Oral Labetalol Versus Oral Clonidine in the Emergency Treatment of Severe Hypertension SUZANNE H. ATKIN, MD, MICHAEL A. JAKER, MD, PATRICK BEATY, MD, MARK A. QUADREL, MD, CYNTHIA CUFFlE, MD, MARIA L. SOTO-GREENE, MD
ABSTRACT: This study was designed to compare the clinical efficacy and safety of oral clonidine and orallabetalol in the treatment of severe hypertension in an emergency department setting. Thirty-six patients with severely elevated blood pressure (mean baseline blood pressure 199/132 mm Hg) without acute end-organ dysfunction were treated with either orallabetalol or oral clonidine in a randomized doubleblind prospective study. Labetalol was administered as an initial dose of 200 mg, followed by hourly 200 mg doses up to 1,200 mg. Clonidine was administered as an initial dose of 0.2 mg, followed by hourly 0.1 mg doses up to 0.7 mg. Labetalol reduced diastolic blood pressure in 94 % of the patients within 6 hours, with a mean reduction in blood pressure of 54/37 mm Hg. Clonidine reduced diastolic blood pressure in 83% of the patients within 6 hours, with a mean reduction in blood pressure of 57/32 mm Hg. The authors conclude that oral labetalol was comparable to clonidine in efficacy, had a similar incidence of side effects, and offered the clinician a useful alternative for the treatment of severe hypertension in an emergency department setting. Further studies are indicated to determine appropriate dosing regimens for oral labetalol in the acute treatment of severe hypertension. KEY INDEXING TERMS: Clonidine; Labetalol; Severe hypertension. [Am J Med Sci 1992; 303(1):9-15.]
T
he treatment of severely elevated blood pressure in a mildly symptomatic or asymptomatic pa-
From the Division of Critical Care Medicine, Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, University Hospital, Newark, New Jersey. Supported by a grant from Schering-Plough Corp., Kenilworth, NJ. The authors thank the nursing staff of the University Hospital Emergency Department, Newark, NJ; Jean Chou, MS, University of Medicine and Dentistry of New Jersey, for statistical analysis; and Micheline Blum, Blum/Weprin Inc., for editorial advice. Correspondence: Suzanne H. Atkin, MD, Emergency Department C396, University Hospital, 150 Bergen Street, Newark, NJ 071032425. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
tient in the emergency department and other outpatient settings is a difficult problem frequently faced by the clinician. The true hypertensive emergency, although common in the past, is rare today.I-3 Most physicians agree that severely elevated blood pressure associated with acute or progressive end-organ dysfunction, such as hypertensive encephalopathy, acute pulmonary edema, acute myocardial infarction, acute renal failure, or dissecting aortic aneurysm should be treated within 1 hour with rapidly acting, titratable, intravenous drugs in a carefully monitored inpatient (usually intensive care unit) setting.3,4 There is, however, less unanimity of opinion as to the most appropriate method of treating the mildly symptomatic or asymptomatic patient who presents with nonemergent but severely elevated blood pressure (diastolic blood pressure greater than 120 mm Hg) without acute endorgan dysfunction. 1,5-8 There are currently several regimens which have been used in the treatment of nonemergent but severely elevated blood pressure. Nifedipine and clonidine have been shown to be effective and relatively safe oral agents when used in an outpatient or emergency department setting for the treatment of severe hypertension. 3,8-11 Both of these drugs, however, have been demonstrated to have potentially serious drawbacks. Oral clonidine loading causes sedation in the majority of patients,8,12 has a slow onset of action/,8 and may result in the return of severely elevated blood pressure if suddenly discontinued. 2,13 While it has a rapid onset of action, nifedipine has been reported to cause rare ischemic events, both with and without hypotension. 14-17 Nifedipine has a short duration of action, sometimes resulting in the recurrence of severe hypertension shortly after discharge from the emergency department.2,6,8,18 Labetalol, an antihypertensive agent with both alpha and beta adrenergic blocking properties, is effective in the treatment of both severe hypertension and hypertensive emergencies when given intravenously as a bolus or a continuous infusion. 19-22 Studies are lacking on the use of labetalol as an, oral agent in the acute treatment of severe hypertension in an outpatient setting. This study was designed to compare the clinical
9
Labetalol Versus Clonldine for Severe Hypertension
efficacy and safety of orallabetalol and oral clonidine in the treatment of severe hypertension in an emergency department setting. Methods
Thirty-six patients with supine diastolic blood pressures (SuDBPs) greater than or equal to 120 mm Hg were included in the study. There were 21 men (19 black and 2 white) and 15 women (all black). The mean age was 47.5 years (range: 23-63 years). All patients were evaluated and treated in the University Hospital Emergency Department, Newark, NJ. The majority of patients, 20/36 (56%), presented to the emergency department with mild symptoms, such as headache, dizziness, or blurred vision, that were possibly related to elevated blood pressure. The remaining 16 patients (44 %) were asymptomatic and presented to the emergency department for prescription refills or were referred for severely elevated blood pressure. All patients had a history of longstanding hypertension; most were known to be poorly compliant with their antihypertensive regimens. The majority of patients had electrocardiographic abnormalities on entry that were consistent with left ventricular hypertrophy (78%); half of the patients had cardiomegaly on chest x-ray. Patients eligible for inclusion in the study were between 18 and 65 years of age. Patients were excluded who had a history or coexistence of accelerated or malignant hypertension (defined as elevated blood pressure with associated acute end-organ damage consisting of Grade III or Grade IV Keith-Wagener retinopathy, acute renal failure, acute myocardial ischemia, acute pulmonary edema, or hypertensive encephalopathy), suspected aortic dissection, pheochromocytoma, cerebrovascular accident within 6 months or new focal neurologic deficits, active angina, coronary bypass surgery within 1 year, heart block greater than first degree or significant arrhythmias, women of childbearing potential, or significant medical illnesses, such as renal disease with serum creatinine greater than 3 mg%, asthma or chronic obstructive pulmonary disease, active seizure disorder, or current alcohol or drug abuse. Patients taking labetalol or clonidine up to 48 hours prior to entry into the study and patients with known allergy to either drug were also excluded from the study. Informed consent was obtained from each patient in accordance with guidelines from the University of Medicine and Dentistry of New Jersey Research Committee Institutional Review Board. A complete history and physical examination, routine laboratory tests, including a complete blood count, serum chemistries, urinalysis, chest x-ray, and electrocardiogram (EKG) were performed on all patients by investigators. After an initial observation period of 30 minutes, during which supine blood pressure was monitored in a quiet room, patients who met inclusion criteria were then randomized into two groups to receive either labetalol or clonidine. There were no statistically significant dif10
ferences between the patient profiles of the labetalol and clonidine groups (Table I). Both the investigator and the patient were blinded as to the identity of the medication. The study was divided into two phases: phase I was the acute drug administration phase and phase II was the followup maintenance period. In phase I, group A initially received 200 mg of labetalol orally on an hourly basis to a maximum dose of 1,200 mg at 6 hours. Group B initially received 0.2 mg of clonidine orally followed by 0.1 mg of clonidine orally each hour to a maximum dose of 0.7 mg at 6 hours. Medication was administered until the goal blood pressure, a mean SuDBP of ::;;100 mm Hg, or a decrease in the mean SuDBP of at least 30 mm Hg compared to baseline and a mean SuDBP of ::;;110 mm Hg, was achieved. Labetalol and clonidine were supplied in identical opaque capsules by ScheringPlough Corporation, Kenilworth, NJ, and were administered by a blinded investigator. Blood pressure was determined by a blinded investigator with a standard mercury sphygmomanometer using phase V of Korotkoff's sounds as the diastolic value. Each blood pressure determination was obtained in both the supine position and after standing for 2 minutes, using the mean of two consecutive measurements taken by the same investigator. After the initial medication dose was administered, supine blood pressure and heart rate were determined at regular intervals of 15 minutes during the first 2 hours, then at intervals of 30 minutes for the remaining 5 hours or until 1 hour after the goal SuDBP was attained. Blood pressure and heart rate in the standing position were obtained at Table 1. Patient Profiles
