral labetalol orally (at arrow), but sustained for 12 hours. (Patient 5, female, 38 yr.) Lower solid line, pulse rate. 400mg Labetalol 200 ~'180
-
p
16
L
0140
E 10 a
r
400mg 400mg
400mg 400mg40m 1
11 :11
80
60
06102 6102 61026 1026102 61026102 610261026102 6102610 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Time (d) Figure 6 A prompt fall in BP in hypertensive encephalopathy, with a 400 mg oral dose of labetalol. Subsequent BP readings n were normal for several days on a standard regimen of labetalol 400 mg three times daily.-.... *, pulse rate (beats (min)).
understood. In refractory essential hypertension there is an inordinately high total peripheral resistance, possibly due to structural changes in the resistance vessels (Andersson et al., 1978). Perhaps in these circumstances the vascular ax-adrenoceptors are damaged, thereby impairing their responsiveness to labetalol.
I am grateful to innumerable colleagues in the medical and nursing staff for helpful cooperation; to Dr S. Sarma for obtaining data from case-notes, to Mr Andrew Seaby for preparing the charts, and Mr J. Goolden for medical photography; and to Miss Lesley Grove for much secretarial work.
References ANDERSSON, O., HANSSON, L. & SIVERTSSON, R. (1978). Primary hypertension refractory to triple drug treatment: a study on central and peripheral haemodynamics. Circulation, 58, 615-622. GHOSE, R.R., MATHUR, Y.B., UPADHYAY, M., MORGAN,
W.D. & KHAN, S. (1978). Treatment of hypertensive emergencies with oral labetalol. Brit. med. J. 2, 96. GHOSE, R.R. & SAMPSON, A. (1977). Rapid onset of action of oral labetalol in severe hypertension. Curr. Med. Res. Opin., 5, 147-151.
ACUTE MANAGEMENT OF SEVERE HYPERTENSION GOLDBERG, A.D., RAFERTY, E.B., CASHMAN, P.M.M. &
STOFF, F.D. (1978). Study of untreated hypertensive subjects by means of continuous intra-arterial blood pressure recordings. Brit. Heart J., 40, 656-664. MARTIN, L.E., HOPKINS, R. & BLAND, R. (1976).
Metabolism of labetalol by animals and man. Bri. J. clin.
193S
Pharmac., suppl., 3 (4), 695-710. SERLIN, M.J., ORME, M.E., MACIVER, M., GREEN, G.J., MACNEE, C.M. & BRECKENRIDGE A.M. (1979). Rate on
onset of hypotensive Action of oral labetalol. Bri. J. Clin. Pharmac., 7, 165-168.
ACUTE MANAGEMENT OF SEVERE HYPERTENSION WITH ORAL LABETALOL R.R. GHOSE Consultant Physician, Singleton Hospital, Swansea, Wales
1 Six previously untreated emergency admissions to hospital with severe hypertension were given oral treatment with labetalol. 2 Pre-treatment diastolic BP exceeded 130 mmHg, and clinical evidence of either accelerated hypertension or encephalopathy was present. 3 Hypotensive response after treatment followed two patterns. 4 Quick-responders (n = 3) showed a sharp fall in BP to normal levels within 2 h, which was subsequently sustained for 10 or more hours. The daily dose of labetalol eventually required to achieve good BP control in this group was relatively low: 600-1200 mg. 5 Slow-responders (n = 3) showed a gradual, less marked fall in BP, which was sustained for many hours. These patients required further doses of labetalol to reduce BP to normal. The eventual daily dose of labetalol that ensured good BP control was high: 1200-2400 mg. 6 Heart rate was little changed by treatment. 7 Complications or side-effects were not observed.
