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CARDIOVASCULAR ANESTHESIA

Vascular Responsiveness to Brachial Artery Infusions of Phenylephrine During Isoflurane and Desflurane Anesthesia

Shahbaz R. Arain, MD^*, David J. Williams, FRCA, Brian J. Robinson, PhD, Toni D. Uhrich, MS^*, and Thomas J. Ebert, MD PhD^*

*Department of Anesthesiology, The Medical College of Wisconsin and Veterans Affairs Medical Center, Milwaukee; Department of Anaesthetics, University Hospital of Wales, Cardiff, UK; and Department of Anaesthesia, Wellington Hospital, Wellington Sound, New Zealand

Address correspondence to Thomas J. Ebert, MD, PhD, VA Medical Center, 112A, 5000 West National Ave., Milwaukee, WI 53295. Address e-mail to tjebert{at}mcw.edu

	Abstract

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Compared with equi-minimum alveolar anesthetic concentration (MAC) isoflurane, desflurane is associated with greater levels of sympathetic nerve activity in humans but similar reductions in blood pressure. To explore these divergent effects, we evaluated vascular ₁-adrenoceptor responses in the human forearm during isoflurane and desflurane anesthesia to determine if ₁-adrenoceptor responses were more substantially attenuated during desflurane administration. Bilateral forearm venous occlusion plethysmography was used to examine arterial blood flow and to determine changes in forearm vascular resistance during brachial artery infusions of saline and phenylephrine (0.2, 0.4, 0.8, and 1.6 µg/min) in 22 conscious subjects and during anesthesia with 0.65 and 1.3 MAC isoflurane or desflurane. Infusion of phenylephrine into the brachial artery increased the forearm vascular resistance in a dose-dependent manner. The arterial response to phenylephrine was significantly attenuated by 0.65 and 1.3 MAC desflurane and similarly attenuated during 1.3 MAC isoflurane (P < 0.05). Impaired arterial ₁-adrenoceptor responsiveness occurred during desflurane. However, this effect was statistically similar (P > 0.05) to the impaired responses during isoflurane. Blood pressure decreases during volatile anesthesia may be, in part, caused by decreased ₁-adrenoceptor responsiveness.

IMPLICATIONS: -receptors on blood vessels regulate constriction and dilation and therefore modulate blood pressure. This research indicates that vasoconstriction via the ₁-receptor vascular response is impaired during isoflurane and desflurane anesthesia.

	Introduction

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During volatile-based anesthesia, vasodilation may occur via direct or reflex inhibition of peripheral sympathetic activity to the vasculature or direct effects on the vascular smooth muscle. An impaired response of vascular ₁-adrenoceptors to endogenous norepinephrine might be involved in the vasodilation from volatile anesthetics. However, this role is controversial. In animal models, endogenous or exogenous norepinephrine-induced vasoconstriction is inhibited by isoflurane (1,2), and in autonomically denervated dogs, ₁-adrenoceptor-mediated vasoconstriction is attenuated by isoflurane (3). These findings contrast with human studies that suggest that the vascular responses to the ₁-agonist, phenylephrine, are preserved during isoflurane (4) and halothane (5) anesthesia.

The effects of desflurane on ₁-adrenoceptor-mediated vasoconstriction have not been studied. Earlier work from this laboratory evaluated the neurocirculatory responses to steady-state concentrations of desflurane in humans and demonstrated greater levels of sympathetic outflow but similar reductions in blood pressure compared with equi-minimum alveolar anesthetic concentration (MAC) isoflurane (6). One explanation for this effect might be related to a neuroeffector uncoupling from desflurane. This would consist of a reduced vascular responsiveness to the endogenous neurotransmitter, norepinephrine. This study examined the effects of isoflurane and desflurane on the forearm vascular response to ₁-adrenoceptor-mediated vasoconstriction from brachial artery infusions of phenylephrine in human subjects. We tested two hypotheses. First, that volatile anesthetics impair ₁-adrenoceptor vascular responses in humans, and second, that this impairment would be greater during desflurane than isoflurane anesthesia.

	Methods

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Approval from the Human Studies Review Board and informed written consent from healthy volunteers were obtained. Volunteers were without systemic disease (ASA physical status I) and not taking prescription medications or illicit drugs. Subjects arrived at the laboratory having fasted for at least 8 h, and they received 15 mL of oral nonparticulate antacid. Women provided a urine sample that was negative for pregnancy before participation. Standard American Society of Anesthesiologists monitoring was used.