Number of patients Age (yr) Mean Range Sex Male Female Race White Black Weight (lbs) Mean Range Baseline blood pressure mm Hg (supine) Systolic Range Diastolic Range Successful responders*
Labetalol Group
Clonidine Group
18
18
48.6 23-63
46.4 29-63
11 7
10 8
2 16
0 18
178.2 114-240
178.1 120-302
201 155-252 132 120-154 94%
196 156-241 131 120-148 83%
* Supine diastolic blood pressure 5,100 mm Hg or diastolic blood pressure 5,110 mm Hg that had been reduced by 30 mm Hg or more from baseline blood pressure. January 1992 Volume 303 Number 1
Atkin at 01
hourly intervals for 7 hours or until 1 hour after the goal SuDBP was attained. At each blood pressure and heart rate determination, a clinical survey was performed by the investigator to record all symptoms or physical signs of possible drug side effects. Patients remained semi-supine between blood pressure recordings and had precautionary peripheral intravenous lines with 5% dextrose in water. The time period during which the patient remained in the emergency department was used by the physician and the nursing staff to educate the patient about hypertension and its complications, to improve long-term compliance. The endpoint was defined as maintenance of goal SuDBP for 1 hour after the final dose of study medication. Once the endpoint was reached, all patients were followed for an additional 1 hour observation period with supine and standing blood pressure and heart rate measurements at 30-minute intervals. Patients were placed in the phase II followup group if they met the following criteria: at the beginning of the observation period, the patient had achieved the endpoint and at the end of the observation period, the mean SuDBP did not rise by more than 15 mm Hg and the patient had no significant adverse effects. These patients were placed on double-blind maintenance therapy after discharge from the emergency department, with instructions to return for a followup visit within 1-5 days, 8-12 hours after their last evening dose of medication. In this maintenance therapy phase, patients who had been randomized to the labetalol treatment group received labetalol 200 mg orally twice daily; patients who had been randomized to the clonidine treatment group received clonidine 0.1 mg orally twice daily. Each patient was instructed to start the first dose of medication approximately 6 hours after the last dose of phase I treatment medication, with a subsequent dose every 12 hours. On return to the emergency department, each patient had a physical examination and routine laboratory tests including a complete blood count, serum chemistries, urinalysis, and an EKG. Blood pressure and heart rate were recorded in both the supine and standing positions and a clinical survey was performed to record spontaneously offered symptoms. Patients were then discharged from the study and followed as outpatients with individualized long-term antihypertensive therapy in the medical clinic. Any patient who did not attain the goal SuDBP during phase I of the study or who did not fit criteria for enrollment into phase II was discontinued from the study, given individualized antihypertensive therapy in the emergency department, and subsequently followed as an outpatient in the medical clinic. Mean systolic and diastolic blood pressures and heart rates of the labetalol and clonidine groups were compared with analysis of variance with repeated measures and with t-test. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Results Phase I: Labetalol Group. Of the 18 patients who re-
ceived labetalol, 17/18 (94%) achieved the goal mean SuDBP of .:s;;100 mm Hg or a decrease in the mean SuDBP of at least 30 mm Hg compared to baseline and a mean SuDBP of .:s;;110 mm Hg within 6 hours. Mean blood pressure and heart rate data are shown in Table 2. The mean baseline supine blood pressure of this group was 201 mm Hg (range: 155-252 mm Hg) and 132 mm Hg diastolic (range: 120-154 mm Hg). The mean final supine blood pressure was 149 mm Hg systolic (range: 100-180 mm Hg) and 95 mm Hg diastolic (range: 70-122 mm Hg). The mean decrease in systolic blood pressure was 54 mm Hg; in diastolic blood pressure, 37 mm Hg. The mean baseline heart rate was 84 beats per minute; the mean final heart rate, 74 beats per minute. Of the 17 patients who achieved the goal SuDBP, 12/17 (71 %) achieved the goal within 3 hours, responding to a total dose of 600 mg or less of labetalol (Figure 1). The most significant side effect of labetalol was hypotension, seen in one patient who was withdrawn from the study after he developed transient hypotension with orthostatic dizziness 2 hours after receiving a single 200 mg dose of labetalol (blood pressure fell from 181/ 139 mm Hg to 100/70 mm Hg). His hypotension and symptoms improved with 400 cc of intravenous saline administered over a I-hour period. Other side effects of labetalol were mild dizziness or lightheadedness in 6/18 patients (33%), two of whom noted exacerbation on standing, mild sleepiness in 5/18 patients (28%), headache in 2/18 (22%), and scalp tingling in one patient. No significant changes were observed in routine laboratory studies or EKGs when baseline evaluations were compared to final data. Phase I: Clonidine Group. Of the 18 patients who received clonidine, 15/18 (83 %) achieved the goal of mean SuDBP of .:s;;100 mm Hg or a decrease in the mean SuDBP of at least 30 mm Hg compared to baseline and a mean SuDBP of .:s;;110 mm Hg within 6 hours. Mean blood pressure and heart rate data are shown in Table 2. The mean initial supine blood pressure of this group was 196 mm Hg systolic (range: 155-252 mm Hg) and 131 mm Hg diastolic (range: 120-148 mm Hg). The mean final supine blood pressure was 140 mm Hg systolic (range: 101-167 mm Hg) and 100 mm Hg diastolic (range: 76-121 mm Hg). The mean decrease in systolic blood pressure was 57 mm Hg; in diastolic blood pressure, 32 mm Hg. The mean baseline heart rate was 83 beats per minute; the mean final heart rate, 74 beats per minute. All 15 responders achieved the goal SuDBP within 4 hours, responding to a total dose of 0.5 mg or less of clonidine; 10/15 (66%) responded to a total dose ofOA mg or less (Figure 1) . . The most prominent side effect attributed to clonidine was sedation, which occurred in 10/18 (56%) of 11
Labetalol Versus Clonidine for Severe Hypertension
Table 2. Comparative Response to Clonidine or Labetalol in Severe Hypertension Labetalol Mean Baseline Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 15 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 30 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 45 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 60 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 90 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 120 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 150 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 180 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 210 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 240 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm Phase II visit Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm
SE
(n = 18) 200 6.2 132 2.0 84 3.0 (n = 18) 193 4.7 125 1.8 82 2.7 (n = 18) 184 5.5 121 2.8 2.6 80 (n = 18) 178 5.0 3.1 115 76 2.9 (n = 18) 175 4.3 114 3.3 78 2.4 (n = 16) 171 3.3 3.2 111 78 2.6 (n = 16) 161 4.1 107 2.6 2.1 78 (n = 11) 170 6.8 104 3.9 76 2.4 (n = 11) 159 5.7 105 3.2 75 2.1 (n = 6) 170 6.7 113 3.8 4.0 74 (n = 6) 166 4.7 111 4.7 74 3.4 (n = 16) 173 6.9 111 3.6 78 1.4
Clonidine Mean (n
SE
Significance
= 18)
196 131 83
48 1.8 2.5 (n = 18) 194 5.0 130 1.7 81 2.3 (n = 18) 191 5.4 128 1.9 80 2.5 (n = 18) 185 5.0 125 2.2 79 2.6 (n = 18) 178 4.5 121 2.3 80 2.6 (n = 17) 165 3.4 116 2.3 78 3.1 (n = 17) 157 3.7 110 2.4 76 3.3 (n = 14) 158 2.9 113 2.3 78 3.6 (n = 14) 149 4.2 108 2.9 74 3.3 (n = 8) 152 4.0 111 2.6 75 3.0 (n = 8) 149 7.2 107 6.0 74 5.2 (n = 14) 161 8.4 108 3.1 72 2.8
NS NS NS NS NS NS NS NS NS NS
.
