- Email: [email protected]
Nicardipine versus placebo for the treatment of postoperative hypertension
February 1990 American Heart Journal
Kaplan 12. Turlapaty P, Vary R, Kaplan JA. Nicardipine a new intravenous calcium antagonist: review of its pharmacology,pharmacokinetics, and perioperative applications. J Cardiothorac Anesth 1989;3:344-55. !3. Lambert CR, Hill JA, Nichols WW, et al. Coronary and systemic hemodynamic effects of nicardipine. Am J Cardiol 1985;55:652-6. 14. Bruno A, Adams HP. Subarachnoid hemorrhage: expanding treatment options. Hosp Ther 1987;58-66. 15. Kaplan JA. The role of nicardipine during anesthesia and surgery. Clin Ther 1989;11:84-93. 16. Begon C, Dartayet B, Edouard A, et al. Intravenous nicardipine for treatment of intraoperative hypertension during abdominal surgery. J Cardiothorac Anesth 1989;3:706-10. 17. Kishi Y, Okumura F, Furuya H. Haemodynamic effects of nicardipine hydrochloride. Br J Anaesth 1984;56:1003-7. 18. Van Wezel HB, Koolen JJ, Visser CA, et al. The efficacy of nicardipine and nitroprusside in preventing post-sternotomy
hypertension. J Cardiothorac Anesth 1989;3:700-6. 19. Chelly JE, Pool JL, Casar G, et al. Treatment of postoperative hypertension with intravenous nicardipine. Clin Pharmacol Ther 1987;41:209. 20. Casar G, Pool JL, Chelly JE, et al. Intravenous nicardipine for treatment of postoperative hypertension. Anesthesiology 1987;67:A141. 21. Banammar MS, Coriat P, Houissa M, et al. Nicardipine vs. trinitrine for treatment of postoperative hypertension. Second Cardiovascular Pharmacotherapy International Symposium, San Francisco, Calif., 1987. 22. Dubois C, Davis D. Nicardipine vs. nitroprusside in the treatment of hypertension followingCABG. Second Cardiovascular Pharmacotherapy International Symposium, San Francisco, Calif., 1987.
Nicardipine versus placebo for the treatment of postoperative hypertension Postoperative hypertension can cause serious complications, including bleeding from fresh anastomoses, cardiovascular accident, and myocardial ischemia. Therefore rapid Control of blood pressure is essential to prevent poor outcome. In this study, 30 American Society of Anesthesiologists class I and II patients who did not have cardiac surgery and subsequently developed postoperative hypertension were randomly assigned to receive either nicardipine, a new dihydropyridine calcium channel blocker, or placebo. Intravenous nicardipine was given as a loading bolus of 10 mg/hr for 5 minutes and was Utrated to 15 mg/hr if needed to achieve a therapeutic response. After therapeutic response, intravenous nicardipine was decreased to 3 mg/hr and subsequently titrated in increments of 1.0 to 2.5 mg/hr to maintain blood pressure control. Systolic and diastolic blood pressures during titration and maintenance did not differ significantly from preoperative levels in patients treated with nicardipine. The mean time to therapeutic response for the nicardipine-treated group was 8.67 __ 1.46 minutes, and the median time to offset of action was 15 minutes. Eleven of the 12 patients who received placebo were crossed over to antihypertensive therapy, and of these, 10 received intravenous nicardipine. In this group all achieved therapeutic response in 7.3 _+ 1.18 minutes. The usefulness of intravenous nicardipine for postoperative hypertension was demonstrated in this study by: (1) the rapid control of blood pressure, (2) its continued efficacy during maintenance, and (3) little need to adjust dosage to control blood pressure. (AM HEART J 1990;119:446-50.)
Michael E. Goldberg, MD, S c o t t Clark, MD, Jeffrey J o s e p h , DO, H o w a r d Moritz, MD, David Maguire, MD, J o s e p h L. Seltzer, MD, a n d P r a s a d T u r l a p a t y , P h D
Philadelphia, Pa., and Trenton, N.J.