After local infiltration with 0.5 mL of 1% lidocaine, a 20-gauge catheter was placed in the brachial artery of the study arm (usually the nondominant arm) for the infusion of phenylephrine and the measurement of mean arterial blood pressure (MAP). An infusion of 0.9% normal saline at 80 mL/h was established to maintain catheter patency and to carry phenylephrine into the artery at selected intervals. The other (noninfusion) arm served as the control and did not have an arterial catheter. Subjects received sequential, 10-min brachial artery infusions of saline and phenylephrine at infusion rates of 0.2, 0.4, 0.8, and 1.6 µg/min, and arterial responses (forearm blood flow [FBF]) were determined. Measurements were made during the last 3 min of each infusion. The total infusion rate in the forearm was always maintained at 80 mL/h.

Determinations of FBF were made simultaneously in both forearms using standard venous occlusion plethysmography with mercury-in-silastic strain gauges. This technique has previously been reviewed and described in detail (7,8). Briefly, both arms were raised and passively supported above the height of the right atrium to ensure adequate venous drainage between measurements. Inflatable blood pressure cuffs were placed about both wrists and upper arms, and a double-stranded, mercury-filled strain gauge was placed around each forearm at the region of greatest circumference. After occlusion of the hand circulation by inflation of the wrist cuffs to 250 mm Hg, FBF was calculated from the rate of increase in forearm volume during cycled inflation of the upper arm cuffs to 50 mm Hg (8 s on and 8 s off). Forearm vascular resistance (FVR) was calculated by dividing MAP with FBF.

The vascular responses to infusions of phenylephrine into the brachial artery were recorded in the conscious state. Anesthesia was induced with 2.5 mg/kg of propofol, and muscle relaxation was achieved with 0.1 mg/kg of vecuronium. After tracheal intubation, the lungs were ventilated with 50% oxygen and air, and normocarbia was maintained. Anesthesia was randomly assigned to either isoflurane (n = 11) or desflurane (n = 11), and it was maintained at either age-adjusted 0.65 or 1.3 MAC (random order by coin flip) in oxygen (9,10). End-tidal anesthetic concentration was determined from end-tidal gas sampling using side-stream infrared spectroscopy (Ohmeda RGM, Madison, WI). Twenty minutes after reaching the targeted end-tidal concentration, incremental infusions of phenylephrine were commenced, and the vascular effects were recorded. The anesthetic concentration was then changed, and 20 min after the new target end-tidal anesthetic concentration was reached, data collection was repeated.

FVR was expressed from individual arms on an absolute basis and as the ratio infused:control arms. Continuous variables were reported as mean ± SD and compared with the repeated-measures analysis of variance (StatView 5, SAS Institute Inc, Cary, NC) with post hoc evaluation of specific time points with Scheffé’s F test. Statistical significance was achieved when P < 0.05.

	Results

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Twenty-two subjects participated in this study. Patient characteristics included (range): 20–31 yr, 155–190 cm, 45–125 kg, 7 women, and 15 men. Anesthesia was associated with increased heart rate (HR) and decreased MAP in a dose-related fashion (Table 1). At 1.3 MAC desflurane or isoflurane anesthesia, FVR was decreased compared with the conscious state. One subject in each of the groups developed sustained hypotension in response to 1.3 MAC anesthesia (MAP < 50 mm Hg) that was refractory to the infusion of 500 mL of 0.9% saline and leg elevation. Further study of these subjects was therefore terminated in the interest of safety, and only the data from their 0.65 MAC dose were available for analysis.

In the experimental arm, incremental infusions of phenylephrine (0.2, 0.4, 0.8, and 1.6 µg/min) caused significant and progressive increases in FVR in all subjects under all conditions (Fig. 1). The mean increase for the Isoflurane group was 17 ± 2.6 U in the conscious state, 14 ± 1.8 U at 0.65 MAC isoflurane (95% confidence interval [CI], -2.5 to 9.9), and 11 ± 2.9 U at 1.3 MAC (significantly less than the conscious state P < 0.05; 95% CI, 0.4 to 14.2). The mean increase for the Desflurane group was 19 ± 2.7 U in the conscious state, 12 ± 1.8 U at 0.65 MAC (95% CI, 1.7 to 16.3), and 11 ± 1.7 U at 1.3 MAC (95% CI, 2.7 to 16.8). These increases were significantly less than the conscious state for both 0.65 and 1.3 MAC desflurane. Similar statistical findings were found when applying repeated-measures analysis of variance to the FVR responses to phenylephrine ramps in the three experimental situations for both isoflurane and desflurane (Fig. 1). There were no differences between isoflurane and desflurane in the phenylephrine responses (95% CI at 0.65 MAC, -4.4 to 3.6; 95% CI at 1.3 MAC, -3.4 to 4.6.) The noninfused arm showed no significant changes in FVR during the experimental contralateral arm infusions.

