AJH
1991;
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Management of Perioperative Hypertension Using Intravenous Isradipine Peter C. Rüegg, Urs Karmann, and Hanspeter Keller
The antihypertensive action of acute intravenous isradipine w a s investigated during f e n t a n y l / p a n c u r o n i u m / n i t r o u s oxide anesthesia for noncardiac surgery. A n intravenous (iv) infusion of 0.5 m g isradipine (n = 10) or placebo (n = 11) w a s a d m i n i s tered double-blind over 5 m i n if m e a n arterial pressure (MAP) w a s > 110 m m Hg. The number of patients w i t h a favorable blood pressure reduction (ΔΜΑΡ > 10% w i t h M A P < 110 m m Hg) w a s 80% w i t h isradipine and 20% w i t h placebo (P < .05), and the m e a n M A P reduction from baseline w a s 26 ± 12 and 2 ± 16 m m Hg, respectively (P < .001). D u e to
reflex activation of the sympathetic nervous system, the heart rate increased b y 14 ± 12 b e a t s / m i n w i t h acute i v isradipine. The antihypertensive effect w a s sustained for 45 m i n . Isradipine w a s also w e l l tol erated. It is concluded that intravenous isradipine is an effective antihypertensive agent for the treat ment of perioperative hypertension during noncar diac surgery. A m J Hypertens 1991;4:203S-206S
D
m e n t m a y b e required. A variety of antihypertensive drugs h a v e b e e n used in this setting, including nitro prusside, nitroglycerin, labetalol, a n d h y d r a l a z i n e ' ; re cently, data w i t h nicardipine h a s also b e e n r e p o r t e d . Isradipine is a calcium antagonist of the dihydropyri dine g r o u p with significant arterial vasodilatory proper ties that preferentially dilate coronary, cerebral, a n d skeletal muscular v a s c u l a t u r e . Studies in vitro h a v e s h o w n isradipine to increase coronary blood flow selec tively a n d to inhibit sinus n o d e function, w i t h o u t affect ing atrioventricular conduction or myocardial contract ile function. In w h o l e animals in w h i c h compensatory sympathetic a n d parasympathetic actions on the heart h a d b e e n eliminated, isradipine, unlike diltiazem or ni fedipine, did not depress myocardial contractile force. In view of its pharmacologic profile of a negligible nega tive inotropic effect a n d a consistent negative chrono tropic action, isradipine w a s expected to produce favor able results as seen with other antihypertensive drugs in the treatment of hypertension during surgery, b u t w i t h out e n d a n g e r i n g patients w h o h a v e impaired cardiac p u m p function, impaired myocardial perfusion, a n d / o r abnormalities of impulse formation or conduction. The objective of the study w a s to assess the efficacy
espite good preoperative preparation, h y p e r tension during anesthesia m a y occur, espe cially in patients with preexisting arterial h y pertension a n d in those undergoing aortic or abdominal surgery. These episodes are attributed to a n increase in systemic vascular resistance following a n o ciceptive stimulation, such as laryngoscopy, in- or extubation, or skin i n c i s i o n , a n d m a y represent a risk for complications such as myocardial ischemia, cardiac fail ure, or cerebral h e m o r r h a g e . Elevated blood pressure often results from inadequate analgesia a n d m a y re spond to analgesic treatment; although a n increase in analgesic d e p t h with volatile cardiodepressive agents may be of benefit in situations with a simultaneous in crease of systemic blood pressure a n d p u l m o n a r y capil lary w e d g e pressure, additional antihypertensive treat1
2-4
5
6
From the Department of Clinical Cardiovascular Research, Sandoz Pharma, Basle; Department of Anesthesiology, Limmattalspital, Schlieren-Zürich; Department of Anesthesiology, Kantonsspital, Winterthur; Switzerland. Address correspondence and reprint requests to Peter C. Rüegg, MD, Department of Clinical Cardiovascular Research, Sandoz Pharma, Building 3 8 6 / 8 4 4 , C H - 4 0 0 2 Basle, Switzerland.