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
..
orthostatic hypotension, which resolved within 15 minutes without treatment, and dry mouth in 2/18 patients (11%). No significant changes were noted in the routine laboratory studies or EKGs when baseline evaluations were compared to final data. Phase II: Labetalol Group. Of the 18 patients who participated in phase I of the study, the 16 who achieved the goal SuDBP were enrolled in phase II. All returned for the scheduled followup visit. All patients reported strict compliance with the medication regimen. Remaining pills were counted for verification. At the followup visit, the mean supine systolic blood pressure was 173 mm Hg (range: 140-230 mm Hg) and the mean fall in systolic blood pressure from the baseline phase I value to the phase II visit was 31 mm Hg. The mean SuDBP was 110 mm Hg (range: 90-138 mm Hg) and the mean fall was 20 mm Hg. Blood pressure and heart rate data are shown in Table 2. The only side effects attributed to the maintenance administration of labetalol were mild headache in 2/16 patients (13%) and mild transient dizziness upon standing in 2/16 patients (13%). Phase II: Clonidine Group. Of the 18 patients who participated in phase I of the study, the 15 who achieved the goal SuDBP were enrolled in phase II. All except one returned for the scheduled followup visit. All patients reported strict compliance with the medication regimen. Remaining pills were counted for verification. At the followup visit, the mean supine systolic blood pressure was 161 mm Hg (range: 106-229 mm Hg) and the mean fall in systolic blood pressure from the baseline phase I value to the phase II visit was 37 mm Hg. The mean SuDBP was 108 mm Hg (range: 87-130 mm Hg) and the mean fall was 23 mm Hg. Blood pressure and heart rate data are shown in Table 2.
NS NS
!ZZZI L.A8ETALOL ~
.. NS NS
2 5 c
NS NS NS
.. p < .05. Not significant (NS) = P ~ .05. bpm = beats per minute (supine). BP = blood pressure (supine). SE = standard error.
Q)
~
...o
4
~ 3
.a
E :::> z
2
TIme
the patients. This ranged in severity from mild drowsiness to deep sleep. Other complaints included dizziness in 3/18 patients (17%), which was severe in one patient after four doses of clonidine and associated with
12
CLONIDINE
6
lhr
2hr
Jhr
4hr
Shr
6hr
Figure 1. Cumulative doses of medication needed to achieve goal blood pressure in those patients who were successful responders. Labetalol, n = 17; clonidine, n = 15. "No patients in the clonidine group who were successful responders required more than 0.5 mg to achieve goal blood pressure. January 1992 Volume 303 Number 1
Atkin et 01
The only side effects attributed to the maintenance administration of clonidine were mild drowsiness in 2/14 patients (14%), dry mouth in 2/14 patients (14%), and mild dizziness upon standing in 2/14 patients (14%). Discussion
Labetalol, which has both alpha1 and nonselective beta adrenoreceptor blocking actions and beta2 partial agonist activity, lowers blood pressure acutely primarily through peripheral vasodilation mediated by its alpha1 blockade. 23 ,24 Reflex tachycardia, seen with some vasodilators, is avoided due to beta1 blocking activity, and cardiac ou.tput remains unchanged. 25 Orallabetalol is well absorbed, resulting in peak plasma concentrations within 2 hours of administration. Peak antihypertensive effects occur within 1-2 hours.9 Clonidine, which has alpha adrenergic agonist activity, acts at the presynaptic receptor to lower blood pressure through a centrally mediated decrease in sympathetic outflow and a reduction in circulating catecholamines. The resulting decrease in vascular tone results in reduction of systemic blood pressure. 26,27 Reduction in plasma renin may also contribute to the antihypertensive effect of clonidine. 27 Oral clonidine is well-absorbed, resulting in peak plasma concentrations within 90 minutes to 5 hours of administration. Peak antihypertensive effects occur within 2-4 hours. 27 While the acute antihypertensive effects of intravenous labetalol have been well-documented, only a few studies conducted exclusively in hospitalized patients have demonstrated the efficacy of orallabetalol in the treatment of severely elevated blood pressure.28-32 No studies have compared oral labetalol with other oral antihypertensive agents in the treatment of severely elevated blood pressure in an outpatient setting. In our study, acute administration of oral labetalol was effective in lowering blood pressure in 94% (17/ 18) of patients; 71 % (12/17) achieved the goal diastolic blood pressure within 3 hours (Figure 1). Of the 16 patients who entered the maintenance phase II part of the study, 69% (11/16) had diastolic blood pressures below 115 mm Hg at the followup visit. Side effects in the labetalol group, which were generally mild, included dizziness, drowsiness, and headache in 44% of the patients in phase I and in 17% of the patients in phase II. One patient experienced transient hypotension after a single 200 mg dose of labetalol. Acute oral administration of clonidine was effective in lowering blood pressure in 83% (15/18) of patients, with all 15 responders achieving the goal diastolic blood pressure within 4 hours (Figure 1). Of the 14 patients who returned for the maintenance phase II part of the study, 71 % (10/14) had diastolic blood pressures below 115 mm Hg at the followup visit. Side effects in the clonidine group were prominent in phase I of the study, with 66% of the patients experiencing mild to severe sedation, dizziness, and dry mouth. In phase II of the THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
study, 36% of the patients experienced similar, but less severe, side effects. Oral clonidine loading has been a popular treatment regimen for the outpatient or emergency department therapy of nonemergent but severely elevated blood pressure. Most studies have emphasized the efficacy and safety of clonidine loading. 3,1o,12,33-35 Nifedipine8,ll has also been used to lower blood pressure acutely. In our study, the response to oral clonidine loading was maximal at a dosage of 0.4-0.5 mg. Once a patient failed to respond to 4 hours of clonidine loading, additional treatment was unlikely to lower blood pressure further. These data are consistent with a previous study of clonidine loading in an emergency department setting.8 Several recent commentaries have questioned the need for acute blood pressure reduction in patients who have severe hypertension but no acute end-organ dysfunction. 1,5,6,36 These have emphasized the lack of proven long-term benefits and the possibility of deleterious effects from antihypertensive loading regimens. While the potential immediate risk of untreated severe hypertension to vital organs and to patient survival is not known, many patients with nonemergent but severe hypertension present with symptoms such as headache, dizziness, and blurred vision. These symptoms suggest that a more acute process may be evolving in this subset of severely hypertensive patients. In our study, 56% of the patients presented with symptoms possibly related to their severely elevated blood pressure. While it is not clear which patients are at risk for development of further acute hypertensive complications, we believe that severely hypertensive patients should be treated with gradual blood pressure reduction with oral agents in an emergency department setting over several hours. The ideal oral agent for the outpatient treatment of nonemergent but severely elevated blood pressure should have the following characteristics: a high degree of efficacy, a favorable side effect profile, the ability to lower blood pressure gradually over several hours, and acceptability as a long-term oral antihypertensive agent. Orallabetalol appears to be a reasonable alternative to both clonidine and nifedipine for this purpose. In our study, labetalol had a success rate comparable to clonidine (Figure 2). Most patients responded to two or three 200 mg doses of labetalol. Side effects were frequent although mild; the transition to oral maintenance therapy was well-tolerated. It has recently been suggested that acute blood pressure management in the patient with severe hypertension be tailored to suit the individual patient. 36,37 Labetalol has been shown to be highly effective as an .antihypertensive agent in black patients, in contrast to other agents such as dilevalol and beta blocking agents such as propranolo1. 38,39 It has been postulated that the alpha adrenergic-blocking property of labetalol may oppose nonrenin mediated factors, which may contribute to hypertension in black patients. 24 In our 13
Labetalol Versus Clonidlne for Severe Hypertension
225
01
••.••••••• - CLONIDINE - - U>.SE:TALOL
200
:::c E E
SYSTOLIC BP 175
Q) ~
~ 150
rn
Q) ~
0....