P o s t o p e r a t i v e h y p e r t e n s i o n occurs with a variable incidence a n d has been r e p o r t e d to occur in 3.251 to 6 % 2 of all patients a d m i t t e d to the recovery room a n d
From the Department of Anesthesiology,JeffersonMedicalCollege,Thomas JeffersonUniversity,and Du Pont Critical Care. Reprint requests: MichaelE. Goldberg,MD, Helene Fuld MedicalCenter, 750 BrunswickAve.,Trenton, NJ 08638. 4/0/17109
446
in 20 % of patients after radical neck dissection. 3 After m y o c a r d i a l revascularization, postoperative hypertension has been r e p o r t e d to be as high as 34 % .4 H y p e r t e n s i o n often occurs within the first 10 to 20 m i n u t e s after surgery a n d resolves in most cases b y 3 hours. 1 Patients who have u n t r e a t e d h y p e r t e n s i o n for 3 hours or longer are more likely to experience complications, which include bleeding from fresh anastomoses, cardiovascular accident, and myocar-
Volume 119
Number 2,
Part 2
Nicardipine vs placebo for postoperative hypertension
447
Table I. Demographic and prestudy clinical characteristics Placebo (n = 12)
Variable
Gender Male Female Race White Black Hispanic Age (yr) Height (cm) Temperature (o C) Respiratory rate (breaths/min) Preoperative SBP (ram Hg) Preoperative DBP (ram Hg) Values are mean _+ SD (range). SBP, Systolic blood pressure; DBP, diastolic
9 3
Intravenous nicardipine (n = 18)
10 8
12 0 0 58.4 + 16.6 (30-76) 170 + 5.6 (160-182.5) 35.7 +-+_1.1 (34.2-37.2) 15.9 + 3.1 (10-20) 135.3 +_ 13.0 (115-150) 81.7 + 10.9 (70-100)
15 3 0 67.7 _+ 8.7 (53-82) 164.9 _+ 7.4 (142.5-177.5) 35.9 _+ 1.0 (33.6-37.4) 16.2 _+ 4.4 (10-28) 139.1 _+ 20.7 (112-185) 79.0 _+ 10.0 (60-100)
blood pressure.
dial ischemia. 2, 5 T h e r e f o r e r a p i d r e d u c t i o n in t h e b l o o d p r e s s u r e is essential t o p r e v e n t p o o r o u t c o m e . Vasodilators and calcium channel blockers have been used to control postoperative hypertension. N i c a r d i p i n e is a n e w d i h y d r o p y r i d i n e c a l c i u m c h a n n e l a n t a g o n i s t t h a t is available in oral a n d i n t r a v e n o u s f o r m u l a t i o n s . N i c a r d i p i n e is r a p i d l y dist r i b u t e d in t h e b o d y 6 a n d h a s a m e a n e l i m i n a t i o n half-life o f 44 to 73 m i n u t e s . 7' 8 T h i s p h a r m a c o k i n e t i c profile allows a d m i n i s t r a t i o n as a n i n f u s i o n w i t h tit r a t i o n t o effect. I n a r a n d o m i z e d , p l a c e b o - c o n t r o l l e d s t u d y , we e x a m i n e d t h e s a f e t y a n d efficacy o f i n t r a v e n o u s n i c a r d i p i n e v e r s u s p l a c e b o in t h e t r e a t m e n t o f postoperative hypertension. METHODS Thirty American Society of Anesthesiologists class I and II patients entered this institutional review board-approved protocol a f t e r informed consent was obtained before honcardiac surgery. Patients were excluded f r o m the protocol if they had a suPine heart rate -->120 beats/ min, clinically significant hepatic disease, myocardial infarction or stroke within 7 days of the study, supraventricular tachycardia, if they had a calcium channel antagonist within 2 hours of the procedure, or if they required adrenergic agents. Postoperative hypertension was defined as a supine systolic blood pressure >--140 m m Hg or diastolic blood.pressure >-95 m m H g a n d blood pressure -->20% over their average preoperative blood pressure. Preoperative blood pressure was determined by averaging three consecutive blood pressure measurements taken 1 minute apart while the patient lay quietly. Preoperative blood pressure measurements were not taken within 6 hours of any invasive procedure. Postoperative blood pressure and heart rate measurements were taken at least 2 minutes apart, and 3 consecutive measurements meeting entry criteria were required. The three measurements could not vary more than 15%, and their average was defined as the baseline blood pres-
sure. Blood pressure measurements were obtained by oscillometry and heart rate measurements were recorded by a Hewlett-Packard ECG monitor. Study drug administration. Once baseline blood pressure criteria were met, nicardipine or placebo was randomly assigned in a 3:2 ratio. Nicardipine was administered by way of an intravenous infusion pump as a loading dose of 10 mg/hr for 5 minutes. An equal volume of placebo was given to those assigned placebo treatment. If no therapeutic response occurred (defined as a >__15% reduction of the blood pressure from the baseline systolic or diastolic blood pressure), the infusion rate was increased to 12.5 mg/hr of nicardipine, or 125 ml/hr, for 5 minutes, and if no therapeutic response occurred, the infusion rate was again increased to 15 mg/hr of nicardipine, or 150 ml/hr, for as long as 15 minutes. Once therapeutic response was achieved, the infusion was decreased to 30 ml/hr (3 mg/hr nicardipine). This maintenance rate was increased or decreased by 10 to 25 ml/hr (1 to 2.5 mg nicardipine) every 15 minutes to maintain control of blood pressure. Measurement of hemoflynamic parameters. Blood pressure and heart rate were measured and recorded every 3 minutes during the initial titration period and at the end of each titration step. Once maintenance infusion was initiated, blood pressure and heart rate were measured at 5minute intervals for 30 minutes; at 45, 60, and 90 minutes; at 2, 3, and 4 hours and every 4 hours until the infusion was stopped. After discontinuation of the drug, blood pressure was monitored until it rose 10 m m Hg above the last blood pressure that was obtained before the infusion was stopped. The offset of action was defined as the 10 mm Hg rise in blood pressure after treatment was stopped. If a therapeutic response did not occur (defined as <15 % reduction in blood pressure f r o m baseline at an infusion of 150 ml/hr for 15 minutes), the blinding code was opened. At no time did patients receiving nicardipine require an alternative antihypertensive treatment. In patients initially receiving placeo, open-Iabel intravenous nicardipine (n = 10) or an alterative antihypertensive agent (n -- 1) was given to control blood pressure.