© 1991 by the American Journal of Hypertension,
Inc.
KEY WORDS: Isradipine, hypertension, surgery, an esthesia.
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a n d safety of isradipine administered intravenously for the treatment of hypertension during general anesthesia for noncardiac surgery. PATIENTS A N D
METHODS
1991-VOL
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the s t a n d a r d formula: M A P = (2 X diastolic + systolic blood p r e s s u r e ) / 3 . The electrocardiogram w a s continu ously monitored a n d tracings of lead V5 recorded. The Fisher Exact probability test (one-tailed) w a s used to test the differences in responder rates b e t w e e n treat m e n t groups. The χ test w a s used for the differences in overall assessments b e t w e e n the treatment groups, a n d the t test to describe differences of M A P values b e t w e e n the treatment groups. The Bonferroni-Holm procedure w a s used to adjust the α-level in the case of multiple testing. 2
A blinded trial w a s carried out using isradipine a n d pla cebo. The objective of the treatment w a s to reduce ele vated m e a n arterial pressure (MAP) by at least 1 0 % from baseline to a target of less t h a n 110 m m H g within 12 min. Patients failing to achieve this goal subse quently received o p e n treatment with a single dose of the active c o m p o u n d . Blood pressure a n d heart rate were recorded for 45 to 60 min after the infusion. Patients aged b e t w e e n 18 a n d 85 years u n d e r g o i n g noncardiac surgery w e r e selected for the study. Ex cluded w e r e patients w h o h a d surgery of the a b d o m i n a l aorta or carotid artery; severe or unstable angina; a re cent myocardial infarction or cerebrovascular incident; congestive heart failure (New York Heart Association functional class III or IV); second- or third-degree atrio ventricular block; or renal or hepatic failure. Written informed consent w a s obtained from each patient. Premedication w a s given 45 min before anes thesia a n d consisted of 0.5 m g atropine a n d 1 m g / k g meperidine. Anesthesia w a s induced with thiopental (4 m g / k g ) a n d succinylcholine (1 m g / k g ) , followed b y p a n c u r o n i u m (0.08 m g / k g ) , a n d maintained with ni trous oxide ( N 0 70%, 0 30%) a n d intermittent intra v e n o u s doses of fentanyl a n d p a n c u r o n i u m . Arterial blood pressure w a s registered (see below) at 10-min intervals. Whenever, during anesthesia, the M A P exceeded 110 m m Hg, a s u p p l e m e n t a r y dose of fentanyl (1 to 2 / / g / k g ) w a s administered intravenously. If, after 5 min, the M A P r e m a i n e d b e t w e e n 110 a n d 140 m m Hg, patients received a double-blind intrave n o u s infusion of either 0.5 m g isradipine or the same volume (10 mL) of a placebo solution over a 5-min p e riod. Immediately before (T ) a n d u p to 12 min (T ) after the start of the infusion, blood pressure w a s m e a s u r e d every 2 min. O n the basis of the M A P value at T , o n e of the following t w o options w a s t h e n followed: 1. If M A P at T w a s ^ 1 1 0 m m H g a n d reduced by ^ 1 0 % com p a r e d with baseline, further m e a s u r e m e n t s at T a n d t h e n at 5-min intervals w e r e taken until T ; 2. If M A P at T w a s > 110 m m H g a n d / o r reduced b y < 1 0 % com pared with baseline, patients received o p e n additional treatment with 0.5 m g isradipine over 5 min. Immedi ately before (T ) a n d u p to 12 min after (T ) the start of the second infusion, blood pressure w a s m e a s u r e d every 2 min, t h e n at 5-min intervals for the remaining 30 min ( T to T ) .