DIASTOLIC BP
125
""0 0 0 CD
100
75
.~ E
0
30
60
90
120
150
lao
90
.............
rn ........ 0
(l)
.0 (l) ........
0
~
eo
-_.1.-_--r--..::........................
..........
....-..........
70
........ ~
0
(l)
:c
60
0
30
60
90
120
150
leo
Time, min
Figure 2. Mean systolic and diastolic blood pressures and heart rates for each group of patients receiving either labetalol (solid line) or clonidine (dotted line) who achieved goal diastolic blood pressure within 3 hours. Labetalol, n = 12. clonidine, n = 10.
study, the majority of patients (94%) were black. It is not clear whether orallabetalol would be as successful in other patient populations. We believe that oral labetalol is an alternative for the treatment of severe hypertension in an emergency department or outpatient setting. In our study, it was successful in safely and gradually lowering blood pressure, it worked well in black patients, had generally mild side effects, and was effective in a twice daily regimen for maintenance therapy. Further studies are needed to define the most effective dosing regimen of orallabetalol for the treatment of severe hypertension in an emergency department setting. References 1. Weber MA: Immediate treatment of severe hypertension widening the options. Arch Intern Med 149:2635-2637, 1989. 2. Ram CV, Hyman D: Hypertensive crises. J Intensive Care Med . 2:151-162, 1987. . 3. Calhoun DA, Oparil S: Treatment of hypertensive crisis. N Engl J Med 323:1177-1183,1990. 4. 1988 Joint National Committee: The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 148:1023-1038, 1988.
14
5. Ferguson RK, Vlasses PH: How urgent is 'urgent' hypertension? Arch Intern Med 149:257-258, 1989. 6. Fagan TC: Acute reduction of blood pressure in asymptomatic patients with severe hypertension. An idea whose time has come and gone. Arch Intern Med 149:2169-2170, 1989. 7. Ferguson RK, Vlasses PH: Hypertensive emergencies and urgencies. JAMA 255:1607-1613, 1986. 8. Jaker M, Atkin S, Soto M, Schmid G, Brosch F: Oral nifedipine vs oral clonidine in the treatment of urgent hypertension. Arch Intern Med 149:260-265, 1989. 9. Catapano M8, Marx JA: Management of urgent hypertension: A comparison of oral treatment regimens in the emergency department. J Emerg Med 4:361-368, 1986. 10. Anderson RJ, Hart GR, Crumpler CP, Reed WG, Matthews CA: Oral clonidine loading in hypertensive urgencies. JAMA 246: 848-850, 1981. 11. Houston MC: Treatment of hypertensive urgencies and emergencies with nifedipine. Am Heart J 111:963-969, 1986. 12. Houston MC: Treatment of hypertensive emergencies and urgencies with oral clonidine loading and titration. Arch Intern Med 146:586-589, 1986. 13. Meese RB, Ram CV: Hypertensive cardiovascular emergencies. Compr Ther 11:28-38, 1985. 14. Wachter RW: Symptomatic hypotension induced by nifedipine in the acute treatment of severe hypertension. Arch Intern M ed 147:556-558, 1987. 15. Friedman CP: Symptomatic hypotension induced by nifedipine . Arch Intern Med 147:1683, 1987. 16. O'Mailia JJ, Sander GE, Giles TD: Nifedipine-associated myocardial ischemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 107:185-186, 1987. 17. Schwartz M, Naschitz JE, Yeshurun D, SharfB: Oral nifedipine in the treatment of hypertensive urgency: Cerebrovascular accident following a single dose. Arch Intern Med 150:686-687, 1990. 18. Gonzales DG, Ram CV: New approaches for the treatment of hypertensive urgencies and emergencies. Chest 93:193-195,1988. 19. Cressman MD, Vidt DG, Gifford RW, Moore WS, Wilson DJ: Intravenous labetalol in the management of severe hypertension and hypertensive emergencies. Am Heart J 107:980-985, 1984. 20. Vidt DG: Intravenous labetalol in the emergency treatment of hypertension. J Clin Hypertens 2:179-186,1985. 21. Huey J, Thomas JP, Hendricks DR, Wehmeyer AE, Johns LJ, MacCosbe PE: Clinical evaluation of intravenous labetalol for the treatment of hypertensive urgency. Am J Hypertens 1:2848289S, 1988. 22. Smith WB, Clifton GG, O'Neill WM, Wallin JD: Antihypertensive effectiveness of intravenous labetalol in accelerated hypertension. Hypertension 5:579-583, 1983. 23. Prichard BN, Lund-Johansen P, Louis WJ, MolinoffPB, Taylor SH, Chamberlain DA: Combined alpha-beta-blockade A roundtable discussion. Drugs 288:103-108, 1984. 24. Flamenbaum W: Propranolol versus labetalol: Interesting differences in efficacy. J Natl Med Assoc 778:14-29, 1985. 25. Holtzman JL, Finley D, Johnson B, Berry DA, Sirgo MA: The effects of single-dose atenolol, labetalol, and propranolol on cardiac and vascular function. Clin Pharmacol Ther 40:268-273, 1986. 26. Lowenstein J: Clonidine. Ann Intern Med 92:74-77,1980. 27. Houston MC: Clonidine hydrochloride: Review of pharmacologic and clinical aspects. Prog Cardiovasc Dis 23:337-349, 1981. 28. Ghose RR, Mathur VB, Upadhyay M, Morgan WD, Khan S: Treatment of hypertensive emergencies with oral labetalol. Br Med J 2:737, 1978. 29. Ghose RR, Sampson A: Rapid onset of action of orallabetalol in severe hypertension. Curr Med Res Opin 5:147-151,1977. 30. Ghose RR: Acute management of severe hypertension with oral labetalol. Br J Clin Pharmacol 8:189S-193S, 1979. January 1992 Volume 303 Number 1
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31. Serlin MJ, Orme ME, Maciver M, Green GJ, Macnee CM, Breckenridge AM: Rate of onset of hypotensive effect of oral labetalol. Br J Clin Pharmacol7:165-168, 1979. 32. Olowoeye JO, Okoro EO, Omotosho AB: Oral labetalol in the urgent treatment of severe hypertension. Trop Geograph Med 38:73-78, 1986. 33. Spitalewitz S, Porush JG, Oguagha C: Use of oral c10nidine for rapid titration of blood pressure in severe hypertension. Chest 83:404-407, 1983. 34. Cohen 1M, Katz MA: Oral c10nidine loading for rapid control of hypertension. Clin Pharmacol Ther 24:11-15,1978. 35. Marks AD, Adlin EV, Channick BJ: Oral c10nidine for rapid control of accelerated hypertension. J Clin Pharmacol27:193-198, 1987.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
36. Zeller KR, Kuhnert LV, Matthews C: Rapid reduction of severe asymptomatic hypertension. Arch Intern Med 149:2186--2189, 1989. 37. Frohlich ED: Hypertensive emergencies: A paradigm for tailoring antihypertensive therapy. J Intensive Care Med 2:123125,1987. 38. Wallin JD, Cook ME, Fletcher E, Holtzman JL, Winer N, Gavras H, Grim CE, Ramanathan KB, Vidt DG, Johnson BF, Hall D, Stom M, Poland M, Cubbon J: Dilevalol in severe hypertension: A multicenter trial of bolus intravenous dosing. Arch Intern Med 149:2655-2669, 1989. 39. Oster G, Huse DM, Delea TE, Savage DD, Colditz GA: Cost effectiveness of labetalol and propranolol in the treatment of hypertension among blacks. J Natl Med Assoc 79:1049-1055, 1987.
