Br. J. clin. Pharmac. (1979), 8, 199S-204S

TREATMENT OF SEVERE HYPERTENSION BY REPEATED BOLUS INJECTIONS OF LABETALOL A.M.M. CUMMING, J.J. BROWN, A.F, LEVER, A. MACKAY, J.I.S. ROBERTSON Medical Research Council Blood Pressure Unit, Western Infirmary, Glasgow Gl1 6NT, UK

1 Repeated intravenous bolus injections of labetalol were administered to 15 severely hypertensive patients. In 11 instances, a standard protocol was followed in which a loading dose of 1 mg/kg was given intravenously over 1 min, followed by up to five bolus injections of 50 mg at 10-min intervals. In two further patients, bolus doses varying from 25-100 mg were given after the loading dose, and in two others the loading dose was omitted. 2 Falls in systolic BP ranging from 26-194 mmHg were seen in 14 patients and of diastolic BP from 16-76 mmHg in 13. In one patient there was no appreciable fall in either systolic or diastolic BP and in one no marked fall in diastolic BP, although systolic BP dropped by 42 mmHg. 3 The reduction in arterial BP was smooth in ten patients. 4 In four patients a steep fall in BP, of 194 to 101 mmHg systolic, was seen within 10 min of an injection of labetalol; in all four hypotension was readily controlled by elevating the foot of the bed. 5 Side-effects included nausea, vomiting, epigastric discomfort, scalp tingling, burning sensations in the throat and groin, shivering, and pain at the site of injection. Side-effects limited the dose given in four patients. 6 In no case was there clinical or electrocardiographic evidence of myocardial ischaemia induced by labetalol. 7 Labetalol, given by bolus injection, appeared less efficient in controlling arterial pressure, and more likely to cause side-effects, than when given, as in a previous study, by incremental infusion. 8 When labetalol is to be given intravenously for the control of severe hypertension, incremental infusion, rather than bolus injection, is preferred.

Introduction

hypertension when given by repeated bolus

injections. IN previous studies (Agabiti-Rosei et al., 1976; Trust et al., 1976), it has been shown that the rapid intravenous injection of labetalol in doses of 1-2 mg/kg promptly and effectively reduces arterial BP in severely hypertensive patients, without increasing heart rate and with lowering of the plasma concentrations of angiotensin II and aldosterone. A subsequent paper (Cumming et al., 1979) has described the administration of labetalol by incremental intravenous infusion. Given in this way, the drug caused generally a more gradual reduction in arterial BP, while, as before, significantly lowering heart rate and plasma concentrations of angiotensin II and aldosterone. However, a steep fall in arterial BP was seen in 6 of the 19 patients of this latter series, and continuous monitoring was necessary

throughout. The present study was carried out to assess the value of labetalol in the treatment of severe

0306-5251/79/170199-06 $01.00

Methods

Fifteen patients (10 males) aged 17-67 yr were studied. Details are given in Table 1. Initial mean BP was 241/144 mmHg (± 9.5/4.5 s.e.m.). Eleven of these patients were untreated. The remaining four patients were still severely hypertensive despite treatment with a variety of antihypertensive agents, including atenolol, propanolol, diazoxide, hydrallazine, amiloride, bendrofluazide and bumetanide. One of the 15 had post-partum eclampsia, with severe hypertension unresponsive to oral diazoxide. In three patients there was associated renal disease, namely unilateral renal artery stenosis in one and bilateral chronic pyelonephritis in two. Two patients (both untreated; one with chronic pyelonephritis) were taking oestrogen-progestagen oral contracep00 Macmillan Journals Ltd 1979

200S

A.M.M. CUMMING, J.J. BROWN, A.F. LEVER, A. MACKAY, J.I.S. ROBERTSON

tives. The remaining ten patients had essential hypertension, there being no clinical, biochemical or radiological evidence of aortic coarctation, primary renal disease, Cushing's syndrome, Conn's syndrome, or phaeochromocytoma. Twelve of the 15 had malignant phase hypertension. Bilateral retinal haemorrhages, exudates and papilloedema were present in eight patients, and in the single remaining eye in one. Three other subjects had bilateral haemorrhages and exudates without swelling of the optic discs. Ten patients had renal impairment, with serum creatinine concentrations ranging from 125-250 kmol/I at the time of study. None of the 19 had clinical or biochemical evidence of hepatic dysfunction. One patient had suffered a previous transient cerebral ischaemic attack and one a subarachnoid haemorrhage associated with a ruptured berry aneurysm. Two had electrocardiographic evidence of myocardial ischaemia. In the 11 patients in whom measurements were made, plasma active renin concentration was above the upper limit of normal in seven, and plasma angiotensin II similarly raised in nine (Table 1). BP was measured in all studies with an automatic recording device (Bosomat or Elag; Stephens, Blackpool, UK). Readings were made at least every 5