P a t i e n t s A total of 30 patients gave their informed consent, n i n e of w h o m w e r e excluded because of a low blood pressure following fentanyl, or changes in the surgical or anesthetic procedure. Thus, 21 patients, of w h o m 17 h a d chronic hypertension, w e r e included in the study; 10 were r a n d o m i z e d into the isradipine group, a n d 11 into the placebo group. The nine m e n a n d 12 w o m e n h a d a m e a n age of 61 years (range 39 to 85 years), a m e a n height of 166 cm (range 153 to 182 cm), a m e a n weight of 75 kg (range 53 to 98 kg), a n d all w e r e white. The m e a n preoperative blood pressure w a s 1 5 3 / 8 9 m m Hg. T h e t w o treatment groups w e r e h o m o geneous a n d comparable with respect to patient charac teristics a n d M A P at baseline. Patients h a d b e e n re ferred to the hospital for surgical interventions o n t h e following organ systems: urogenital (n = 6), gastrointes tinal tract (n = 4), blood vessels (n = 4), h e a d a n d neck (n = 3), b o n e (n = 2), or other (n = 2). Eight patients in the isradipine g r o u p a n d seven in the placebo g r o u p h a d received chronic antihypertensive treatment before the study, w h i c h w a s continued as concomitant medication in all b u t t w o patients in each group. In the isradipine group, of the six patients w h o continued to receive a n antihypertensive therapy, five received a diuretic alone (n = 2), or in combination w i t h reserpine (n = 2) or a ^-blocker (n = 1); the last patient received a /?-blocker only. In the placebo group, of the five patients w h o continued to receive a n antihypertensive treatment, four received a diuretic alone (n = 1), or in combination with reserpine (n = 2) or a calcium antagonist (n = 1); the last patient received a n ACE inhibitor. All b u t o n e of the patients completed the trial as p l a n n e d ; t h e excep tion w a s a 39-year-old w o m a n w h o , while u n d e r g o i n g an a b d o m i n a l hysterectomy, s h o w e d a s u d d e n d r o p in M A P from 115 to 51 m m H g b e t w e e n 10 a n d 12 m i n after the infusion of placebo. This w a s found to be d u e to compression of the caval vein; the patient w a s there fore excluded from the rest of the trial.
Blood pressure a n d heart rate w e r e m e a s u r e d with a n automatic device based on oscillometry (Nippon Colin, Japan; O h m e d a NIBP, US; or Marquette Electronics, US) w h i c h provided systolic, diastolic, a n d m e a n arterial blood pressure values. The latter w a s calculated using
Efficacy Immediately prior to the administration of the s u p p l e m e n t a r y dose of fentanyl, m e a n M A P w a s 125 ± 10 m m H g and, 5 m i n later, 124 ± 11 m m H g . The m e a n time from the start of anesthesia to the start of
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TABLE 1. CHANGES (MEANS ± SD) WITH INTRAVENOUS ISRADIPINE AND PLACEBO IN PATIENTS WITH ARTERIAL HYPERTENSION (MAP > 110 MM HG) DURING NONCARDIAC SURGERY Mean Arterial Pressure (MAP; mm Hg)
Trial
Time
Period
(min)
Blinded
ot 2 4 6 8 10 12
122 113 96 90 89 93 97
±9 ±22 ± 19 ±20 ±20 ± 15 ± 12
15 20 30 45
93 99 101 99
± ± ± ±
Open§
Placebo
Isradipine
*** *** *** *** ***
126 ± 12 123 ± 10 126 ± 10 124 ± 10 125 ± 1 1 122 ± 14 124 ± 16#
12 13 12 15
Heart Rate (beats/min) Isradipine
83 84 93 95 93 92 96
±20 ± 18 ± 19ft ±21 ±20 ± 19 ±20
95 91 95 83
±23 ± 18 ±21 ± 15
Respondert Rate (n, %)
Placebo
73 ± 1 4 74 ± 14 * 75 ± 14 ** 73 ± 13 73 ± 13 * 73 ± 14 ** 73 ± 13ft
Isradipine
0 3 7 8 9 9 8
(30%) (70%) (80%) (90%) (90%) (80%)
7 5 4 5
(88%) (63%) (50%) (63%)
Placebo
** *** *** ** *
0 0 0 0 0 2 (18%) 2 (20%)tt
t Patients whose MAP was reduced by ^ 10% from baseline to 140 m m Hg), heart failure, a n d / o r acute coronary is chemia were excluded, a n d the duration of the placebo period w a s restricted to 15 min. Thus, the data were obtained in low-risk patients, most of w h o m were 13