448
Goldberget
February 1990 American Heart Journal
al.
SBP (mmHg) 195
I--'-I
185
--
175
--
165
--
155
--
145
--
Placebo Nicardipine
135
125 115 Fig.
1.
Prestudy
Baseline
Titration
Systolic blood pressure during each period (mean _+ standard error).
Venous blood samples were obtained to measure nicardipine plasma concentration before treatment (baseline), once therapeutic response occurred, before the drug was discontinued, and at the offset of action. Statistical analyses were performed with SAS version 5.16. All data are expressed as mean _+ SEM. A p value _< 0.05 was considered statistically significant. RESULTS
Thirty patients qualified for the study--12 received placebo and 18 received nicardipine. There were no significant differences between the nicardipine and placebo group in the demographic and prestudy clinical characteristics (Table I). In particular, there were no differences in preoperative systolic and diastolic blood pressures between groups (Table I). The percent increases in preoperative to postoperative (baseline) systolic and diastolic blood pressures in the nicardipine group were 31.9% _+ 3.32% and 22.38% _+ 2.76%, respectively; in the placebo group, the percent increases in systolic and diastolic blood pressures were 29.11% + 4.01% and 16.39% _+ 3.94%, respectively. The mean times to initiation of treatment in patients randomized to placebo and intravenous nicardipine were 0.66 + 0.07 and 0.75 _+ 0.15 hour after surgery, respectively. Postoperative hypertension was controlled with intravenous nicardipine in all patients initially randomized to nicardipine compared with 1 of the 12 patients who received placebo (p < 0.05). Figs. 1 and 2 demonstrate systolic and diastolic blood pressures during prestudy, baseline, and titration periods. There were significant elevations in blood pressure before surgery (baseline) when compared with preoperative levels, which were subsequently reduced by nicardipine. In patients treated with nicardipine, the
systolic and diastolic blood pressures during titration and maintenance did not differ significantly from preoperative levels. No significant differences occurred in heart rate between patients treated with placebo or nicardipine at any time. Furthermore, heart rate did not change significantly from baseline values during either nicardipine or placebo treatment. For example, the change in heart rate from the baseline to the end of titration between nicardipine- and placebo-treated patients was +4.17% _+ 1.87% a n d - 0 . 9 9 % _+ 2.6%, respectively. Therapeutic response: Dosage of nicardipine and time
Therapeutic response occurred in nine patients at a nicardipine dose of 10 mg/hr, in six patients at 12.5 mg/hr, and in three patients at 15 mg/ hr. The mean time to therapeutic response for patients randomized to intravenous nicardipine was 8.67 + 1.46 minutes, and the time to therapeutic response ranged from 2.98 to 28.0 minutes. Of the 11 placebo nonresponders, 10 patients were treated with open-label intravenous nicardipine. All 10 patients achieved therapeutic response in a mean time of 7.3 _+ 1.18 minutes. to r e s p o n s e .
Therapeutic response: Nicardipine maintenance dosage and offset of action. The mean maintenance d o s e
of nicardipine was 2.48 _+ 0.38 mg/hr and ranged between 0.2 to 9.0 mg/hr. Furthermore, the mean duration of nicardipine infusion in the maintenance period was 4,75 + 0.8 hours and ranged between 0.2 and 8.42 hours. Clinical offset of action was evaluated in all patients initially randomized to nicardipine and in 10 of 12 patients subsequently treated with intravenous nicardipine. There was a clinical offset of action in 23 patients (82%) after intravenous nicardipine was discontinued. The offset of action ranged from 5 to
Volume 119 U,,nber 2, Parl ~
Nicardipine vs placebo for postoperative hypertension OBP (mmHg)
449
Placebo
105
Nicardipine
100
-r
*P
vs Baseline
95 9O
85 80 75 70 65
'Prestudy
Fig. 2.
Baseline
Tilration
Diastolic blood pressure during each period (mean + standard error).