15
ABSTRACT: This study was designed to compare the clinical efficacy and safety of oral clonidine and orallabetalol in the treatment of severe hypertension in an emergency department setting. Thirty-six patients with severely elevated blood pressure (mean baseline blood pressure 199/132 mm Hg) without acute end-organ dysfunction were treated with either orallabetalol or oral clonidine in a randomized doubleblind prospective study. Labetalol was administered as an initial dose of 200 mg, followed by hourly 200 mg doses up to 1,200 mg. Clonidine was administered as an initial dose of 0.2 mg, followed by hourly 0.1 mg doses up to 0.7 mg. Labetalol reduced diastolic blood pressure in 94 % of the patients within 6 hours, with a mean reduction in blood pressure of 54/37 mm Hg. Clonidine reduced diastolic blood pressure in 83% of the patients within 6 hours, with a mean reduction in blood pressure of 57/32 mm Hg. The authors conclude that oral labetalol was comparable to clonidine in efficacy, had a similar incidence of side effects, and offered the clinician a useful alternative for the treatment of severe hypertension in an emergency department setting. Further studies are indicated to determine appropriate dosing regimens for oral labetalol in the acute treatment of severe hypertension. KEY INDEXING TERMS: Clonidine; Labetalol; Severe hypertension. [Am J Med Sci 1992; 303(1):9-15.]
T
he treatment of severely elevated blood pressure in a mildly symptomatic or asymptomatic pa-
From the Division of Critical Care Medicine, Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, University Hospital, Newark, New Jersey. Supported by a grant from Schering-Plough Corp., Kenilworth, NJ. The authors thank the nursing staff of the University Hospital Emergency Department, Newark, NJ; Jean Chou, MS, University of Medicine and Dentistry of New Jersey, for statistical analysis; and Micheline Blum, Blum/Weprin Inc., for editorial advice. Correspondence: Suzanne H. Atkin, MD, Emergency Department C396, University Hospital, 150 Bergen Street, Newark, NJ 071032425. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
tient in the emergency department and other outpatient settings is a difficult problem frequently faced by the clinician. The true hypertensive emergency, although common in the past, is rare today.I-3 Most physicians agree that severely elevated blood pressure associated with acute or progressive end-organ dysfunction, such as hypertensive encephalopathy, acute pulmonary edema, acute myocardial infarction, acute renal failure, or dissecting aortic aneurysm should be treated within 1 hour with rapidly acting, titratable, intravenous drugs in a carefully monitored inpatient (usually intensive care unit) setting.3,4 There is, however, less unanimity of opinion as to the most appropriate method of treating the mildly symptomatic or asymptomatic patient who presents with nonemergent but severely elevated blood pressure (diastolic blood pressure greater than 120 mm Hg) without acute endorgan dysfunction. 1,5-8 There are currently several regimens which have been used in the treatment of nonemergent but severely elevated blood pressure. Nifedipine and clonidine have been shown to be effective and relatively safe oral agents when used in an outpatient or emergency department setting for the treatment of severe hypertension. 3,8-11 Both of these drugs, however, have been demonstrated to have potentially serious drawbacks. Oral clonidine loading causes sedation in the majority of patients,8,12 has a slow onset of action/,8 and may result in the return of severely elevated blood pressure if suddenly discontinued. 2,13 While it has a rapid onset of action, nifedipine has been reported to cause rare ischemic events, both with and without hypotension. 14-17 Nifedipine has a short duration of action, sometimes resulting in the recurrence of severe hypertension shortly after discharge from the emergency department.2,6,8,18 Labetalol, an antihypertensive agent with both alpha and beta adrenergic blocking properties, is effective in the treatment of both severe hypertension and hypertensive emergencies when given intravenously as a bolus or a continuous infusion. 19-22 Studies are lacking on the use of labetalol as an, oral agent in the acute treatment of severe hypertension in an outpatient setting. This study was designed to compare the clinical
9
Labetalol Versus Clonldine for Severe Hypertension
efficacy and safety of orallabetalol and oral clonidine in the treatment of severe hypertension in an emergency department setting. Methods
Thirty-six patients with supine diastolic blood pressures (SuDBPs) greater than or equal to 120 mm Hg were included in the study. There were 21 men (19 black and 2 white) and 15 women (all black). The mean age was 47.5 years (range: 23-63 years). All patients were evaluated and treated in the University Hospital Emergency Department, Newark, NJ. The majority of patients, 20/36 (56%), presented to the emergency department with mild symptoms, such as headache, dizziness, or blurred vision, that were possibly related to elevated blood pressure. The remaining 16 patients (44 %) were asymptomatic and presented to the emergency department for prescription refills or were referred for severely elevated blood pressure. All patients had a history of longstanding hypertension; most were known to be poorly compliant with their antihypertensive regimens. The majority of patients had electrocardiographic abnormalities on entry that were consistent with left ventricular hypertrophy (78%); half of the patients had cardiomegaly on chest x-ray. Patients eligible for inclusion in the study were between 18 and 65 years of age. Patients were excluded who had a history or coexistence of accelerated or malignant hypertension (defined as elevated blood pressure with associated acute end-organ damage consisting of Grade III or Grade IV Keith-Wagener retinopathy, acute renal failure, acute myocardial ischemia, acute pulmonary edema, or hypertensive encephalopathy), suspected aortic dissection, pheochromocytoma, cerebrovascular accident within 6 months or new focal neurologic deficits, active angina, coronary bypass surgery within 1 year, heart block greater than first degree or significant arrhythmias, women of childbearing potential, or significant medical illnesses, such as renal disease with serum creatinine greater than 3 mg%, asthma or chronic obstructive pulmonary disease, active seizure disorder, or current alcohol or drug abuse. Patients taking labetalol or clonidine up to 48 hours prior to entry into the study and patients with known allergy to either drug were also excluded from the study. Informed consent was obtained from each patient in accordance with guidelines from the University of Medicine and Dentistry of New Jersey Research Committee Institutional Review Board. A complete history and physical examination, routine laboratory tests, including a complete blood count, serum chemistries, urinalysis, chest x-ray, and electrocardiogram (EKG) were performed on all patients by investigators. After an initial observation period of 30 minutes, during which supine blood pressure was monitored in a quiet room, patients who met inclusion criteria were then randomized into two groups to receive either labetalol or clonidine. There were no statistically significant dif10
ferences between the patient profiles of the labetalol and clonidine groups (Table I). Both the investigator and the patient were blinded as to the identity of the medication. The study was divided into two phases: phase I was the acute drug administration phase and phase II was the followup maintenance period. In phase I, group A initially received 200 mg of labetalol orally on an hourly basis to a maximum dose of 1,200 mg at 6 hours. Group B initially received 0.2 mg of clonidine orally followed by 0.1 mg of clonidine orally each hour to a maximum dose of 0.7 mg at 6 hours. Medication was administered until the goal blood pressure, a mean SuDBP of ::;;100 mm Hg, or a decrease in the mean SuDBP of at least 30 mm Hg compared to baseline and a mean SuDBP of ::;;110 mm Hg, was achieved. Labetalol and clonidine were supplied in identical opaque capsules by ScheringPlough Corporation, Kenilworth, NJ, and were administered by a blinded investigator. Blood pressure was determined by a blinded investigator with a standard mercury sphygmomanometer using phase V of Korotkoff's sounds as the diastolic value. Each blood pressure determination was obtained in both the supine position and after standing for 2 minutes, using the mean of two consecutive measurements taken by the same investigator. After the initial medication dose was administered, supine blood pressure and heart rate were determined at regular intervals of 15 minutes during the first 2 hours, then at intervals of 30 minutes for the remaining 5 hours or until 1 hour after the goal SuDBP was attained. Blood pressure and heart rate in the standing position were obtained at Table 1. Patient Profiles