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k n o w n hypertensives u n d e r chronic antihypertensive treatment. In order to exclude pain as a contributing factor to the raised blood pressure, patients were eligible for participation only if their blood pressure remained elevated after administration of a s u p p l e m e n t a r y dose of fentanyl. The data indicate that a n intravenous infu sion of isradipine produces a n immediate a n d adequate reduction in blood pressure in most patients that w a s sustained during the 45-min observation period; h o w ever, as the s p o n t a n e o u s time course of the blood pres sure in these patients is not k n o w n , conclusions regard ing the duration of action cannot be m a d e . Treatment w a s associated with a minor, b u t significant, increase in heart rate, suggesting that the intrinsic negative chrono tropic action of i s r a d i p i n e ' w a s overridden by a reflex sympathetic activation elicited by the blood pressure reduction. As inhalation anesthetics a n d calcium antagonists h a v e similar pharmacologic effects, cardiovascular in teractions with isradipine and, for example, h a l o t h a n e are likely to occur. However, isradipine, in contrast to other calcium antagonists, h a s b e e n s h o w n to be devoid of significant cardiodepressant effects in a n i m a l s a n d in p a t i e n t s ; thus, a combined treatment with isradipine a n d a n anesthetic is unlikely to produce unfavorable effects on myocardial function. O n the other h a n d , the additive blood pressure-lowering effect of the d i h y d r o pyridines a n d higher concentrations of volatile anesthet ics m a y lead to arterial h y p o t e n s i o n . Interaction stud ies of isradipine with anesthetics are n e e d e d before their w i d e s p r e a d use in this indication can be r e c o m m e n d e d . It is concluded that isradipine effectively a n d safely reduces blood pressure in hypertensive patients during noncardiac surgery; however, further investigations are n e e d e d to define the potential therapeutic role of isradi pine in this setting. 11
3. 4. 5.
6.
7.
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REFERENCES 1.
2.
Goldman L, Calder DL: Risks of general anesthesia and elective operation in the hypertensive patient. Anesthesi ology 1979;50:285-292. Frobes AM, Dolly FG: Acute hypertension during induc
15.
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tion of anaesthesia and endotracheal intubation in nor motensive man. Br J Anaesth 1970;42:618-624. Prys-Roberts C: Hypertension and anaesthesia — fifty years on. Anesthesiology 1979;50:281-284. Reid D, Aylmer A: Hypertension in anaesthesia. Can Anesth Soc J 1984;31:222-230. Steen PA, Tinkler JH, Tarhan S: Myocardial infarction after anesthesia and surgery. JAMA 1978,239:25662569. Roizen MF, Hamilton WK, Sohn YJ: Treatment of stressinduced increases in pulmonary capillary wedge pres sure using volatile anesthetics. Anesthesiology 1981; 55:446-450. Thompson D, Ampel L: Perioperative hypertension. The primary care physician's role. Postgrad Med 1988; 84:261-268. Scott DB: The use of labetalol in anaesthesia. Br J Clin Pharmacol 1982;13(suppl 1):133S-135S. Begon C, Dartayet B, Edouard A, et al: Intravenous ni cardipine for treatment of intraoperative hypertension during abdominal surgery. J Cardiothorac Anesth 1989;3:707-711. Hof RP, Hof A, Scholtysik G, Menninger K: Effects of the new calcium antagonist PN 200-110 on the myocardium and the regional peripheral circulation in anaesthetized cats and dogs. J Cardiovasc Pharmacol 1984;6:407-416. Wada Y, Satoh K, Taira Ν: Separation of coronary vaso dilator from cardiac effects of PN 200-110, a new dihy dropyridine calcium antagonist, in the dog heart. J Car diovasc Pharmacol 1985;7:190-196. Hof RP: Comparison of cardiodepressant and vasodila tor effects of PN 200-110 (isradipine), nifedipine and diltiazem in anesthetized rabbits. Am J Cardiol 1987;59:37B-42B. Fifer MA, Colucci WS, Lorell BH, et al: Inotropic, vascu lar and neuroendocrine effects of nifedipine in heart fail ure: comparison with nitroprusside. J Am Coll Cardiol 1985;5:731-737. Mauser M, Voelker W, Ickrath O, Karsch KR: Differences of the myocardial properties of the new dihydropyridine calcium channel blocker isradipine as compared to nife dipine with or without additional betablockade in pa tients with coronary artery disease. Am J Cardiol 1989;63:40-44. Merin RG: Calcium channel blocking drugs and anaes thetics: is the drug interaction beneficial or detrimental? Anaesthesiology 1987;66:111-113.