120 minutes, but the median time to offset of action was 15 minutes. The mean response dose of placebo nonresponders who were later given intravenous nicardipine was 7.3 -+ 1.18 minutes and 12.75 _+ 0.65 rag/hr. DISCUSSION
Many antihypertensive agents have been used to treat postoperative hypertension. All these agents have side effects associated with their use that may lead to complications. Many consider sodium nitroprusside the treatment of choice for postoperative hypertension because of its vasodilatory effect that results in a rapid decrease in blood pressure. Nitroprusside, however, has several potential disadvantages. Of critical importance is the baroreceptor-mediated reflex increase in heart rate that nitroprusside causes, which increases myocardial oxygen demand. 9 Furthermore, nitroprusside therapy has been associated with the phenomenon of intracoronary steal. 1~ Nitroglycerin has also been used to treat intraoperative hypertension in patients with coronary artery disease because of its beneficial effects on subendocardial flow. 11 The venous pooling and decreased venous return caused by nitroglycerin can also precipitate a reflex increase in the heart rate. Nitroglycerin is often not as effective as nitroprusside at reducing short-term elevations in blood pressure. Hydralazine has been used to treat postoperative hypertension, but because its primary action is arterial dilation, it often causes reflex tachycardia that may in fact increase myocardial oxygen demand. 12 Another disadvantage of intravenous hydralazine is its slow onset of action, which may result in overdosage of the drug in attempts to titrate it to effect. More recent attention has been focused on the calcium channel blocking agents to treat postoperative
hypertension, particularly nifedipine. Nifedipine's effect is more specific in blocking calcium influx in vascular smooth muscle than either verapamil or diltiazem.7,13 However, nifedipine is difficult to administer because of its poor solubility and therefore must be given by either the oral or sublingual route. 14 These routes of administration preclude easy titration to effect. Nicardipine is a dihydropyridine derivative similar to nifedipine, 15 but unlike nifedipine it is water soluble and can be administered parenterally. Unlike the vasodilators nitroprusside, nitroglycerin, and hydralazine, nicardipine has not been associated with large increases in heart rate after its administration. In addition, nicardipine has a relatively rapid onset and offset of action, which allows dose titration. In this study, intravenous nicardipine rapidly controlled blood pressure in all patients who received it, whereas the placebo controlled hypertension in only 1 of 12 patients. Therapeutic response to intravenous nicardipine was rapid and occurred a mean of 10 to 12 minutes after administration. The usefulness of nicardipine for the treatment of postoperative hypertension was demonstrated in this study by: (1) the rapid control of blood pressure, (2) the continued efficacy of nicardipine during maintenance therapy, and (3) little need to adjust dosage to control blood pressure. These features and the fact nicardipine reduces systemic vascular resistance while decreasing coronary artery resistance, 16suggest that nicardipine might be extremely useful for patients who have coronary artery disease associated with acute postoperative hypertension. REFERENCES
1. Gal TJ, Cooperman LH. Hypertension in the immediate postoperative period. Br J Anaesth 1975;47:70-4.
450
--
"---(iotctberg
e t al.
2. Seltzer JL, Gerson JI, Grogono AW. Hypertension in the perioperative period. NY State J Med 1980;80:29-31. 3. McGuirt WF, May JS. Postoperative hypertension associated with radical neck dissection. Arch Otolaryngol Head Neck Surg 1987;113:1098-100. 4. Estafanous FG, Tarazi RC, Viljoen JF, E1Tawil MY. Systemic hypertension following myocardial revascularization. AM HEARTJ 1973;85:732-9. 5. Gray RJ, Bateman TM, Czer LSC, Conklin C, Matloff JM. Use of esmolol in hypertension after cardiac surgery. Am J Cardiol 1985;56:49F-56F. 6. Dow RJ, Graham DJM. A review of the human metabolism and pharmacokinetics of nicardipine hydrochloride. Br J Clin Pharmacol 1986;22:195S-202S. 7. Campbell B, Kelman A, Sumner D, et al. Non-invasive measurement of the acute haemodynamic effects of a new calcium channel blocker, nicardipine. Br J Clin Pharmacol 1984; 17:188P-9P. 8. Jamieson MJ, Jeffers TA, Dow R, Graham D. Nicardipine infusion: pharmacokinetics, haemodynamics and effects on the systolic time intervals. Br J Clin Pharmacol 1985;19:536P. 9. Knight PI~ Lane GA, Hensinger RN, Bolles RS, Bjoraker DG. Catecholamine and renin-angiotensin response during hypotensive anesthesia induced by sodium nitroprusside or trimethaphan camsylate. Anesthesiology 1983;59:248-53.
