ANESTH ANALC 1991;72:63944

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Deliberate Hypotension in Patients With Intracranial Arteriovenous Malformations: Esmolol Compared With Isoflurane and Sodium Nitroprusside Eugene Ornstein, PhD, MD, William L. Young, Richard S. Matteo, MD, and Jaime Diaz ORNSTEIN E, YOUNG WL, OSTAPKOVICH N, MATTE0 RS, DIAZ 1. Deliberate hypotension in patients with intracranial arteriovenous malformations: esmolol compared with isoflurane and sodium nitroprusside. Anesth Analg 1991;72:63944.

Thirty patients undergoing resection of arteriovenous malformations with deliberate hypotension were randomized to receive 1 of 3 hypotensive agents. Anesthesia was maintained with isoflurane and nitrous oxide in all patients. Mean arterial pressure was reduced 20% to 60-65 mm Hg with use of either isoflurane (54%), sodium nifroprusside ( 5 8 ,ug.kg-'.min-'), or esmolol (524 mglmin). Esmolol was associated with a decrease in cardiac output from 6.2 1.3 to 3.8 0.8 Limin, which, because of a 22% increase in systemic vascular resistance, far exceeded the reduction in mean arterial pressure. Systemic vascular resistance increased despite a 32% decrease in plasma renin activity. In contrast, with sodium nitroprusside or isoflurane, the decrease in mean arterial pressure was associated with

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Esmolol is an ultrashort acting cardioselective p-adrenergic blocker with an elimination half-life of approximately 9 min. In a previous controlled study of 25 patients undergoing spinal fusion or cerebrovascular operation, esmolol was shown to be as effective as sodium nitroprusside as the primary agent for the provision of deliberate hypotension (1). Both agents reliably reduce mean arterial pressure (MAP) to 15% below control levels obtained during maintenance anesthesia with 0.75% isoflurane. Esmolol-induced Supported by a grant from Du Pont Company. Presented at the annual meeting of the International Anesthesia Research Society, Honolulu, Hawaii, March 1990. Received from the Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York. Accepted for publication January 2, 1991. Address correspondence to Dr. Ornstein, Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, 630 West 168 Street, New York, NY 10032. 01991 by the International Anesthesia Research Society 0003-2999/91/53,50

MD,

Noeleen Ostapkovich,

REEGT,

decreases in systemic vascular resistance of similar magnitude, with no change in cardiac outpuf. Plasma renin acfivity levels increased 48% with sodium nitroprusside and 126% with isoflurane. Heart rate increased 13% with sodium nitroprusside, remained unchanged with isoflurane, and decreased 23% with esmolol. Although esmolol may be used as a primary hypotensive agent, the potential for marked myocardial depression must be recognized. The differences in pharmacologic properties for the different hypotensive agents suggest that combinations of these agents may provide a pharmacologic profile superior to either agent alone. Key Words: ANESTHETIC TECHNIQUES,

HYPOTENSIVE. ANESTHESIA, NEUROSURGICAL. ANESTHETICS, voLATILE-isoflurane. SYMPATHETIC NERVOUS SYSTEM, PHARMACOLOGY-eSmO101. PHARMACOLOGY,

NITROPRUSSIDE.

hypotension was smooth in onset and offset, without the associated increase in heart rate seen with use of nitroprusside. In fact, patients given esmolol had an approximately 12% reduction in heart rate. Also, rebound hypertension was not seen in patients given esmolol. In light of this previous study, esmolol might be considered an ideal hypotensive agent for patients at risk for ischemic heart disease. However, with pulmonary artery catheters not being routinely used in patients undergoing spinal fusion, the lack of invasive cardiovascular monitoring in the aforementioned study precluded this recommendation. Because esmolol is a p-blocker, the main cause of hypotension is probably a reduction in cardiac output. However, p-blockers might, through their effect on the reninangiotensin axis (2), also lead to a reduction in systemic vascular resistance, thus attenuating the

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reduction in cardiac output required for the provision of a given level of hypotension. The present study addresses this issue by investigating the mechanism of hypotension provided by esmolol, nitroprusside, and high-dose isoflurane. Central hemodynamic data were collected by pulmonary artery catheterization, and plasma renin activity was measured in serial blood samples from patients undergoing deliberate hypotension during craniotomy for resection of intracranial arteriovenous malformations (AVM).