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Management of Perioperative Hypertension Using Intravenous Isradipine Peter C. Rüegg, Urs Karmann, and Hanspeter Keller
The antihypertensive action of acute intravenous isradipine w a s investigated during f e n t a n y l / p a n c u r o n i u m / n i t r o u s oxide anesthesia for noncardiac surgery. A n intravenous (iv) infusion of 0.5 m g isradipine (n = 10) or placebo (n = 11) w a s a d m i n i s tered double-blind over 5 m i n if m e a n arterial pressure (MAP) w a s > 110 m m Hg. The number of patients w i t h a favorable blood pressure reduction (ΔΜΑΡ > 10% w i t h M A P < 110 m m Hg) w a s 80% w i t h isradipine and 20% w i t h placebo (P < .05), and the m e a n M A P reduction from baseline w a s 26 ± 12 and 2 ± 16 m m Hg, respectively (P < .001). D u e to
reflex activation of the sympathetic nervous system, the heart rate increased b y 14 ± 12 b e a t s / m i n w i t h acute i v isradipine. The antihypertensive effect w a s sustained for 45 m i n . Isradipine w a s also w e l l tol erated. It is concluded that intravenous isradipine is an effective antihypertensive agent for the treat ment of perioperative hypertension during noncar diac surgery. A m J Hypertens 1991;4:203S-206S
D
m e n t m a y b e required. A variety of antihypertensive drugs h a v e b e e n used in this setting, including nitro prusside, nitroglycerin, labetalol, a n d h y d r a l a z i n e ' ; re cently, data w i t h nicardipine h a s also b e e n r e p o r t e d . Isradipine is a calcium antagonist of the dihydropyri dine g r o u p with significant arterial vasodilatory proper ties that preferentially dilate coronary, cerebral, a n d skeletal muscular v a s c u l a t u r e . Studies in vitro h a v e s h o w n isradipine to increase coronary blood flow selec tively a n d to inhibit sinus n o d e function, w i t h o u t affect ing atrioventricular conduction or myocardial contract ile function. In w h o l e animals in w h i c h compensatory sympathetic a n d parasympathetic actions on the heart h a d b e e n eliminated, isradipine, unlike diltiazem or ni fedipine, did not depress myocardial contractile force. In view of its pharmacologic profile of a negligible nega tive inotropic effect a n d a consistent negative chrono tropic action, isradipine w a s expected to produce favor able results as seen with other antihypertensive drugs in the treatment of hypertension during surgery, b u t w i t h out e n d a n g e r i n g patients w h o h a v e impaired cardiac p u m p function, impaired myocardial perfusion, a n d / o r abnormalities of impulse formation or conduction. The objective of the study w a s to assess the efficacy
espite good preoperative preparation, h y p e r tension during anesthesia m a y occur, espe cially in patients with preexisting arterial h y pertension a n d in those undergoing aortic or abdominal surgery. These episodes are attributed to a n increase in systemic vascular resistance following a n o ciceptive stimulation, such as laryngoscopy, in- or extubation, or skin i n c i s i o n , a n d m a y represent a risk for complications such as myocardial ischemia, cardiac fail ure, or cerebral h e m o r r h a g e . Elevated blood pressure often results from inadequate analgesia a n d m a y re spond to analgesic treatment; although a n increase in analgesic d e p t h with volatile cardiodepressive agents may be of benefit in situations with a simultaneous in crease of systemic blood pressure a n d p u l m o n a r y capil lary w e d g e pressure, additional antihypertensive treat1