February 1990 American Heart Journal
10. Mann T, Cohn PF, Holman BL, Green LH, Markis JE, Phillips DA. Effect of nitroprusside on regional myocardial blood flow in coronary artery disease: results in 25 patients and comparison with nitroglycerin. Circulation 1978;57:732-8. 11. Kaplan JA, Dunbar RW, Jones ]~L. Nitroglycerin infusion during coronary-artery surgery. Anesthesiology 1976;45:14-21. 12. Garcia JY, Vidt DG. Current management of hypertensive emergencies. Drugs 1978;34:263-73. 13. Bertel O, Conen LD: Treatment of hypertensive emergencies with the calcium channel blocker nifedipine. Am J Med 1985; 79(suppl 4A):31-5. 14. Turlapaty P, Vary R, Kaplan JA. Nicardipine, a new intravenous calcium antagonist: a review of its pharmacology, pharmacokinetics, and perioperative applications. J Cardiothoracic Anesth 1989;3:344-55. 15. Sorkin EM, Clissold SP. Nicardipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of angina pectoris, hypertension and related cardiovascular disorders. Drugs 1987;33:296-345. 16. Lambert CR, Hill JA, Nichols WW, Feldman RL, Pepine CJ. Coronary and systemic hemodynamic effects of nicardipine. Am J Cardiol 1985;55:652-6.
Kaplan 12. Turlapaty P, Vary R, Kaplan JA. Nicardipine a new intravenous calcium antagonist: review of its pharmacology,pharmacokinetics, and perioperative applications. J Cardiothorac Anesth 1989;3:344-55. !3. Lambert CR, Hill JA, Nichols WW, et al. Coronary and systemic hemodynamic effects of nicardipine. Am J Cardiol 1985;55:652-6. 14. Bruno A, Adams HP. Subarachnoid hemorrhage: expanding treatment options. Hosp Ther 1987;58-66. 15. Kaplan JA. The role of nicardipine during anesthesia and surgery. Clin Ther 1989;11:84-93. 16. Begon C, Dartayet B, Edouard A, et al. Intravenous nicardipine for treatment of intraoperative hypertension during abdominal surgery. J Cardiothorac Anesth 1989;3:706-10. 17. Kishi Y, Okumura F, Furuya H. Haemodynamic effects of nicardipine hydrochloride. Br J Anaesth 1984;56:1003-7. 18. Van Wezel HB, Koolen JJ, Visser CA, et al. The efficacy of nicardipine and nitroprusside in preventing post-sternotomy
hypertension. J Cardiothorac Anesth 1989;3:700-6. 19. Chelly JE, Pool JL, Casar G, et al. Treatment of postoperative hypertension with intravenous nicardipine. Clin Pharmacol Ther 1987;41:209. 20. Casar G, Pool JL, Chelly JE, et al. Intravenous nicardipine for treatment of postoperative hypertension. Anesthesiology 1987;67:A141. 21. Banammar MS, Coriat P, Houissa M, et al. Nicardipine vs. trinitrine for treatment of postoperative hypertension. Second Cardiovascular Pharmacotherapy International Symposium, San Francisco, Calif., 1987. 22. Dubois C, Davis D. Nicardipine vs. nitroprusside in the treatment of hypertension followingCABG. Second Cardiovascular Pharmacotherapy International Symposium, San Francisco, Calif., 1987.
Nicardipine versus placebo for the treatment of postoperative hypertension Postoperative hypertension can cause serious complications, including bleeding from fresh anastomoses, cardiovascular accident, and myocardial ischemia. Therefore rapid Control of blood pressure is essential to prevent poor outcome. In this study, 30 American Society of Anesthesiologists class I and II patients who did not have cardiac surgery and subsequently developed postoperative hypertension were randomly assigned to receive either nicardipine, a new dihydropyridine calcium channel blocker, or placebo. Intravenous nicardipine was given as a loading bolus of 10 mg/hr for 5 minutes and was Utrated to 15 mg/hr if needed to achieve a therapeutic response. After therapeutic response, intravenous nicardipine was decreased to 3 mg/hr and subsequently titrated in increments of 1.0 to 2.5 mg/hr to maintain blood pressure control. Systolic and diastolic blood pressures during titration and maintenance did not differ significantly from preoperative levels in patients treated with nicardipine. The mean time to therapeutic response for the nicardipine-treated group was 8.67 __ 1.46 minutes, and the median time to offset of action was 15 minutes. Eleven of the 12 patients who received placebo were crossed over to antihypertensive therapy, and of these, 10 received intravenous nicardipine. In this group all achieved therapeutic response in 7.3 _+ 1.18 minutes. The usefulness of intravenous nicardipine for postoperative hypertension was demonstrated in this study by: (1) the rapid control of blood pressure, (2) its continued efficacy during maintenance, and (3) little need to adjust dosage to control blood pressure. (AM HEART J 1990;119:446-50.)
Michael E. Goldberg, MD, S c o t t Clark, MD, Jeffrey J o s e p h , DO, H o w a r d Moritz, MD, David Maguire, MD, J o s e p h L. Seltzer, MD, a n d P r a s a d T u r l a p a t y , P h D
Philadelphia, Pa., and Trenton, N.J.