Number of patients Age (yr) Mean Range Sex Male Female Race White Black Weight (lbs) Mean Range Baseline blood pressure mm Hg (supine) Systolic Range Diastolic Range Successful responders*
Labetalol Group
Clonidine Group
18
18
48.6 23-63
46.4 29-63
11 7
10 8
2 16
0 18
178.2 114-240
178.1 120-302
201 155-252 132 120-154 94%
196 156-241 131 120-148 83%
* Supine diastolic blood pressure 5,100 mm Hg or diastolic blood pressure 5,110 mm Hg that had been reduced by 30 mm Hg or more from baseline blood pressure. January 1992 Volume 303 Number 1
Atkin at 01
hourly intervals for 7 hours or until 1 hour after the goal SuDBP was attained. At each blood pressure and heart rate determination, a clinical survey was performed by the investigator to record all symptoms or physical signs of possible drug side effects. Patients remained semi-supine between blood pressure recordings and had precautionary peripheral intravenous lines with 5% dextrose in water. The time period during which the patient remained in the emergency department was used by the physician and the nursing staff to educate the patient about hypertension and its complications, to improve long-term compliance. The endpoint was defined as maintenance of goal SuDBP for 1 hour after the final dose of study medication. Once the endpoint was reached, all patients were followed for an additional 1 hour observation period with supine and standing blood pressure and heart rate measurements at 30-minute intervals. Patients were placed in the phase II followup group if they met the following criteria: at the beginning of the observation period, the patient had achieved the endpoint and at the end of the observation period, the mean SuDBP did not rise by more than 15 mm Hg and the patient had no significant adverse effects. These patients were placed on double-blind maintenance therapy after discharge from the emergency department, with instructions to return for a followup visit within 1-5 days, 8-12 hours after their last evening dose of medication. In this maintenance therapy phase, patients who had been randomized to the labetalol treatment group received labetalol 200 mg orally twice daily; patients who had been randomized to the clonidine treatment group received clonidine 0.1 mg orally twice daily. Each patient was instructed to start the first dose of medication approximately 6 hours after the last dose of phase I treatment medication, with a subsequent dose every 12 hours. On return to the emergency department, each patient had a physical examination and routine laboratory tests including a complete blood count, serum chemistries, urinalysis, and an EKG. Blood pressure and heart rate were recorded in both the supine and standing positions and a clinical survey was performed to record spontaneously offered symptoms. Patients were then discharged from the study and followed as outpatients with individualized long-term antihypertensive therapy in the medical clinic. Any patient who did not attain the goal SuDBP during phase I of the study or who did not fit criteria for enrollment into phase II was discontinued from the study, given individualized antihypertensive therapy in the emergency department, and subsequently followed as an outpatient in the medical clinic. Mean systolic and diastolic blood pressures and heart rates of the labetalol and clonidine groups were compared with analysis of variance with repeated measures and with t-test. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Results Phase I: Labetalol Group. Of the 18 patients who re-
ceived labetalol, 17/18 (94%) achieved the goal mean SuDBP of .:s;;100 mm Hg or a decrease in the mean SuDBP of at least 30 mm Hg compared to baseline and a mean SuDBP of .:s;;110 mm Hg within 6 hours. Mean blood pressure and heart rate data are shown in Table 2. The mean baseline supine blood pressure of this group was 201 mm Hg (range: 155-252 mm Hg) and 132 mm Hg diastolic (range: 120-154 mm Hg). The mean final supine blood pressure was 149 mm Hg systolic (range: 100-180 mm Hg) and 95 mm Hg diastolic (range: 70-122 mm Hg). The mean decrease in systolic blood pressure was 54 mm Hg; in diastolic blood pressure, 37 mm Hg. The mean baseline heart rate was 84 beats per minute; the mean final heart rate, 74 beats per minute. Of the 17 patients who achieved the goal SuDBP, 12/17 (71 %) achieved the goal within 3 hours, responding to a total dose of 600 mg or less of labetalol (Figure 1). The most significant side effect of labetalol was hypotension, seen in one patient who was withdrawn from the study after he developed transient hypotension with orthostatic dizziness 2 hours after receiving a single 200 mg dose of labetalol (blood pressure fell from 181/ 139 mm Hg to 100/70 mm Hg). His hypotension and symptoms improved with 400 cc of intravenous saline administered over a I-hour period. Other side effects of labetalol were mild dizziness or lightheadedness in 6/18 patients (33%), two of whom noted exacerbation on standing, mild sleepiness in 5/18 patients (28%), headache in 2/18 (22%), and scalp tingling in one patient. No significant changes were observed in routine laboratory studies or EKGs when baseline evaluations were compared to final data. Phase I: Clonidine Group. Of the 18 patients who received clonidine, 15/18 (83 %) achieved the goal of mean SuDBP of .:s;;100 mm Hg or a decrease in the mean SuDBP of at least 30 mm Hg compared to baseline and a mean SuDBP of .:s;;110 mm Hg within 6 hours. Mean blood pressure and heart rate data are shown in Table 2. The mean initial supine blood pressure of this group was 196 mm Hg systolic (range: 155-252 mm Hg) and 131 mm Hg diastolic (range: 120-148 mm Hg). The mean final supine blood pressure was 140 mm Hg systolic (range: 101-167 mm Hg) and 100 mm Hg diastolic (range: 76-121 mm Hg). The mean decrease in systolic blood pressure was 57 mm Hg; in diastolic blood pressure, 32 mm Hg. The mean baseline heart rate was 83 beats per minute; the mean final heart rate, 74 beats per minute. All 15 responders achieved the goal SuDBP within 4 hours, responding to a total dose of 0.5 mg or less of clonidine; 10/15 (66%) responded to a total dose ofOA mg or less (Figure 1) . . The most prominent side effect attributed to clonidine was sedation, which occurred in 10/18 (56%) of 11
Labetalol Versus Clonidine for Severe Hypertension
Table 2. Comparative Response to Clonidine or Labetalol in Severe Hypertension Labetalol Mean Baseline Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 15 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 30 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 45 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 60 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 90 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 120 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 150 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 180 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 210 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm At 240 minutes Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm Phase II visit Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm
SE
(n = 18) 200 6.2 132 2.0 84 3.0 (n = 18) 193 4.7 125 1.8 82 2.7 (n = 18) 184 5.5 121 2.8 2.6 80 (n = 18) 178 5.0 3.1 115 76 2.9 (n = 18) 175 4.3 114 3.3 78 2.4 (n = 16) 171 3.3 3.2 111 78 2.6 (n = 16) 161 4.1 107 2.6 2.1 78 (n = 11) 170 6.8 104 3.9 76 2.4 (n = 11) 159 5.7 105 3.2 75 2.1 (n = 6) 170 6.7 113 3.8 4.0 74 (n = 6) 166 4.7 111 4.7 74 3.4 (n = 16) 173 6.9 111 3.6 78 1.4
Clonidine Mean (n
SE
Significance
= 18)
196 131 83
48 1.8 2.5 (n = 18) 194 5.0 130 1.7 81 2.3 (n = 18) 191 5.4 128 1.9 80 2.5 (n = 18) 185 5.0 125 2.2 79 2.6 (n = 18) 178 4.5 121 2.3 80 2.6 (n = 17) 165 3.4 116 2.3 78 3.1 (n = 17) 157 3.7 110 2.4 76 3.3 (n = 14) 158 2.9 113 2.3 78 3.6 (n = 14) 149 4.2 108 2.9 74 3.3 (n = 8) 152 4.0 111 2.6 75 3.0 (n = 8) 149 7.2 107 6.0 74 5.2 (n = 14) 161 8.4 108 3.1 72 2.8
NS NS NS NS NS NS NS NS NS NS
.