2-4
5
6
From the Department of Clinical Cardiovascular Research, Sandoz Pharma, Basle; Department of Anesthesiology, Limmattalspital, Schlieren-Zürich; Department of Anesthesiology, Kantonsspital, Winterthur; Switzerland. Address correspondence and reprint requests to Peter C. Rüegg, MD, Department of Clinical Cardiovascular Research, Sandoz Pharma, Building 3 8 6 / 8 4 4 , C H - 4 0 0 2 Basle, Switzerland.
© 1991 by the American Journal of Hypertension,
Inc.
KEY WORDS: Isradipine, hypertension, surgery, an esthesia.
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a n d safety of isradipine administered intravenously for the treatment of hypertension during general anesthesia for noncardiac surgery. PATIENTS A N D
METHODS
1991-VOL
4, NO. 2, PART 2
the s t a n d a r d formula: M A P = (2 X diastolic + systolic blood p r e s s u r e ) / 3 . The electrocardiogram w a s continu ously monitored a n d tracings of lead V5 recorded. The Fisher Exact probability test (one-tailed) w a s used to test the differences in responder rates b e t w e e n treat m e n t groups. The χ test w a s used for the differences in overall assessments b e t w e e n the treatment groups, a n d the t test to describe differences of M A P values b e t w e e n the treatment groups. The Bonferroni-Holm procedure w a s used to adjust the α-level in the case of multiple testing. 2
A blinded trial w a s carried out using isradipine a n d pla cebo. The objective of the treatment w a s to reduce ele vated m e a n arterial pressure (MAP) by at least 1 0 % from baseline to a target of less t h a n 110 m m H g within 12 min. Patients failing to achieve this goal subse quently received o p e n treatment with a single dose of the active c o m p o u n d . Blood pressure a n d heart rate were recorded for 45 to 60 min after the infusion. Patients aged b e t w e e n 18 a n d 85 years u n d e r g o i n g noncardiac surgery w e r e selected for the study. Ex cluded w e r e patients w h o h a d surgery of the a b d o m i n a l aorta or carotid artery; severe or unstable angina; a re cent myocardial infarction or cerebrovascular incident; congestive heart failure (New York Heart Association functional class III or IV); second- or third-degree atrio ventricular block; or renal or hepatic failure. Written informed consent w a s obtained from each patient. Premedication w a s given 45 min before anes thesia a n d consisted of 0.5 m g atropine a n d 1 m g / k g meperidine. Anesthesia w a s induced with thiopental (4 m g / k g ) a n d succinylcholine (1 m g / k g ) , followed b y p a n c u r o n i u m (0.08 m g / k g ) , a n d maintained with ni trous oxide ( N 0 70%, 0 30%) a n d intermittent intra v e n o u s doses of fentanyl a n d p a n c u r o n i u m . Arterial blood pressure w a s registered (see below) at 10-min intervals. Whenever, during anesthesia, the M A P exceeded 110 m m Hg, a s u p p l e m e n t a r y dose of fentanyl (1 to 2 / / g / k g ) w a s administered intravenously. If, after 5 min, the M A P r e m a i n e d b e t w e e n 110 a n d 140 m m Hg, patients received a double-blind intrave n o u s infusion of either 0.5 m g isradipine or the same volume (10 mL) of a placebo solution over a 5-min p e riod. Immediately before (T ) a n d u p to 12 min (T ) after the start of the infusion, blood pressure w a s m e a s u r e d every 2 min. O n the basis of the M A P value at T , o n e of the following t w o options w a s t h e n followed: 1. If M A P at T w a s ^ 1 1 0 m m H g a n d reduced by ^ 1 0 % com p a r e d with baseline, further m e a s u r e m e n t s at T a n d t h e n at 5-min intervals w e r e taken until T ; 2. If M A P at T w a s > 110 m m H g a n d / o r reduced b y < 1 0 % com pared with baseline, patients received o p e n additional treatment with 0.5 m g isradipine over 5 min. Immedi ately before (T ) a n d u p to 12 min after (T ) the start of the second infusion, blood pressure w a s m e a s u r e d every 2 min, t h e n at 5-min intervals for the remaining 30 min ( T to T ) .