P o s t o p e r a t i v e h y p e r t e n s i o n occurs with a variable incidence a n d has been r e p o r t e d to occur in 3.251 to 6 % 2 of all patients a d m i t t e d to the recovery room a n d
From the Department of Anesthesiology,JeffersonMedicalCollege,Thomas JeffersonUniversity,and Du Pont Critical Care. Reprint requests: MichaelE. Goldberg,MD, Helene Fuld MedicalCenter, 750 BrunswickAve.,Trenton, NJ 08638. 4/0/17109
446
in 20 % of patients after radical neck dissection. 3 After m y o c a r d i a l revascularization, postoperative hypertension has been r e p o r t e d to be as high as 34 % .4 H y p e r t e n s i o n often occurs within the first 10 to 20 m i n u t e s after surgery a n d resolves in most cases b y 3 hours. 1 Patients who have u n t r e a t e d h y p e r t e n s i o n for 3 hours or longer are more likely to experience complications, which include bleeding from fresh anastomoses, cardiovascular accident, and myocar-
Volume 119
Number 2,
Part 2
Nicardipine vs placebo for postoperative hypertension
447
Table I. Demographic and prestudy clinical characteristics Placebo (n = 12)
Variable
Gender Male Female Race White Black Hispanic Age (yr) Height (cm) Temperature (o C) Respiratory rate (breaths/min) Preoperative SBP (ram Hg) Preoperative DBP (ram Hg) Values are mean _+ SD (range). SBP, Systolic blood pressure; DBP, diastolic
9 3
Intravenous nicardipine (n = 18)
10 8
12 0 0 58.4 + 16.6 (30-76) 170 + 5.6 (160-182.5) 35.7 +-+_1.1 (34.2-37.2) 15.9 + 3.1 (10-20) 135.3 +_ 13.0 (115-150) 81.7 + 10.9 (70-100)
15 3 0 67.7 _+ 8.7 (53-82) 164.9 _+ 7.4 (142.5-177.5) 35.9 _+ 1.0 (33.6-37.4) 16.2 _+ 4.4 (10-28) 139.1 _+ 20.7 (112-185) 79.0 _+ 10.0 (60-100)
blood pressure.
dial ischemia. 2, 5 T h e r e f o r e r a p i d r e d u c t i o n in t h e b l o o d p r e s s u r e is essential t o p r e v e n t p o o r o u t c o m e . Vasodilators and calcium channel blockers have been used to control postoperative hypertension. N i c a r d i p i n e is a n e w d i h y d r o p y r i d i n e c a l c i u m c h a n n e l a n t a g o n i s t t h a t is available in oral a n d i n t r a v e n o u s f o r m u l a t i o n s . N i c a r d i p i n e is r a p i d l y dist r i b u t e d in t h e b o d y 6 a n d h a s a m e a n e l i m i n a t i o n half-life o f 44 to 73 m i n u t e s . 7' 8 T h i s p h a r m a c o k i n e t i c profile allows a d m i n i s t r a t i o n as a n i n f u s i o n w i t h tit r a t i o n t o effect. I n a r a n d o m i z e d , p l a c e b o - c o n t r o l l e d s t u d y , we e x a m i n e d t h e s a f e t y a n d efficacy o f i n t r a v e n o u s n i c a r d i p i n e v e r s u s p l a c e b o in t h e t r e a t m e n t o f postoperative hypertension. METHODS Thirty American Society of Anesthesiologists class I and II patients entered this institutional review board-approved protocol a f t e r informed consent was obtained before honcardiac surgery. Patients were excluded f r o m the protocol if they had a suPine heart rate -->120 beats/ min, clinically significant hepatic disease, myocardial infarction or stroke within 7 days of the study, supraventricular tachycardia, if they had a calcium channel antagonist within 2 hours of the procedure, or if they required adrenergic agents. Postoperative hypertension was defined as a supine systolic blood pressure >--140 m m Hg or diastolic blood.pressure >-95 m m H g a n d blood pressure -->20% over their average preoperative blood pressure. Preoperative blood pressure was determined by averaging three consecutive blood pressure measurements taken 1 minute apart while the patient lay quietly. Preoperative blood pressure measurements were not taken within 6 hours of any invasive procedure. Postoperative blood pressure and heart rate measurements were taken at least 2 minutes apart, and 3 consecutive measurements meeting entry criteria were required. The three measurements could not vary more than 15%, and their average was defined as the baseline blood pres-
sure. Blood pressure measurements were obtained by oscillometry and heart rate measurements were recorded by a Hewlett-Packard ECG monitor. Study drug administration. Once baseline blood pressure criteria were met, nicardipine or placebo was randomly assigned in a 3:2 ratio. Nicardipine was administered by way of an intravenous infusion pump as a loading dose of 10 mg/hr for 5 minutes. An equal volume of placebo was given to those assigned placebo treatment. If no therapeutic response occurred (defined as a >__15% reduction of the blood pressure from the baseline systolic or diastolic blood pressure), the infusion rate was increased to 12.5 mg/hr of nicardipine, or 125 ml/hr, for 5 minutes, and if no therapeutic response occurred, the infusion rate was again increased to 15 mg/hr of nicardipine, or 150 ml/hr, for as long as 15 minutes. Once therapeutic response was achieved, the infusion was decreased to 30 ml/hr (3 mg/hr nicardipine). This maintenance rate was increased or decreased by 10 to 25 ml/hr (1 to 2.5 mg nicardipine) every 15 minutes to maintain control of blood