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
..
orthostatic hypotension, which resolved within 15 minutes without treatment, and dry mouth in 2/18 patients (11%). No significant changes were noted in the routine laboratory studies or EKGs when baseline evaluations were compared to final data. Phase II: Labetalol Group. Of the 18 patients who participated in phase I of the study, the 16 who achieved the goal SuDBP were enrolled in phase II. All returned for the scheduled followup visit. All patients reported strict compliance with the medication regimen. Remaining pills were counted for verification. At the followup visit, the mean supine systolic blood pressure was 173 mm Hg (range: 140-230 mm Hg) and the mean fall in systolic blood pressure from the baseline phase I value to the phase II visit was 31 mm Hg. The mean SuDBP was 110 mm Hg (range: 90-138 mm Hg) and the mean fall was 20 mm Hg. Blood pressure and heart rate data are shown in Table 2. The only side effects attributed to the maintenance administration of labetalol were mild headache in 2/16 patients (13%) and mild transient dizziness upon standing in 2/16 patients (13%). Phase II: Clonidine Group. Of the 18 patients who participated in phase I of the study, the 15 who achieved the goal SuDBP were enrolled in phase II. All except one returned for the scheduled followup visit. All patients reported strict compliance with the medication regimen. Remaining pills were counted for verification. At the followup visit, the mean supine systolic blood pressure was 161 mm Hg (range: 106-229 mm Hg) and the mean fall in systolic blood pressure from the baseline phase I value to the phase II visit was 37 mm Hg. The mean SuDBP was 108 mm Hg (range: 87-130 mm Hg) and the mean fall was 23 mm Hg. Blood pressure and heart rate data are shown in Table 2.
NS NS
!ZZZI L.A8ETALOL ~
.. NS NS
2 5 c
NS NS NS
.. p < .05. Not significant (NS) = P ~ .05. bpm = beats per minute (supine). BP = blood pressure (supine). SE = standard error.
Q)
~
...o
4
~ 3
.a
E :::> z
2
TIme
the patients. This ranged in severity from mild drowsiness to deep sleep. Other complaints included dizziness in 3/18 patients (17%), which was severe in one patient after four doses of clonidine and associated with
12
CLONIDINE
6
lhr
2hr
Jhr
4hr
Shr
6hr
Figure 1. Cumulative doses of medication needed to achieve goal blood pressure in those patients who were successful responders. Labetalol, n = 17; clonidine, n = 15. "No patients in the clonidine group who were successful responders required more than 0.5 mg to achieve goal blood pressure. January 1992 Volume 303 Number 1
Atkin et 01
The only side effects attributed to the maintenance administration of clonidine were mild drowsiness in 2/14 patients (14%), dry mouth in 2/14 patients (14%), and mild dizziness upon standing in 2/14 patients (14%). Discussion
Labetalol, which has both alpha1 and nonselective beta adrenoreceptor blocking actions and beta2 partial agonist activity, lowers blood pressure acutely primarily through peripheral vasodilation mediated by its alpha1 blockade. 23 ,24 Reflex tachycardia, seen with some vasodilators, is avoided due to beta1 blocking activity, and cardiac ou.tput remains unchanged. 25 Orallabetalol is well absorbed, resulting in peak plasma concentrations within 2 hours of administration. Peak antihypertensive effects occur within 1-2 hours.9 Clonidine, which has alpha adrenergic agonist activity, acts at the presynaptic receptor to lower blood pressure through a centrally mediated decrease in sympathetic outflow and a reduction in circulating catecholamines. The resulting decrease in vascular tone results in reduction of systemic blood pressure. 26,27 Reduction in plasma renin may also contribute to the antihypertensive effect of clonidine. 27 Oral clonidine is well-absorbed, resulting in peak plasma concentrations within 90 minutes to 5 hours of administration. Peak antihypertensive effects occur within 2-4 hours. 27 While the acute antihypertensive effects of intravenous labetalol have been well-documented, only a few studies conducted exclusively in hospitalized patients have demonstrated the efficacy of orallabetalol in the treatment of severely elevated blood pressure.28-32 No studies have compared oral labetalol with other oral antihypertensive agents in the treatment of severely elevated blood pressure in an outpatient setting. In our study, acute administration of oral labetalol was effective in lowering blood pressure in 94% (17/ 18) of patients; 71 % (12/17) achieved the goal diastolic blood pressure within 3 hours (Figure 1). Of the 16 patients who entered the maintenance phase II part of the study, 69% (11/16) had diastolic blood pressures below 115 mm Hg at the followup visit. Side effects in the labetalol group, which were generally mild, included dizziness, drowsiness, and headache in 44% of the patients in phase I and in 17% of the patients in phase II. One patient experienced transient hypotension after a single 200 mg dose of labetalol. Acute oral administration of clonidine was effective in lowering blood pressure in 83% (15/18) of patients, with all 15 responders achieving the goal diastolic blood pressure within 4 hours (Figure 1). Of the 14 patients who returned for the maintenance phase II part of the study, 71 % (10/14) had diastolic blood pressures below 115 mm Hg at the followup visit. Side effects in the clonidine group were prominent in phase I of the study, with 66% of the patients experiencing mild to severe sedation, dizziness, and dry mouth. In phase II of the THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
study, 36% of the patients experienced similar, but less severe, side effects. Oral clonidine loading has been a popular treatment regimen for the outpatient or emergency department therapy of nonemergent but severely elevated blood pressure. Most studies have emphasized the efficacy and safety of clonidine loading. 3,1o,12,33-35 Nifedipine8,ll has also been used to lower blood pressure acutely. In our study, the response to oral clonidine loading was maximal at a dosage of 0.4-0.5 mg. Once a patient failed to respond to 4 hours of clonidine loading, additional treatment was unlikely to lower blood pressure further. These data are consistent with a previous study of clonidine loading in an emergency department setting.8 Several recent commentaries have questioned the need for acute blood pressure reduction in patients who have severe hypertension but no acute end-organ dysfunction. 1,5,6,36 These have emphasized the lack of proven long-term benefits and the possibility of deleterious effects from antihypertensive loading regimens. While the potential immediate risk of untreated severe hypertension to vital organs and to patient survival is not known, many patients with nonemergent but severe hypertension present with symptoms such as headache, dizziness, and blurred vision. These symptoms suggest that a more acute process may be evolving in this subset of severely hypertensive patients. In our study, 56% of the patients presented with symptoms possibly related to their severely elevated blood pressure. While it is not clear which patients are at risk for development of further acute hypertensive complications, we believe that severely hypertensive patients should be treated with gradual blood pressure reduction with oral agents in an emergency department setting over several hours. The ideal oral agent for the outpatient treatment of nonemergent but severely elevated blood pressure should have the following characteristics: a high degree of efficacy, a favorable side effect profile, the ability to lower blood pressure gradually over several hours, and acceptability as a long-term oral antihypertensive agent. Orallabetalol appears to be a reasonable alternative to both clonidine and nifedipine for this purpose. In our study, labetalol had a success rate comparable to clonidine (Figure 2). Most patients responded to two or three 200 mg doses of labetalol. Side effects were frequent although mild; the transition to oral maintenance therapy was well-tolerated. It has recently been suggested that acute blood pressure management in the patient with severe hypertension be tailored to suit the individual patient. 36,37 Labetalol has been shown to be highly effective as an .antihypertensive agent in black patients, in contrast to other agents such as dilevalol and beta blocking agents such as propranolo1. 38,39 It has been postulated that the alpha adrenergic-blocking property of labetalol may oppose nonrenin mediated factors, which may contribute to hypertension in black patients. 24 In our 13
Labetalol Versus Clonidlne for Severe Hypertension
225
01
••.••••••• - CLONIDINE - - U>.SE:TALOL
200
:::c E E
SYSTOLIC BP 175
Q) ~
~ 150
rn
Q) ~
0....