Introduction
LABETALOL is rapidly absorbed from the gut in normal man. Peak plasma levels of labetalol occur within 2 h of taking an oral dose (Martin et al., 1976). The hypotensive action of labetalol after oral administration of 100, 200 and 400 mg doses is doserelated and occurs maximally over the first 3 h in mild-to-moderate hypertension, and is sustained for a period of 8 h (Serlin et al., 1979). A prompt hypotensive response has been observed within 2 h of treatment with 300 or 400 mg in severe hypertension (Ghose & Sampson, 1977) and an oral regime of labetalol has been shown capable of treating hypertensive emergencies such as accelerated hyper-
tension, or hypertensive encephalopathy (Ghose et al., 1978). Further clinical experience is presented which suggests that an oral regimen may be useful in the general medical ward for the acute management of severe hypertension with complications.
of characteristic neuro-retinitis on fundoscopic examination. Encephalopathy was suspected clinically by characteristic symptoms which disappeared after BP reduction was achieved by treatment. All patients were treated in bed in the supine position. BP was recorded at set intervals using a Roche Arteriosonde ultrasound device for automated measurement; heart rate was assessed by counting the radial pulse. The dose of labetalol to be used in the patients was calculated by a simple arbitrary formula using the diastolic BP (DBP). The first digit of the DBP is omitted, and zero is added to the last two digits, giving a figure representing the size of the proposed dose. For example, if the DBP is 130 mmHg (the lowest dose figure acceptable for entry to the study) then (1) 30 + 0 = 300 mg dose. The maximum dose recommended is 400 mg. The second dose was given at 6 hours. No further doses were administered if the DBP fell to 100 mmHg or below.
Methods Results
Previously untreated patients with severe hypertension complicated by either accelerated-phase or encephalopathy, were treated by oral labetalol. Accelerated hypertension was diagnosed on the basis 0306-5251/79/170189-05 $01.00
Clinical details and responses of the patients are shown in Table 1. Subsequent investigations showed that all patients had essential hypertension. BP and © Macmillan Journals Ltd 1979
190S
R.R. GHOSE 220
o,180-
E 160 E 140 120
'~100 CL
o0
mn
80-
6040-
200
3 4 pm
5 6
7 8 9 10 11 12 1
2
3 4 5 6 7 8 9
am
Time Figure 1 Quick response to labetalol 200 mg orally (at arrow) with a prompt fall in BP within 1 h (patient 1, male, 50 yr) Reduced BP level sustained for approximately 12 h with this dose.
240 220 200 E
E
~'180160140-
120) (D
C'a
o co
8
120 80
6040-
20 6
7
PM
8 9
10 11 12 1 am
2
3
4
5 6
7
8
9 10 11 12
Time Figure 2 This patient (no. 2, female, 32 yr) showed a relatively slow fall over 5 h, with subsequent variability, after labetalol 400 mg orally (at arrows). The dose was sustained over a period of 10 hours. Lower solid line, pulse rate. Table 1 Type of patient treated and effect of labetalol treatment in six severely hypertensive patients Patient
Sex/Age
Diagnosis
Serum creatinine
Pmol/l 160 88 355 i11
AH 1 M/50 AH 2 F/32 AH 3 M/38 AH 4 M/49 87 AH 5 F/38 HE 110 6 M/48 AH, Accelerated hypertension; HE, hypertensive encephalopathy.
Blood pressure (mmHg) Pretreatment
210/140 228/150 210/164 190/140 230/150 230/140
24 hour post-treatment
120/70 180/110 170/110 150/100 150/90 140/80
ACUTE MANAGEMENT OF SEVERE HYPERTENSION
191S
220 r 200-
1801160140 130 120 Cn cn 100 a) 0. -o0 80 0 60 40
I
E E
-
0
*
*
i
11 12
2 3
1
4
5
6
nm pill
7
I
* L.
8
9
*
10 11 12 1 am
2
3
4
5
Time
Figure 3 Initial rapid fall in BP over 2 h, with sustained BP for 10 h, after labetalol 400 mg orally (at arrow), remained at moderate-grade hypertension. A further 400 mg oral dose (at arrow) produced a slight decline in BP. Lower solid line, pulse rate. 220 200 180 I 160 E 140 E 120 en 100 80 60 40120 0..
