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ANESTHETIC PHARMACOLOGY

Sympathetic and Vascular Consequences from Remifentanil in Humans

Department of Anesthesiology, Medical College of Wisconsin and Veterans Affairs Medical Center, Milwaukee

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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We explored the possible mechanisms of hypotension during the administration of sedation-analgesia doses of remifentanil in young (ASA physical status I) volunteers (n = 24). Cardiorespiratory and sympathetic variables were collected at baseline and at plasma concentrations of remifentanil (2 and 4 ng/mL). Monitoring included electrocardiogram, heart rate (HR), direct blood pressure, muscle sympathetic nerve activity, and forearm blood flow (FBF). A cold pressor test (1-min hand immersion in ice water) quantified analgesia effectiveness (visual analog scale, 0–100). Visual analog scale to the cold pressor test (62 at baseline) decreased to 27 and 18 during remifentanil infusions. Respiratory rate decreased and end-tidal carbon dioxide (ETCO₂) increased with increasing doses of remifentanil; HR, direct blood pressure, muscle sympathetic nerve activity, SpO₂ remained unchanged, but FBF increased compared with placebo. In a second study (n = 7), timed respiration was used to maintain ETCO₂ during remifentanil, but FBF still increased. In a third study (n = 11), direct effects of remifentanil on vascular tone were determined with progressive infusions from 1 to 100 µg/h into the brachial artery; FBF increased significantly from 3.5 to 4.3 mL/min per 100 mL of tissue (13%–18% increase). Sedative doses of remifentanil resulted in analgesia but no changes in neurocirculatory end-points except FBF. Direct effects of remifentanil on regional vascular tone may play a role in promoting hypotension.

IMPLICATIONS: Remifentanil occasionally has been associated with hypotension, the mechanism of which is unclear. This study found that remifentanil directly causes the forearm arterial vasculature to dilate.

	Introduction

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Remifentanil is a relatively new, ultrashort-acting, potent µ-opioid agonist. It is unique from other frequently used parenteral opioids because of its rapid onset, lack of accumulation, and rapid offset through plasma cholinesterase metabolism. These properties make it an ideal analgesic for alleviating brief, moderate to intense perioperative pain. However, several studies have shown dose-dependent cardiovascular (and respiratory) depression with both bolus (1) and infusion (2–4) regimens.

The mechanism(s) by which remifentanil causes hemodynamic consequences is not clear, but it is not likely caused by histamine release (5,6). The observation that premedication with glycopyrrolate attenuated the dose-dependent decrease in systolic blood pressure (BP) from remifentanil by maintaining heart rate (HR) suggests that a possible mechanism for the cardiovascular effects may be via vagal-cardiac activation (5). In fact, a study in rabbits by Shinohara et al. (7) further supports the hypothesis of vagal-cardiac activation with remifentanil. Some opioids also may have a direct effect to relax vascular smooth muscle, although remifentanil has not been studied in this regard (8).

The purpose of this study was to further define potential mechanisms of hemodynamic effects from remifentanil in humans by recording sympathetic outflow and measuring forearm blood flow (FBF). Moderate sedative doses of remifentanil were studied to avoid respiratory effects that may have mandated intubation and mechanical ventilation. The tested hypothesis was that sympatho-inhibition contributes to the hemodynamic effects of remifentanil.

	Methods

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After approval by the Human Studies Subcommittee, written informed consent was obtained from 42 volunteer subjects to participate in 3 separate studies. The first study was designed so a volunteer would receive either a placebo (n = 12) or IV sedative doses of remifentanil (n = 12). After obtaining baseline data, a computer-controlled Harvard infusion pump (Stanpump Software, Palo Alto, CA) was programmed to deliver two effect-site target concentrations of remifentanil (2 and 4 ng/mL) (placebo group received saline infusion for a similar time period). During baseline and each dose, a cold pressor test (CPT) was performed. One hand was immersed in ice water for 60 s, and the associated pain was rated on a visual analog scale where 0 is no pain and 100 is worst pain imaginable.