P a t i e n t s A total of 30 patients gave their informed consent, n i n e of w h o m w e r e excluded because of a low blood pressure following fentanyl, or changes in the surgical or anesthetic procedure. Thus, 21 patients, of w h o m 17 h a d chronic hypertension, w e r e included in the study; 10 were r a n d o m i z e d into the isradipine group, a n d 11 into the placebo group. The nine m e n a n d 12 w o m e n h a d a m e a n age of 61 years (range 39 to 85 years), a m e a n height of 166 cm (range 153 to 182 cm), a m e a n weight of 75 kg (range 53 to 98 kg), a n d all w e r e white. The m e a n preoperative blood pressure w a s 1 5 3 / 8 9 m m Hg. T h e t w o treatment groups w e r e h o m o geneous a n d comparable with respect to patient charac teristics a n d M A P at baseline. Patients h a d b e e n re ferred to the hospital for surgical interventions o n t h e following organ systems: urogenital (n = 6), gastrointes tinal tract (n = 4), blood vessels (n = 4), h e a d a n d neck (n = 3), b o n e (n = 2), or other (n = 2). Eight patients in the isradipine g r o u p a n d seven in the placebo g r o u p h a d received chronic antihypertensive treatment before the study, w h i c h w a s continued as concomitant medication in all b u t t w o patients in each group. In the isradipine group, of the six patients w h o continued to receive a n antihypertensive therapy, five received a diuretic alone (n = 2), or in combination w i t h reserpine (n = 2) or a ^-blocker (n = 1); the last patient received a /?-blocker only. In the placebo group, of the five patients w h o continued to receive a n antihypertensive treatment, four received a diuretic alone (n = 1), or in combination with reserpine (n = 2) or a calcium antagonist (n = 1); the last patient received a n ACE inhibitor. All b u t o n e of the patients completed the trial as p l a n n e d ; t h e excep tion w a s a 39-year-old w o m a n w h o , while u n d e r g o i n g an a b d o m i n a l hysterectomy, s h o w e d a s u d d e n d r o p in M A P from 115 to 51 m m H g b e t w e e n 10 a n d 12 m i n after the infusion of placebo. This w a s found to be d u e to compression of the caval vein; the patient w a s there fore excluded from the rest of the trial.