pressure. Measurement of hemoflynamic parameters. Blood pressure and heart rate were measured and recorded every 3 minutes during the initial titration period and at the end of each titration step. Once maintenance infusion was initiated, blood pressure and heart rate were measured at 5minute intervals for 30 minutes; at 45, 60, and 90 minutes; at 2, 3, and 4 hours and every 4 hours until the infusion was stopped. After discontinuation of the drug, blood pressure was monitored until it rose 10 m m Hg above the last blood pressure that was obtained before the infusion was stopped. The offset of action was defined as the 10 mm Hg rise in blood pressure after treatment was stopped. If a therapeutic response did not occur (defined as <15 % reduction in blood pressure f r o m baseline at an infusion of 150 ml/hr for 15 minutes), the blinding code was opened. At no time did patients receiving nicardipine require an alternative antihypertensive treatment. In patients initially receiving placeo, open-Iabel intravenous nicardipine (n = 10) or an alterative antihypertensive agent (n -- 1) was given to control blood pressure.
448
Goldberget
February 1990 American Heart Journal
al.
SBP (mmHg) 195
I--'-I
185
--
175
--
165
--
155
--
145
--
Placebo Nicardipine
135
125 115 Fig.
1.
Prestudy
Baseline
Titration
Systolic blood pressure during each period (mean _+ standard error).
Venous blood samples were obtained to measure nicardipine plasma concentration before treatment (baseline), once therapeutic response occurred, before the drug was discontinued, and at the offset of action. Statistical analyses were performed with SAS version 5.16. All data are expressed as mean _+ SEM. A p value _< 0.05 was considered statistically significant. RESULTS
Thirty patients qualified for the study--12 received placebo and 18 received nicardipine. There were no significant differences between the nicardipine and placebo group in the demographic and prestudy clinical characteristics (Table I). In particular, there were no differences in preoperative systolic and diastolic blood pressures between groups (Table I). The percent increases in preoperative to postoperative (baseline) systolic and diastolic blood pressures in the nicardipine group were 31.9% _+ 3.32% and 22.38% _+ 2.76%, respectively; in the placebo group, the percent increases in systolic and diastolic blood pressures were 29.11% + 4.01% and 16.39% _+ 3.94%, respectively. The mean times to initiation of treatment in patients randomized to placebo and intravenous nicardipine were 0.66 + 0.07 and 0.75 _+ 0.15 hour after surgery, respectively. Postoperative hypertension was controlled with intravenous nicardipine in all patients initially randomized to nicardipine compared with 1 of the 12 patients who received placebo (p < 0.05). Figs. 1 and 2 demonstrate systolic and diastolic blood pressures during prestudy, baseline, and titration periods. There were significant elevations in blood pressure before surgery (baseline) when compared with preoperative levels, which were subsequently reduced by nicardipine. In patients treated with nicardipine, the
systolic and diastolic blood pressures during titration and maintenance did not differ significantly from preoperative levels. No significant differences occurred in heart rate between patients treated with placebo or nicardipine at any time. Furthermore, heart rate did not change significantly from baseline values during either nicardipine or placebo treatment. For example, the change in heart rate from the baseline to the end of titration between nicardipine- and placebo-treated patients was +4.17% _+ 1.87% a n d - 0 . 9 9 % _+ 2.6%, respectively. Therapeutic response: Dosage of nicardipine and time
Therapeutic response occurred in nine patients at a nicardipine dose of 10 mg/hr, in six patients at 12.5 mg/hr, and in three patients at 15 mg/ hr. The mean time to therapeutic response for patients randomized to intravenous nicardipine was 8.67 + 1.46 minutes, and the time to therapeutic response ranged from 2.98 to 28.0 minutes. Of the 11 placebo nonresponders, 10 patients were treated with open-label intravenous nicardipine. All 10 patients achieved therapeutic response in a mean time of 7.3 _+ 1.18 minutes. to r e s p o n s e .
Therapeutic response: Nicardipine maintenance dosage and offset of action. The mean maintenance d o s e
of nicardipine was 2.48 _+ 0.38 mg/hr and ranged between 0.2 to 9.0 mg/hr. Furthermore, the mean duration of nicardipine infusion in the maintenance period was 4,75 + 0.8 hours and ranged between 0.2 and 8.42 hours. Clinical offset of action was evaluated in all patients initially randomized to nicardipine and in 10 of 12 patients subsequently treated with intravenous nicardipine. There was a clinical offset of action in 23 patients (82%) after intravenous nicardipine was discontinued. The offset of action ranged from 5 to
Volume 119 U,,nber 2, Parl ~
Nicardipine vs placebo for postoperative hypertension OBP (mmHg)
449
Placebo
105
Nicardipine
100
-r
*P
vs Baseline
95 9O
85 80 75 70 65
'Prestudy
Fig. 2.