Methods This study was approved by the Institutional Review Board of the College of Physicians and Surgeons of Columbia University and written informed consent was obtained from all patients. A total of 30 ASA physical status I1 patients with intracranial AVM scheduled for elective craniotomy were studied. Patients with a history of bronchospastic disorders, cardiac failure, significant hepatic or renal disease, atrioventricular block greater than first degree, or any other contraindication to the use of @blockers were excluded from the study. All women of childbearing potential had negative pregnancy tests before admission into the study. All patients were orally premedicated with 10 mg of diazepam approximately 90 min before arrival at the operating room. Once an intravenous infusion was begun, 2-5 mg of midazolam was administered approximately 15 min before induction. Electrocardiographic leads were applied, and a radial artery was cannulated before induction of anesthesia with 5-8 mg/kg of thiopental. Anesthesia was maintained with 0.75% isoflurane, end-tidal, in N20/02, 60%: 40% , with vecuronium in 10-mg increments administered as required. During initial craniotomy, isoflurane concentration was occasionally increased to a maximum of 1.2%. After tracheal intubation, a pulmonary artery catheter was threaded through either the basilic or cephalic vein in the antecubital fossa. Cannulation was successful in 26 patients. Because of neurosurgical concerns about venous drainage of the AVM, no attempt was made to cannulate the jugular venous system. When requested by the surgeon, deliberate hypotension was provided, but always after at least 60 min of stable maintenance anesthesia (0.75% isoflurane, end-tidal). The hypotensive level sought in this study was a 15%-25% reduction in MAP below control levels obtained just before the administration of the

hypotensive agent. Patients were randomized into three groups, based on the hypotensive agent to be used. Patients in group 1 received isoflurane in an inspired concentration from 1.5% to a maximum of 4%, those in group 2 received nitroprusside in an infusion ranging from 0.5 pg.kg-'.min-' to a maximum of 8 pg.kg-l.min-', and those in group 3 received esmolol as a 60-mg bolus over 90 s followed by an infusion of 8 mglmin. If this dose of esmolol did not lower blood pressure to the desired level after 4 min, the 60-mg bolus was repeated and followed by 16- or 24-mg/min infusions. Measurements included mean, systolic, and diastolic blood pressures, heart rate, central' venous and pulmonary capillary wedge pressures, and cardiac output by thermodilution. Systemic vascular resistance was calculated as 80 X (MAP - CVP)

co where CVP is the central venous pressure and CO is the cardiac output. In addition, arterial blood samples were obtained in prechilled test tubes containing ethylenediaminetetraacetic acid (final concentration, 3 mg/mL). Plasma was separated immediately in a refrigerated centrifuge and was frozen for later plasma renin activity analysis by radioimmunoassay (RIANEN, Du Pont Co.). Using the paired Student's t-test, hemodynamic variables were compared within groups between the baseline just before the initiation of hypotension and the point at which a 15%-25% reduction in MAP was obtained. Comparisons between groups for demographic data and for changes induced by the various hypotensive agents were made with analysis of variance and post hoc application of Fisher's protected least significant differences. The threshold for statistical significance was taken as P < 0.05. Data are expressed as mean ? SD.

Results There were no significant differences between groups in age, weight, and in preinduction heart rate or blood pressure (Table 1). One patient from group 1 was resistant to isoflurane, with no significant reduction in MAP noted despite the administration of 4% isoflurane for 10 min. This patient was given propranolol(2 mg IV) and was dropped from subsequent analysis. Hemodynamic variables and plasma renin activity before and during hypotension are compared for

ESMOLOL HYPOTENSION IN AVM SURGERY

ANESTH ANALG 1991;72:63944

Table 1. Demographic and Baseline Hemodynamic Data Isoflurane

Age (yr) Weight (kg) Heart rate (beatdmin) Mean arterial pressure (mm Hg) Systolic blood pressure (mm Hg) Values are mean

f SD

35 66 80 90

11 I1 2 17 2 11 2 2

128 2 16

Nitroprusside 35 2 11 69 2 I0 77 ? 15 92 t 8 129

?