Monitoring included HR (bpm) via surface electrocardiogram, BP (mm Hg) via radial cannulation, respiratory rate (RR; breaths/min) via pneumo-bellows across the abdomen, and end-tidal CO₂ (ETCO₂) via nasal cannula. FBF was derived with venous occlusion plethysmography in one arm. The underlying principle of venous occlusion plethysmography is that if venous return from the arm is occluded while arterial inflow continues unimpeded, the forearm will expand at a rate proportional to the rate of arterial inflow (9). In the supine position, the elbow (opposite the infusion arm) was supported in a slightly flexed and elevated position so that the forearm was above heart level, thereby ensuring adequate venous drainage between measurements. Inflatable BP cuffs were placed about the wrist and upper arm, and a double-stranded, mercury-in-Silastic, temperature-compensated strain gauge was placed around the forearm at its largest girth. The wrist cuffs were inflated to 200 mm Hg to exclude hand circulation from measurements. FBF was measured over 2 min by calculating the rate of the increase in forearm volume during inflation of the arm cuff to 50 mm Hg for 7-s periods, each followed by a 8-s period of deflation. Forearm vascular resistance was calculated by dividing the mean arterial BP (MAP) by FBF (10). Muscle sympathetic nerve activity (MSNA) was measured via percutaneous impalement of the peroneal nerve. This technique, which has been previously described (11), involved locating the nerve with an external probe that delivered brief electrical pulses (1 Hz; 3–7 mA) to the region just distal to the fibular head. Two 5-µ-tipped, epoxy-coated tungsten needles were inserted into the leg; one needle was placed just outside the nerve fascicle (reference electrode), and one was advanced into the peroneal nerve (recording electrode). Characteristic bursts of efferent neural activity were obtained by fine manipulations of the recording electrode. After filtering and amplifying the signal, MSNA was observed and quantified.

A second study (n = 7) was undertaken to give sedative doses of remifentanil while controlling ETCO₂ with timed respiration. The protocol was identical to the first study other than prompted breathing to maintain baseline levels of CO₂.

A third study was conducted with remifentanil infused into the brachial artery (n = 11) to seek a direct vascular effect. Remifentanil was given at rates of 5, 10, 20, and 100 µg/h. This was given as sequential escalating 7-min infusions with data collection during the last 2 min of each infusion step. Monitors for this study included a brachial artery cannula for BP (and remifentanil infusion), electrocardiogram, pulse oximeter, and bilateral FBF. The noninfused forearm served as a control and theoretically was not affected by the local infusion in the other arm.

Consecutive measurements were compared over time (baseline and low and moderate sedation) and between groups (placebo, remifentanil with natural breathing, and remifentanil with directed breathing) with repeated-measures analysis of variance. Comparisons for the intraarterial study were made over time (increased dose) and between arms (control versus infusion arm). P < 0.05 was considered significant.

	Results

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Forty-two volunteers participated in three studies. All subjects were young (19–37 yr) and healthy with an ASA physical status of I. All groups were similar with respect to demographics (mean [range]: age, 24 yr; height, 174 cm [160–188]; weight, 71 kg [48–91]; and 15 women).

In the study of placebo versus remifentanil without regulation of breathing, HR, MAP, and MSNA (in bursts/min) were not significantly different (Fig. 1). In 7 of 12 subjects receiving systemic remifentanil in the uncontrolled breathing group, successful nerve recordings were obtained and maintained throughout infusions. Nerve recordings were successfully obtained and maintained from all placebo participants (Study 1) and all controlled-breathing participants (Study 2). FBF, ETCO₂, and RR were significantly different between groups (Fig. 1). Despite the lack of BP changes, the amount of remifentanil was sufficient to blunt the pain response during the CPT. Figure 2 shows the peak change in MAP and the peak change in MSNA (in bursts/100 heart beats), as well as the pain score as reported by the visual analog scale during the CPT.

View larger version (24K): [in this window] [in a new window]   Figure 1. Hemodynamic, neurocirculatory, and respiratory responses to infusions of remifentanil versus placebo. Heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) remained stable throughout the study period. During remifentanil infusions, respiration decreased, and end-tidal carbon dioxide (ETCO2) increased. Remifentanil also caused significant increases in forearm blood flow (FBF). Data are mean ± SEM. *P < 0.05 compared with placebo response.

View larger version (29K): [in this window] [in a new window]   Figure 2. Response to the 1-min cold pressor test (CPT) before and during remifentanil infusion. The changes in mean arterial blood pressure (MAP) and muscle sympathetic nerve activity (MSNA) are the increases larger than the preceding steady-state measurements. Remifentanil significantly attenuated the normal pressor response to this painful stimulus. This was likely because of less pain to cold stimulus during remifentanil and less sympathetic activation. Data are mean ± SEM. *P < 0.05 compared with baseline response. VAS = visual analog scale.

View larger version (25K): [in this window] [in a new window]   Figure 3. Hemodynamic and respiratory responses to infusions of remifentanil while controlling end-tidal carbon dioxide (ETCO2). Heart rate (HR) and blood pressure (BP) did not change for the duration of the study. ETCO2 was intentionally and successfully maintained at baseline levels; however, this did not prevent an increase in forearm blood flow (FBF). Data are mean ± SEM. *P < 0.05 difference between historical controls (Study 1, uncontrolled CO2) and controlled CO2 response.

View larger version (20K): [in this window] [in a new window]   Figure 4. The upper panel displays forearm blood flow (FBF) responses to intraarterial infusions of remifentanil into one arm and are compared with the noninfused control arm. Remifentanil progressively increased FBF in the infused arm (y = 3.33 x 0.052; r = 0.946) but did not significantly influence the control arm (y = 2.38 x 0.013; r = 0.537). The middle panel is a ratio of FBF in the infused arm divided by the control arm (y = 1.51 x 0.040). The bottom panel displays respiratory rate (RR), which was not significantly altered by the local arterial infusion of remifentanil into the forearm. Data are mean ± SEM. *P < 0.05 compared with control arm.