Baseline
Tilration
Diastolic blood pressure during each period (mean + standard error).
120 minutes, but the median time to offset of action was 15 minutes. The mean response dose of placebo nonresponders who were later given intravenous nicardipine was 7.3 -+ 1.18 minutes and 12.75 _+ 0.65 rag/hr. DISCUSSION
Many antihypertensive agents have been used to treat postoperative hypertension. All these agents have side effects associated with their use that may lead to complications. Many consider sodium nitroprusside the treatment of choice for postoperative hypertension because of its vasodilatory effect that results in a rapid decrease in blood pressure. Nitroprusside, however, has several potential disadvantages. Of critical importance is the baroreceptor-mediated reflex increase in heart rate that nitroprusside causes, which increases myocardial oxygen demand. 9 Furthermore, nitroprusside therapy has been associated with the phenomenon of intracoronary steal. 1~ Nitroglycerin has also been used to treat intraoperative hypertension in patients with coronary artery disease because of its beneficial effects on subendocardial flow. 11 The venous pooling and decreased venous return caused by nitroglycerin can also precipitate a reflex increase in the heart rate. Nitroglycerin is often not as effective as nitroprusside at reducing short-term elevations in blood pressure. Hydralazine has been used to treat postoperative hypertension, but because its primary action is arterial dilation, it often causes reflex tachycardia that may in fact increase myocardial oxygen demand. 12 Another disadvantage of intravenous hydralazine is its slow onset of action, which may result in overdosage of the drug in attempts to titrate it to effect. More recent attention has been focused on the calcium channel blocking agents to treat postoperative
hypertension, particularly nifedipine. Nifedipine's effect is more specific in blocking calcium influx in vascular smooth muscle than either verapamil or diltiazem.7,13 However, nifedipine is difficult to administer because of its poor solubility and therefore must be given by either the oral or sublingual route. 14 These routes of administration preclude easy titration to effect. Nicardipine is a dihydropyridine derivative similar to nifedipine, 15 but unlike nifedipine it is water soluble and can be administered parenterally. Unlike the vasodilators nitroprusside, nitroglycerin, and hydralazine, nicardipine has not been associated with large increases in heart rate after its administration. In addition, nicardipine has a relatively rapid onset and offset of action, which allows dose titration. In this study, intravenous nicardipine rapidly controlled blood pressure in all patients who received it, whereas the placebo controlled hypertension in only 1 of 12 patients. Therapeutic response to intravenous nicardipine was rapid and occurred a mean of 10 to 12 minutes after administration. The usefulness of nicardipine for the treatment of postoperative hypertension was demonstrated in this study by: (1) the rapid control of blood pressure, (2) the continued efficacy of nicardipine during maintenance therapy, and (3) little need to adjust dosage to control blood pressure. These features and the fact nicardipine reduces systemic vascular resistance while decreasing coronary artery resistance, 16suggest that nicardipine might be extremely useful for patients who have coronary artery disease associated with acute postoperative hypertension. REFERENCES
1. Gal TJ, Cooperman LH. Hypertension in the immediate postoperative period. Br J Anaesth 1975;47:70-4.
450
--
"---(iotctberg
e t al.
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February 1990 American Heart Journal
10. Mann T, Cohn PF, Holman BL, Green LH, Markis JE, Phillips DA. Effect of nitroprusside on regional myocardial blood flow in coronary artery disease: results in 25 patients and comparison with nitroglycerin. Circulation 1978;57:732-8. 11. Kaplan JA, Dunbar RW, Jones ]~L. Nitroglycerin infusion during coronary-artery surgery. Anesthesiology 1976;45:14-21. 12. Garcia JY, Vidt DG. Current management of hypertensive emergencies. Drugs 1978;34:263-73. 13. Bertel O, Conen LD: Treatment of hypertensive emergencies with the calcium channel blocker nifedipine. Am J Med 1985; 79(suppl 4A):31-5. 14. Turlapaty P, Vary R, Kaplan JA. Nicardipine, a new intravenous calcium antagonist: a review of its pharmacology, pharmacokinetics, and perioperative applications. J Cardiothoracic Anesth 1989;3:344-55. 15. Sorkin EM, Clissold SP. Nicardipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of angina pectoris, hypertension and related cardiovascular disorders. Drugs 1987;33:296-345. 16. Lambert CR, Hill JA, Nichols WW, Feldman RL, Pepine CJ. Coronary and systemic hemodynamic effects of nicardipine. Am J Cardiol 1985;55:652-6.