DIASTOLIC BP
125
""0 0 0 CD
100
75
.~ E
0
30
60
90
120
150
lao
90
.............
rn ........ 0
(l)
.0 (l) ........
0
~
eo
-_.1.-_--r--..::........................
..........
....-..........
70
........ ~
0
(l)
:c
60
0
30
60
90
120
150
leo
Time, min
Figure 2. Mean systolic and diastolic blood pressures and heart rates for each group of patients receiving either labetalol (solid line) or clonidine (dotted line) who achieved goal diastolic blood pressure within 3 hours. Labetalol, n = 12. clonidine, n = 10.
study, the majority of patients (94%) were black. It is not clear whether orallabetalol would be as successful in other patient populations. We believe that oral labetalol is an alternative for the treatment of severe hypertension in an emergency department or outpatient setting. In our study, it was successful in safely and gradually lowering blood pressure, it worked well in black patients, had generally mild side effects, and was effective in a twice daily regimen for maintenance therapy. Further studies are needed to define the most effective dosing regimen of orallabetalol for the treatment of severe hypertension in an emergency department setting. References 1. Weber MA: Immediate treatment of severe hypertension widening the options. Arch Intern Med 149:2635-2637, 1989. 2. Ram CV, Hyman D: Hypertensive crises. J Intensive Care Med . 2:151-162, 1987. . 3. Calhoun DA, Oparil S: Treatment of hypertensive crisis. N Engl J Med 323:1177-1183,1990. 4. 1988 Joint National Committee: The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 148:1023-1038, 1988.
14
5. Ferguson RK, Vlasses PH: How urgent is 'urgent' hypertension? Arch Intern Med 149:257-258, 1989. 6. Fagan TC: Acute reduction of blood pressure in asymptomatic patients with severe hypertension. An idea whose time has come and gone. Arch Intern Med 149:2169-2170, 1989. 7. Ferguson RK, Vlasses PH: Hypertensive emergencies and urgencies. JAMA 255:1607-1613, 1986. 8. Jaker M, Atkin S, Soto M, Schmid G, Brosch F: Oral nifedipine vs oral clonidine in the treatment of urgent hypertension. Arch Intern Med 149:260-265, 1989. 9. Catapano M8, Marx JA: Management of urgent hypertension: A comparison of oral treatment regimens in the emergency department. J Emerg Med 4:361-368, 1986. 10. Anderson RJ, Hart GR, Crumpler CP, Reed WG, Matthews CA: Oral clonidine loading in hypertensive urgencies. JAMA 246: 848-850, 1981. 11. Houston MC: Treatment of hypertensive urgencies and emergencies with nifedipine. Am Heart J 111:963-969, 1986. 12. Houston MC: Treatment of hypertensive emergencies and urgencies with oral clonidine loading and titration. Arch Intern Med 146:586-589, 1986. 13. Meese RB, Ram CV: Hypertensive cardiovascular emergencies. Compr Ther 11:28-38, 1985. 14. Wachter RW: Symptomatic hypotension induced by nifedipine in the acute treatment of severe hypertension. Arch Intern M ed 147:556-558, 1987. 15. Friedman CP: Symptomatic hypotension induced by nifedipine . Arch Intern Med 147:1683, 1987. 16. O'Mailia JJ, Sander GE, Giles TD: Nifedipine-associated myocardial ischemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 107:185-186, 1987. 17. Schwartz M, Naschitz JE, Yeshurun D, SharfB: Oral nifedipine in the treatment of hypertensive urgency: Cerebrovascular accident following a single dose. Arch Intern Med 150:686-687, 1990. 18. Gonzales DG, Ram CV: New approaches for the treatment of hypertensive urgencies and emergencies. Chest 93:193-195,1988. 19. Cressman MD, Vidt DG, Gifford RW, Moore WS, Wilson DJ: Intravenous labetalol in the management of severe hypertension and hypertensive emergencies. Am Heart J 107:980-985, 1984. 20. Vidt DG: Intravenous labetalol in the emergency treatment of hypertension. J Clin Hypertens 2:179-186,1985. 21. Huey J, Thomas JP, Hendricks DR, Wehmeyer AE, Johns LJ, MacCosbe PE: Clinical evaluation of intravenous labetalol for the treatment of hypertensive urgency. Am J Hypertens 1:2848289S, 1988. 22. Smith WB, Clifton GG, O'Neill WM, Wallin JD: Antihypertensive effectiveness of intravenous labetalol in accelerated hypertension. Hypertension 5:579-583, 1983. 23. Prichard BN, Lund-Johansen P, Louis WJ, MolinoffPB, Taylor SH, Chamberlain DA: Combined alpha-beta-blockade A roundtable discussion. Drugs 288:103-108, 1984. 24. Flamenbaum W: Propranolol versus labetalol: Interesting differences in efficacy. J Natl Med Assoc 778:14-29, 1985. 25. Holtzman JL, Finley D, Johnson B, Berry DA, Sirgo MA: The effects of single-dose atenolol, labetalol, and propranolol on cardiac and vascular function. Clin Pharmacol Ther 40:268-273, 1986. 26. Lowenstein J: Clonidine. Ann Intern Med 92:74-77,1980. 27. Houston MC: Clonidine hydrochloride: Review of pharmacologic and clinical aspects. Prog Cardiovasc Dis 23:337-349, 1981. 28. Ghose RR, Mathur VB, Upadhyay M, Morgan WD, Khan S: Treatment of hypertensive emergencies with oral labetalol. Br Med J 2:737, 1978. 29. Ghose RR, Sampson A: Rapid onset of action of orallabetalol in severe hypertension. Curr Med Res Opin 5:147-151,1977. 30. Ghose RR: Acute management of severe hypertension with oral labetalol. Br J Clin Pharmacol 8:189S-193S, 1979. January 1992 Volume 303 Number 1
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31. Serlin MJ, Orme ME, Maciver M, Green GJ, Macnee CM, Breckenridge AM: Rate of onset of hypotensive effect of oral labetalol. Br J Clin Pharmacol7:165-168, 1979. 32. Olowoeye JO, Okoro EO, Omotosho AB: Oral labetalol in the urgent treatment of severe hypertension. Trop Geograph Med 38:73-78, 1986. 33. Spitalewitz S, Porush JG, Oguagha C: Use of oral c10nidine for rapid titration of blood pressure in severe hypertension. Chest 83:404-407, 1983. 34. Cohen 1M, Katz MA: Oral c10nidine loading for rapid control of hypertension. Clin Pharmacol Ther 24:11-15,1978. 35. Marks AD, Adlin EV, Channick BJ: Oral c10nidine for rapid control of accelerated hypertension. J Clin Pharmacol27:193-198, 1987.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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