	Discussion

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The stability of sympathetic outflow with sedative infusions of remifentanil contrasts markedly with the substantial decreases in MSNA and BP noted with sedative infusions of propofol and the smaller decreases in the MSNA noted during sedation with midazolam in an earlier study from our laboratory¹. Interestingly, plasma norepinephrine levels have been reported to remain stable or to increase when larger doses of other nonhistamine-releasing opioids have been studied (12,13). Despite the stability of MSNA and BP when opioids are given alone, as noted in this and other studies, it seems that combining opioids with benzodiazepines is more often associated with hypotension (14–16). We suggest that significant hypotension from small to moderate doses of remifentanil is more likely related to interactions with other anesthetics or adjuvants.

The significant increase in FBF during remifentanil infusions was curious because there was no significant change in any other hemodynamic or autonomic variable measured, including BP. This implies that the vasodilation in one regional circulation (forearm) might have been opposed by vasoconstriction in other circulatory beds. Because CO₂, a known vasodilator, increased progressively with sequential doses of remifentanil, a second study was conducted, during which ETCO₂ was controlled with timed respiration. Hypercapnia was eliminated with this protocol, but an increase in FBF was still recorded simultaneous to an unchanged MAP and MSNA.

We considered the possibility that this response might be because of a direct effect of remifentanil on forearm vascular smooth muscle because sympathetic outflow was unchanged. Interestingly, several studies report that opioids have direct vascular effects in experimental animal and tissue preparations, although the findings have not been entirely consistent. Introna et al. (17) found that fentanyl directly increased isolated coronary artery tension at smaller doses and decreased tension at large doses. Tverskoy et al. (18) noted that fentanyl increased intestinal circulation, whereas morphine decreased it. White et al. (8) noted vasodilation in the isolated hind limb preparation of dogs, which occurred with fentanyl, alfentanil, and sufentanil, and was not eliminated with either naloxone (a µ-antagonist) or sympathetic denervation. These findings have not been extended to human studies, and the potential direct effects of remifentanil have not been evaluated in either human or animal preparations.

Thus, in a third study, microinfusions of remifentanil into the brachial artery were given while measurements of FBF were obtained. This model established a regional concentration of remifentanil predicted to be similar to those seen with systemic infusions but avoided systemic effects because of the rapid dilution and subsequent metabolism when remifentanil exited the forearm via venous outflow. The opposite arm (noninfused) served as the control and was presumably not exposed to remifentanil and did not vasodilate. The absence of a systemic response to the local infusion was supported by the lack of subjective sensations of sleepiness or relaxation or objective changes in RR and ETCO₂ that had been consistently noted with the systemic infusions in Studies 1 and 2. FBF in the infused arm significantly increased, providing additional evidence that direct vascular effects might account for the vasodilation because CO₂ levels and sympathetic outflow were unchanged. The exact mechanism of the vasodilation is unknown, but possibilities include a presynaptic inhibition of norepinephrine release at the postsynaptic terminal, an action on a peripheral vascular µ-receptor, activation of nitric oxide via stimulation of the endothelium, or the release of another vasoactive factor at the local level. Further study is required to clarify the precise mechanism.

The limitations of this study were that only small and moderate doses of remifentanil were studied in young, healthy individuals, and these doses did not result in hypotension. However, they were sufficient to achieve significant analgesia to the CPT and to effect significant changes in RR and ETCO₂. The hemodynamic changes reported during the use of remifentanil may have been due in part to the use of larger doses of remifentanil, an interaction with other anesthetic adjuvant drugs, or to a confounding pathological factor in patients with systemic disease or reduced volume status. In addition, direct vascular effects of remifentanil might be involved in promoting a hypotensive response to larger doses of remifentanil. Another limitation was the lack of randomization for Study 2 that controlled CO₂ levels via prompted breathing. Thus, the comparison to Study 1 with uncontrolled CO₂ responses is technically a historical control comparison.

In conclusion, remifentanil seems to cause regional vasodilation in humans at small and moderate sedative doses without affecting systemic hemodynamic variables or sympathetic outflow. The exact mechanism is unknown but may be caused by a direct effect on the peripheral vascular tissue. This vasodilation may contribute to the occasional hypotension noted with sedative infusions of remifentanil in patients (1–4).

	Acknowledgments

 
Supported in part by VA Merit Review Grant.

	Footnotes

 
¹Ebert TJ, Trotier TS, Guttersen RV, Uhrich TD. Sympathetic and hemodynamic effects of conscious sedation with midazolam and propofol in humans. Anesthesiology 1999;91:A36.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999