min throughout the study and at least every 1 min after the loading dose of labetalol was given. The pulse was recorded automatically and also checked frequently by the observer. After initial assessment of BP for at least 2 hr, a loading dose of labetalol (1 mg/kg) was given over 1 min into a vein of the opposite ann to which the recording device was attached. This loading dose was followed after 4 min by a bolus injection of labetalol 50 mg given over 1 minute. Further boluses of 50 mg were given at 10 min intervals until either BP was controlled or a total of five bolus doses plus the loading dose had been administered, or until sideeffects were intolerable. Eleven of the fifteen patients were studied strictly according to the above protocol. In four patients, the protocol was modified as follows: (1) loading dose, two 50 mg doses, one 100 mg dose, one further 50 mg dose; (2) loading dose, two 50 mg doses, one 25 mg dose, one further 50 mg dose; (3) two 25 mg doses followed by three 50 mg doses; (4) two 25 mg doses followed by two 50 mg doses. Patients were kept under continuous observation, being recumbent throughout and for 12 hr after the last injection. Facilities for elevating the foot of the bed were always available. Table 1

Patient No.

Sex and age

Aetiology

Retinal appearances

Clinical details of the 15 patients treated Current treatment

A ctive renin

(p/ml;

normal range

10-50) F(32) 2 3 4

M (47) M (67) F(17)

Oral Contraceptive Essential Essential Chronic

H,E,P.

503

H,E,P. H,E,P.

213 99

Pyelonephritis 5 6 7

M (60) M (64) M (53)

8 9

F(64) F(19)

10 11 12

M (55) M (67) F (25)

13

M (30)

14 15

M (30)

M(61)

Atenolol Amiloride Bumetanide

Essential Essential Renal artery Stenosis Essential Chronic Pyelonephritis Essential Essential Post partum Eclampsia Essential

H,E,P.

Essential Essential

H,E,P. H,E.

H,E. H,E,P. H,E.

216 55

Propranolol 41

H,E,P. H,E,P. H,E,P.

243 37 19

Diazoxide (oral)

Propranolol Hydrallazine Bendrofluazide 240 21

SEVERE HYPERTENSION

Blood samples were withdrawn from a vein of the opposite ann to that used for labetalol administration. In 12 patients, samples for plasma labetalol assay (Martin et al., 1976) were taken before labetalol administration and immediately before each subsequent labetalol bolus. In all patients, a blood sample was taken for measurement of serum creatinine before labetalol administration and, in untreated cases only, for assay of plasma active renin (Millar et al., 1978) and angiotensin II (Dusterdieck & McElwee, 1971) concentrations. Electrocardiograms were assessed according to the Minnesota code (Blackburn et al., 1960). Evidence of myocardial ischaemia in the electrocardiogram of the resting patient was as defined by Oliver (1974), namely Code 4,1 or 5,1: ST depression of 1.0 mm or more, or T wave inversion of 5.0 mm or more, respectively.

Results Changes in arterial pressure Values for systolic and diastolic BPs immediately before the initial administration of labetalol, and H,

=

after the last dose, in all 15 patients are shown in Table 1 together with the absolute changes in BP for each patient. In the 11 patients who followed the strict protocol, mean systolic and diastolic BPs achieved after each dose are shown in Figure la and b; these patients were separated into five groups according to the number of injections given. There was no clear relationship between the initial level of arterial BP and the dose required to reduce BP. In one patient (no. 13) there was a negligible fall in both systolic and diastolic BPs, whereas in case no. I systolic BP was lowered by 42 mmHg, but diastolic BP fell by only 6 mmHg. In all the remaining patients, a fall in both systolic and diastolic BPs occurred. However, in no fewer than nine patients of the series, the final diastolic BP was 110 mmHg or higher. In four of these (patients 7, 8, 9 and 13), injections of labetalol had to be discontinued before the predetermined maximum dosage had been achieved, because of intolerable side-effects, namely vomiting (two patients), shivering (one), and pain at the injection site (two). Three of the patients who had an unsatisfactory response to labetalol were already receiving antihypertensive therapy, which included propranolol in two instances and atenolol in one. Generally, the reduction in BP was smooth and

Haemorrhages; E, exudates; P, papilloedema.