Blood pressure a n d heart rate w e r e m e a s u r e d with a n automatic device based on oscillometry (Nippon Colin, Japan; O h m e d a NIBP, US; or Marquette Electronics, US) w h i c h provided systolic, diastolic, a n d m e a n arterial blood pressure values. The latter w a s calculated using
Efficacy Immediately prior to the administration of the s u p p l e m e n t a r y dose of fentanyl, m e a n M A P w a s 125 ± 10 m m H g and, 5 m i n later, 124 ± 11 m m H g . The m e a n time from the start of anesthesia to the start of
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I S R A D I P I N E A N D PERIOPERATIVE H Y P E R T E N S I O N
205S
TABLE 1. CHANGES (MEANS ± SD) WITH INTRAVENOUS ISRADIPINE AND PLACEBO IN PATIENTS WITH ARTERIAL HYPERTENSION (MAP > 110 MM HG) DURING NONCARDIAC SURGERY Mean Arterial Pressure (MAP; mm Hg)
Trial
Time
Period
(min)
Blinded
ot 2 4 6 8 10 12
122 113 96 90 89 93 97
±9 ±22 ± 19 ±20 ±20 ± 15 ± 12
15 20 30 45
93 99 101 99
± ± ± ±
Open§
Placebo
Isradipine
*** *** *** *** ***
126 ± 12 123 ± 10 126 ± 10 124 ± 10 125 ± 1 1 122 ± 14 124 ± 16#
12 13 12 15
Heart Rate (beats/min) Isradipine
83 84 93 95 93 92 96
±20 ± 18 ± 19ft ±21 ±20 ± 19 ±20
95 91 95 83
±23 ± 18 ±21 ± 15
Respondert Rate (n, %)
Placebo
73 ± 1 4 74 ± 14 * 75 ± 14 ** 73 ± 13 73 ± 13 * 73 ± 14 ** 73 ± 13ft
Isradipine
0 3 7 8 9 9 8
(30%) (70%) (80%) (90%) (90%) (80%)
7 5 4 5
(88%) (63%) (50%) (63%)
Placebo
** *** *** ** *
0 0 0 0 0 2 (18%) 2 (20%)tt
t Patients whose MAP was reduced by ^ 10% from baseline to 140 m m Hg), heart failure, a n d / o r acute coronary is chemia were excluded, a n d the duration of the placebo period w a s restricted to 15 min. Thus, the data were obtained in low-risk patients, most of w h o m were 13
206S
R Ü E G G ET AL
AJH-FEBRUARY
k n o w n hypertensives u n d e r chronic antihypertensive treatment. In order to exclude pain as a contributing factor to the raised blood pressure, patients were eligible for participation only if their blood pressure remained elevated after administration of a s u p p l e m e n t a r y dose of fentanyl. The data indicate that a n intravenous infu sion of isradipine produces a n immediate a n d adequate reduction in blood pressure in most patients that w a s sustained during the 45-min observation period; h o w ever, as the s p o n t a n e o u s time course of the blood pres sure in these patients is not k n o w n , conclusions regard ing the duration of action cannot be m a d e . Treatment w a s associated with a minor, b u t significant, increase in heart rate, suggesting that the intrinsic negative chrono tropic action of i s r a d i p i n e ' w a s overridden by a reflex sympathetic activation elicited by the blood pressure reduction. As inhalation anesthetics a n d calcium antagonists h a v e similar pharmacologic effects, cardiovascular in teractions with isradipine and, for example, h a l o t h a n e are likely to occur. However, isradipine, in contrast to other calcium antagonists, h a s b e e n s h o w n to be devoid of significant cardiodepressant effects in a n i m a l s a n d in p a t i e n t s ; thus, a combined treatment with isradipine a n d a n anesthetic is unlikely to produce unfavorable effects on myocardial function. O n the other h a n d , the additive blood pressure-lowering effect of the d i h y d r o pyridines a n d higher concentrations of volatile anesthet ics m a y lead to arterial h y p o t e n s i o n . Interaction stud ies of isradipine with anesthetics are n e e d e d before their w i d e s p r e a d use in this indication can be r e c o m m e n d e d . It is concluded that isradipine effectively a n d safely reduces blood pressure in hypertensive patients during noncardiac surgery; however, further investigations are n e e d e d to define the potential therapeutic role of isradi pine in this setting. 11
3. 4. 5.
6.
7.
14
8. 9.
15
10.
12
14
15
11.
12.
13.
14.
REFERENCES 1.
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