13

Esmolol 36 70 76 97

t8 t 14 t 18

t 10

132 t 12

( n = 10 in each group)

each hypotensive regimen in Table 2. Comparisons between hypotensive agents are shown in Figure 1. At baseline, just before the initiation of hypotension, all groups had similar central and peripheral blood pressures, cardiac outputs, systemic vascular resistances, and plasma renin activities. A 20% decrement to a MAP of 60-65 mm Hg was easily obtainable with all three hypotensive agents. The mean doses required were 2.3% ? 0.7% isoflurane, endtidal; 2.3 ? 1.3 pgkg-l-rnin-' nitroprusside; and 16.8 ? 6.2 mg/min esmolol. The changes in MAP were associated with changes in systolic and diastolic pressures that were similar in the three groups. Esmolol hypotension was accompanied by a 23% decrease in heart rate from 88 ? 17 to 67 5 10 beats/min (P < 0.002). Nitroprusside, on the other hand, was associated with a 13% increase in heart rate from 91 2 23 to 103 2 24 beats/min ( P < 0.001). A 9% increase in heart rate in the isoflurane group did not achieve statistical significance ( P = 0.08). Heart rates exceeding 120 beats/min were seen during deliberate hypotension in three patients given nitroprusside, in two patients given isoflurane, and in none of the patients given esmolol. Patients with persistent tachycardia were given propranolol in 1-mg increments after obtaining the hemodynamic data. The maximum heart rate seen in the esmolol group was 82 beats/min. As to mechanism of the hypotensive effect, both nitroprusside and isoflurane caused significant decreases in systemic vascular resistance of 28% and 22%, respectively, with small changes in cardiac output that were not statistically significant. These changes in systemic vascular resistance accounted completely for the hypotensive action. In contrast, the effect of esmolol was to significantly depress 1.3 to 3.8 2 cardiac output by 37% from 6.2 0.8 Wmin ( P < 0.001). There was an associated 22% increase in systemic vascular resistance with esmolol use despite a reduction in plasma renin activity from 10.4 2 9.0 to 7.1 t 7.4 ng.mL-'.h-' (P < 0.05). Esmolol-induced hypotension resulted in an ap-

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proximately 32% reduction in plasma renin activity, nitroprusside-induced hypotension was accompanied by a moderate 48% increase in plasma renin activity (from 9.4 2 4.1 to 13.4 ? 7.1 ng.mL-'.h-'; P < 0.05), and the hypotension induced by high-dose isoflurane was associated with the greatest increase in plasma renin activity, with levels increasing 126% (from 10.4 2 8.2 to 23.0 ? 19.9 ngmL-'.h-'; P < 0.05). Cardiac filling pressures were unchanged with isoflurane. Both central venous and pulmonary capillary wedge pressures increased significantly with esmolol (52% and 23%, respectively). Although central venous pressure was unchanged with nitroprusside, there was a significant decrease in pulmonary capillary wedge pressure.

Discussion Nitroprusside is probably the most commonly used drug for the provision of deliberate hypotension. Its popularity is related to its potency and short duration of action; however, certain limitations and risks are associated with its use. These include reflex tachycardia (3), tachyphylaxis (4), rebound hypertension (5), pulmonary shunting (6), and the potential for cyanide toxicity (7). Consequently, to minimize these concerns and to limit the total dose of nitroprusside administered, several adjunctive pharmacologic agents have been combined with nitroprusside. Among these agents are isoflurane, a potent inhalation anesthetic with vasodilating properties, and propranolol, a p-blocker that decreases baseline sympathetic tone and attenuates the stress response (8). Unlike isoflurane, which has been used as a primary agent for induced hypotension (9), p-blockers available before the release of esmolol had elimination half-lives that were too long for this use and thus served as secondary rather than primary hypotensive agents (8,10,11). Esmolol's elimination half-life of 9 min provides both ease in achieving the desired level of hypotension by regulating the dose and ease in terminating the hypotensive effect after the termination of the infusion. In contrast to isoflurane, esmolol administration can be continued in the intensive care unit should a reduction in blood pressure be indicated in the postoperative period, as is frequently the case after operation for AVM. Although one patient was resistant to 4% isoflurane, all three agents were effective in providing 20% reduction in MAP. The hypotensive mechanism with nitroprusside and isoflurane is peripheral vasodilation, as demonstrated by a reduction in systemic