View larger version (36K): [in this window] [in a new window]   Figure 1. Top: The change (from baseline) in forearm vascular resistance (FVR) with increasing dose of phenylephrine infused into the brachial artery of the experimental arm. *Significantly reduced phenylephrine response compared with conscious responses (P < 0.05). Bottom: The change (from baseline) in FVR in the control arm (simultaneous with increasing dose of phenylephrine infused into the brachial artery of the experimental arm). Data are mean ± SD. FVR units are mm Hg/(mL · min-1 · 100-mL forearm volume-1).

	Discussion

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The isolated human forearm technique uses an intact, skeletal muscle, vascular bed to determine vascular responsiveness. This obviates many of the problems of in vitro studies that use isolated, large conduction and capacitance vessels that often require exogenous vasoconstrictor substances to maintain vessel tone. Large conduit vessels may not accurately reflect the responses from smaller resistance-type vessels. The isolated forearm technique also limits systemic effects from locally infused drugs. This permits specific evaluation of the phenylephrine vascular response without opposing reflex neural effects on vascular smooth muscle from systemic hypertension (Fig. 1). In addition, the human forearm measurements reflect primarily muscle blood flow. The skeletal muscle circulation of humans comprises up to 30% of the total circulation and is therefore a major determinant of systemic vascular resistance.

In vitro animal studies have suggested that volatile anesthetics act directly on vascular smooth muscle by attenuating adrenoceptor-mediated contraction (1,2,11). The mechanism might involve modulation of pre-synaptic norepinephrine release (2,11), intracellular cal-cium fluxes (e.g., attenuated Ca²⁺ release) (12), and endothelial-mediated actions (13). A study using the denervated canine model (ganglionic, cholinergic, and ß-adrenergic blockade) has clearly indicated that both halothane and isoflurane attenuate ₁- and ₂-adrenoceptor mediated arterial vasoconstriction (14).

The animal studies are in contrast to human studies that indicate the pressor response to phenylephrine is unaffected by either isoflurane (4) or halothane (5). However, in the former study, a systemic administration of phenylephrine was used, which resulted in hypertension and, presumably, activation of reflex responses. In addition, all of the patients were undergoing coronary artery bypass grafting and might have had altered vascular tone and reactivity from co-existing systemic vascular disease (15,16). In support of our findings, a study in human subjects has suggested that both isoflurane and sevoflurane suppress the cardiovascular responses to endogenous catecholamines (17).

The demonstration that desflurane provides a similar attenuation of ₁-adrenoceptor-mediated vasoconstriction to equi-MAC isoflurane is interesting. Earlier work from this laboratory has suggested that desflurane might be associated with neurovascular uncoupling in humans. We noted larger levels of sympathetic outflow and circulating norepinephrine concentrations at steady-state concentrations of desflurane above 1.0 MAC compared with isoflurane but similar reductions in blood pressure (6). One explanation of these findings might be a reduced vascular responsiveness to norepinephrine (mixed ₁- and ₂-adrenoceptor agonist) from desflurane. This study specifically refutes that possibility with regard to the ₁-receptor.

This study has an important limitation. We studied only healthy volunteers and are thus unable to extend these findings to disease states where vascular mechanisms might be altered. Several studies with divergent findings that suggest that -receptor responses are preserved under anesthesia have focused primarily on patients with cardiovascular or other systemic disease (4,5,16). In this study, we implicate the activity of the ₁-receptor; however, phenylephrine may not be a pure ₁-adrenoceptor agonist, as is generally accepted, and may have some ₂-adrenoceptor (as well as ß-adrenoceptor) mediated effects (18).

In conclusion, the results of this study suggest that both isoflurane and desflurane attenuate, to an equal extent, arterial ₁-adrenoceptor mediated vasoconstriction. These data imply that vasoconstrictor responses to therapeutically administered doses of phenylephrine will be attenuated whether small or large concentrations of volatile anesthetics are being administered.

	Acknowledgments

 
Supported, in part, by a Veterans Affairs Merit Review grant and a National Institute of Health R01 Award #GM49943.

	References

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