Angiotensin II (pg/mi;

Creatinine

normal range 5-35)

(normal up to 115)

p

mol/1;

BP (mmHg), immediately before first dose of labetalol

BP (mmHg), lowest pressure within 10 minutes of last dose of

(mmHg)

Fall in diastolic BP (mmHg)

Fall in systolic BP

labetalol

170

163

204/124

162/118

42

6

86 67

250 152

225/150 300/152

160/125 124/76

65 176

25 76

144

278/172

184/138

94

34

60 32

93 150

212/124 300/142

152/104 106/66

60 194

20 76

75

133 182

235/156 298/156

190/136 272/120

45 26

20 36

96 22 28

125 106 92 87

255/170 215/136 230/130 218/124

174/136 114/90 106/70 158/108

81 101 124 60

34 46 50 16

163

184/114

180/112

4

2

150 95

238/156 230/152

160/118 160/110

78 70

38 42

96 41

201S

A.M.M. CUMMING, J.J. BROWN, A.F. LEVER, A. MACKAY, J.I.S. ROBERTSON

202S

r00F 280 n= 1

c& 260-.

b

16or

E

i 240 e)

'a

I

ao

E 140 E

220

F

a)I-0

° 200 mi

-0

120 -

n=1

n=4

co

180

0

'a0.

~0

160

n=2

100f n=3

n=4

n=1

n=2

80L

Load 50 Labetalol (mg)

50

50

50

50

t

n= 1

n.qr

50

50 50 Labetalol (mg)

50

50

10-min intervals

10-min intervals

Figure la and b Mean arterial systolic and diastolic BPs in the 11 patients of the present series who followed the strict protocol. Patients are grouped according to the number of doses of labetalol needed.

n=3

1000-

800

F

E c)

C

600 F

j,

Co

En

j4n=4

In-=7r

.0

400 p

I

'~'

n=8

I n=6

iv

200 [

I load 50 I

50 5 0 50 50 50 50 Labetalol (mg)

controlled. However, four patients (nos. 3, 6, 10 and 11) had a steep fall in systolic BP, of 194 to 101 mmHg, within 10 min of injection of labetalol, the corresponding falls in diastolic BP being 76 to 46 mmHg. In one patient, this sudden BP drop occurred after only the loading dose of labetalol had been given (Figure la and b), when BP fell from 300/142 mmHg to 140/78 mmHg within 4 min followed by a further fall to 106/66 mmHg 2 min later. In all these four patients who experienced a precipitate reduction in arterial BP, elevating the foot of the bed was followed by an increase in BP to at least 158/98 mmHg within 3, 4, 6 or 8 min, respectively. None of these four patients developed electrocardiographic evidence of myocardial ischaemia or detectable neurological deficit. All patients were kept recumbent for 12 hr after receiving labetalol, and subsequent postural hypotension was not observed. The duration of effect of labetalol varied widely. In the patients in whom labetalol effectively reduced arterial BP, their BPs remained stable without further therapy for 2-24 hours.

I

10-min intervals

Figure 2 Mean (± s.e.m.) of plasma labetalol concentration after various doses of labetalol. Number of patients contributing to each mean indicated.

Side-effects Side-effects noted in the entire series included nausea (five patients), vomiting (two), scalp tingling (three),

SEVERE HYPERTENSION

burning sensation in the throat (one), burning sensation in the groin (one), pain at the site of injection, without evidence of extravasation of labetalol or of venospasm (two), faintness (three), pallor (four) and shivering (one). Changes in heart

rate

250 230

E E

210

C)

190

en

a)

The fall in BP induced by labetalol was accompanied by a small but significant reduction in heart rate, from an initial mean of 87.8 beats/min + 12.5 s.e.m. to 78.2 + 3.2 (paired t test 2.9; P < 0.02). Serious bradycardia was not a problem, the lowest pulse rate recorded in the series after injection of labetalol being 60 beats/minute. This was in the patient who had the steepest fall in BP and whose initial heart rate had been 100 beats/minute. The slowest pulse rate before labetalol administration was 72 beats/min in a patient already receiving propranolol. Thirteen of the 15 patients had electrocardiograms before the administration of labetalol, and 14 subsequently. In only two patients was there electrocardiographic evidence of ischaemia as defined in the methods section; however, both these patients had identical patterns before the drug was given. Two other patients had slight deepening of T wave inversion on the day following labetalol administration (code 5, 3 to 5, 2), but in neither instance did this exceed 2 mm, and did not satisfy Oliver's (1974) criteria for ischaemia. One patient showed disappearance of a 4, 2 abnormality (ST depression of 0.6 mm) after labetalol treatment.