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Table 2. Hernodynamic Variables Before and During Deliberate Hypotension MAP (mm Hg) n Control Hypotension

SBP (mm Hg) n Control Hypotension

DBP (mm Hg) n Control Hypotension

HR (beatslmin) n Control Hypotension CO (L/min) n Control Hypotension CVP (mm Hg) n Control Hypotension

Isoflurane

Nitroprusside

Esmolol

9 82 t 5 64 t 4a

10 83 2 5 65 t 4"

10 82 t 6 65 t 6"

9 105 t 6 86 t 6"

10 110 t 6 88 t 7"

10 106 t 6 82 t 6"

9 66 t 5 53 t 4"

10 68 2 5 54 t 6"

10 69 t 9 54 t 6"

9 83 2 13 91 2 20

10 91 t 23 103 t 24"

10 88 t 17 67 t lo"

9

7 6.9 t 1.9 7.6 2 2.1

9 6.2 t 1.3 3.8 t 0.8"

9 6 2 4 7 t 4

7 6 2 4 5 2 2

9 7 t 3 10 t 3"

9 10 rt 3 10 t 4

7 11 2 3 8 2 4"

9 10 2 4 12 t 4a

9 1006 t 215 779 2 226"

7 956 t 285 681 t 177"

9 995 t 201 1195 t 275'

8 10.4 t 8.2 23.0 t 19.9"

8 9.4 2 4.1 13.4 ? 7.1"

8 10.4 t 9.0 7.1 t 7.4"

6.2 6.4

2 ?

1.1 2.2

PCWP (mm Hg)

n Control Hypotension SVR (dyne.cm.s-')

n Control Hypo tension

PRA (ng.mL-'.h-') n Control Hypotension

CO, cardiac output; CVP, central venous pressure; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; PRA, plasma renin activity; PCWP, pulmonary capillary wedge pressure; SBP, systolic blood pressure; SVR, systemic vascular resistance. Values are mean ? SD. "Significantly different from control levels during stable isoflurane anesthesia just before the initiation of hypotension.

vascular resistance with essentially no change in cardiac output. In contrast, the hypotensive effect of esmolol is due to a profound decrease in cardiac output that exceeds both the reductions in blood pressure and heart rate. Plasma renin levels were found to increase with nitroprusside but even more so with isoflurane. Although Macnab et al. reported that nitroprussideinduced hypotension caused a greater increase in plasma renin activity than isoflurane-induced hypotension, their study differed in their use of supplemental fentanyl, of a higher isoflurane concentration at baseline, and of halothane rather than isoflurane in

the control group (12). As previously demonstrated with other P-blockers (2), esmolol is associated with a reduction in plasma renin activity. Despite this reduction in plasma renin activity, there is a significant reflex increase in systemic vascular resistance associated with esmolol-induced hypotension. This increase in afterload could potentially further compromise cardiac function especially in patients with limited myocardial reserve. As a result, the decrease in cardiac output may far exceed the decrease in MAP and may compromise organ perfusion. In 3 of 9 patients given esmolol in the present study, cardiac output decreased below 3.0 L/min during hypoten-

ESMOLOL HYPOTENSION IN AVM SURGERY

ANESTH ANALG 1991;72:63944

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Deliberate hypotension in patients with intracranial arteriovenous malformations: esmolol compared with isoflurane and sodium nitroprusside.

Thirty patients undergoing resection of arteriovenous malformations with deliberate hypotension were randomized to receive 1 of 3 hypotensive agents. ...
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