0
0
0
2 3
4
5 6 7
8 9 10 11 12 1
pm
2
3
4
5
6
7
8
am
Time h and sustained for 12 hours. (Patient 4, male, 49 yr). Lower maximal 3 fall in BP was A 4 by prompt Figure solid line, pulse rate.
pulse rate are recorded against time in Figures 1-6. There were three quick-responders (Nos. 1, 4 and 6) who eventually required labetalol 600, 900 and 1200 mg daily, respectively; and three slowresponders (Nos. 2, 3 and 5), requiring doses of 2400, 1500 and 2100 mg, respectively. All cases responded to oral labetalol therapy by a reduction in BP to satisfactory levels 24 h after commencement, and no complications or side-effects were noted. Discussion The two patterns of hypotensive response noted after oral labetalol presumably represent two ends of a
spectrum of activity. Separation into two groups, quick-responders and slow-responders, may be useful clinically, as recognition of these patterns is helpful to bedside management. The quick-responder does not require a second dose for 10012 h, but the slowresponders need further doses at 6 or 8 h intervals. The differences between the groups could relate to their different metabolic or pharmacokinetic characteristics in the handling of labetalol; or to different haemodynamic, volume or humoral characteristics of the underlying hypertensive process. The immediate fall in BP after oral labetalol is predominantly related to haemodynamic consequences of a-adrenoceptor blockade. Individual sensitivity of resistance to the action of labetalol is poorly
192S
R.R. GHOSE 240 220 200x 180-
E
T)a v00 .2 co
160 140 120 100
80604020-
0L 2 3
4
5 6 7
pm
8 9 10 11 12 1 2 am
3
4
5
6 7
8 9 10
Time Figure 5 Slow response to 400 mg oral labetalol orally (at arrow), but sustained for 12 hours. (Patient 5, female, 38 yr.) Lower solid line, pulse rate. 400mg Labetalol 200 ~'180
-
p
16
L
0140
E 10 a
r
400mg 400mg
400mg 400mg40m 1
11 :11
80
60
06102 6102 61026 1026102 61026102 610261026102 6102610 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Time (d) Figure 6 A prompt fall in BP in hypertensive encephalopathy, with a 400 mg oral dose of labetalol. Subsequent BP readings n were normal for several days on a standard regimen of labetalol 400 mg three times daily.-.... *, pulse rate (beats (min)).
understood. In refractory essential hypertension there is an inordinately high total peripheral resistance, possibly due to structural changes in the resistance vessels (Andersson et al., 1978). Perhaps in these circumstances the vascular ax-adrenoceptors are damaged, thereby impairing their responsiveness to labetalol.
I am grateful to innumerable colleagues in the medical and nursing staff for helpful cooperation; to Dr S. Sarma for obtaining data from case-notes, to Mr Andrew Seaby for preparing the charts, and Mr J. Goolden for medical photography; and to Miss Lesley Grove for much secretarial work.
References ANDERSSON, O., HANSSON, L. & SIVERTSSON, R. (1978). Primary hypertension refractory to triple drug treatment: a study on central and peripheral haemodynamics. Circulation, 58, 615-622. GHOSE, R.R., MATHUR, Y.B., UPADHYAY, M., MORGAN,
W.D. & KHAN, S. (1978). Treatment of hypertensive emergencies with oral labetalol. Brit. med. J. 2, 96. GHOSE, R.R. & SAMPSON, A. (1977). Rapid onset of action of oral labetalol in severe hypertension. Curr. Med. Res. Opin., 5, 147-151.
ACUTE MANAGEMENT OF SEVERE HYPERTENSION GOLDBERG, A.D., RAFERTY, E.B., CASHMAN, P.M.M. &
STOFF, F.D. (1978). Study of untreated hypertensive subjects by means of continuous intra-arterial blood pressure recordings. Brit. Heart J., 40, 656-664. MARTIN, L.E., HOPKINS, R. & BLAND, R. (1976).
Metabolism of labetalol by animals and man. Bri. J. clin.
193S
Pharmac., suppl., 3 (4), 695-710. SERLIN, M.J., ORME, M.E., MACIVER, M., GREEN, G.J., MACNEE, C.M. & BRECKENRIDGE A.M. (1979). Rate on
onset of hypotensive Action of oral labetalol. Bri. J. Clin. Pharmac., 7, 165-168.