203S

170 150

0 0

m

130

=

Labetalol concentrations in plasma

Plasma labetalol concentrations (Figure 2) varied widely in different patients even after similar doses of labetalol. However, there was a consistent rise in mean plasma labetalol concentration 10 min after each dose of labetalol (Figure 2). There was, however, no close relationship between fall in BP and plasma labetalol concentration. One of the lowest plasma labetalol concentrations (33 ng/ml) was seen in the patient who had a steep fall in BP after only the loading dose of 75 mg. Pretreatment plasma renin and effects on creatinine

and

angiotensin II values,

A wider and higher scatter of plasma active renin and angiotensin II concentrations was observed (Table 1), perhaps reflecting the number of patients with malignant hypertension. While there was a suggestion in the present work that those patients with the highest initial levels of active renin and angiotensin II

1

110

I

Arch aortography Time (min) 30

30

30

Dose (labetalol infusion) 20

30

30

30

30 20 80

60 30 100

50

40 Labetalol (mg/h)

Figure 3 Patient (43-yr-old male) with severe hypertension and dissecting aneurysm of the aorta, showing control of BP before and during arch aortography by regulated intravenous infusion of labetalol. Target BP was 160/1 1 0 mmHg.

required more labetalol for BP control, the relationship was not close. There was a slight, but insignificant increase in plasma creatinine concentration within three days of labetalol administration, from a pre-treatment mean of 143.5 + 10.6 s.e.m. ,mol/l to 155.4 + 12.9; (paired t test=1.8; P>0.05.) This remained largely unchanged one week after treatment (mean 150.7 + 11.7). Discussion As we have previously emphasized (Brown et al., 1977; Cumming et al., 1979) parenteral therapy even for severe hypertension is only rarely required. If, when such treatment is given, arterial BP is lowered too precipitately, there is a risk of causing cerebral infarction, probably in part because the autoregulation of cerebral blood flow is reset upwards in severe hypertension (Strandgaard et al., 1973; Graham, 1975). There is also a risk at least with some drugs of provoking or worsening myocardial ischaemia (Brown et al., 1977). We and others have reviewed elsewhere some of the comparative merits and demerits of several available drugs when parenteral antihypertensive treatment is needed (Richardson & Raper, 1978; Cumming et al., 1979).

204S

A.M.M. CUMMING, J.J. BROWN, A.F. LEVER, A. MACKAY, J.I.S. ROBERTSON

The present study was carried out to assess whether intravenous bolus injections of labetalol were inferior or superior to incremental infusions of the drug (Cumming et al., 1979). Because of the nature of hypertensive emergencies, and the wide variety of clinical circumstances encountered, accurate comparisons between series of patients studied in this fashion are difficult. Although the present work has confirmed the ability of intravenous labetalol to control severe hypertension, we did here encounter a higher incidence of severe (but reversible) side-effects than in the previous study in which graded infusions of the drug were given (Cumming et al., 1979). Indeed, only three of the present series of 15 patients escaped side-effects of some sort. Moreover, these unwanted symptoms did not always accompany a satisfactory fall in BP. Interestingly, of four patients previously uncontrolled on therapy, one, receiving oral diazoxide, did respond to intravenous labetalol, whereas three others, receiving fl-adrenoceptor blockers, did so less well. This is consistent with the suggestion made by Brogden et al. (1978), that a satisfactory response to intravenous labetalol may be less often obtained in patients already on other

antihypertensive agents, and in particular, 1adrenoceptor blockers. On present evidence, we consider that if intravenous therapy with labetalol is to be undertaken, continuous incremental infusions, though more timeconsuming, give more reliable results with generally less discomfort to the patient than can be achieved by repeated bolus injections. The effectiveness of graded infusions in hypertensive emergencies is illustrated in Figure 3, which shows control of arterial BP by continuous labetalol infusion in a severely hypertensive man presenting with a dissecting aneurysm of the aorta. In this patient, the dose was successfully adjusted, according to the response, during arch aortography. Furthermore, we have confirmed previous investigations that the use of intravenous labetalol was accompanied by a small reduction in heart rate (Agabiti-Rosei et al., 1976; Trust et al., 1976; Cumming et al., 1979). Those investigations also found a variable duration of effect after parenteral labetalol. Whichever method of administration is used, close and continuous supervision is mandatory.

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ROBERTSON, J.I.S. (1977). Labetalol in hypertension. Lancet, i, 1147. CUMMING, A.M.M., BROWN, J.J., FRASER, R., LEVER, A.F., MORTON, J.J., RICHARDS, D.A. &

ROBERTSON, J.I.S. (1979). Blood pressure reduction by incremental infusion of labetalol in patients with severe hypertension. Br. J. clin. Pharmac. (in press). DUSTERDIECK, G.O. & McELWEE, G. (1971). Estimation of angiotensin II concentration in human plasma by radioimmunoassay. Some applications to physiological and clinical states. Eur. J. clin. Invest., 2, 32-38. GRAHAM, D.I. (1975). Ischaemic brain damage of

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