Anesth Analg 2005;101:1677-1680
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000184119.85400.0E
ANESTHETIC PHARMACOLOGY
Section Editor:
James G. Bovill
Vasodilation from Sufentanil in Humans
Thomas J. Ebert, MD, PhD,
David J. Ficke, BS,
Shahbaz R. Arain, MD,
Melissa N. Holtz, BS, and
Hariharan Shankar, MD
Department of Anesthesiology, Medical College of Wisconsin and VA Medical Center, Milwaukee, Wisconsin
Address correspondence to Thomas J Ebert, MD, PhD, VA Medical Center/CC-112A, 5000 West National Ave, Milwaukee, WI 53295. Address e-mail to tjebert{at}mcw.edu.
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Abstract
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Sufentanil is a potent opioid that occasionally has been associated with hypotension. The mechanism behind this hypotension is unclear. We hypothesized that sufentanil had a direct effect on vascular smooth muscle to cause vasodilation. Sufentanil was infused into the brachial artery of 10 young, healthy volunteers at rates of 0.083, 0.167, 0.333, and 0.833 µg/min. Forearm blood flow was measured in both the experimental and control arms with venous occlusion plethysmography. The forearm blood flow in the infused arm increased in a dose-dependent fashion from 3.2 to 5.2 mL/min per 100 mL of tissue whereas simultaneous measurements in the control (non-infused) arm did not increase. Heart rate and mean arterial blood pressure were unchanged during the infusions. Furthermore, respiratory rate did not change at any infusion level and sedation did not occur. Thus, the data support that significant systemic "spillover" of sufentanil did not occur. We conclude that sufentanil has a direct, vasodilatory effect on human vascular tissue that is likely independent of a neurogenic or systemic mechanism.
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Introduction
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Sufentanil is the most potent synthetic opioid in clinical use today, which mandates that it be carefully titrated to prevent respiratory depression and chest wall rigidity. The administration of sufentanil has been associated with unpredictable cardiovascular depression, including bradycardia and hypotension (1–3). Unlike the respiratory effects of sufentanil, the hypotension has been particularly difficult to characterize because it does not appear to be dose-dependent (4).
The mechanism causing the hypotension is probably not related to histamine release (5,6). However, sufentanil may affect the autonomic nervous system. For example, opioids have been shown to enhance vagal tone and diminish sympathetic outflow (7–9), which may contribute to hypotension. O'Keefe et al. (10) found that sufentanil caused peripheral vasodilation in anesthetized dogs and concluded that a neurogenic mechanism was involved.
In addition to autonomic imbalances contributing to hypotension from sufentanil, directly mediated vascular smooth muscle relaxation has been proposed based upon findings in a canine model (11). Moreover, we have noted a direct effect of another synthetic opioid, remifentanil, that resulted in vasodilation in the human forearm (12). The current study explored the vascular action that resulted from the infusion of increasing doses of sufentanil directly into the brachial artery of humans. This technique permits establishing clinically relevant concentrations of sufentanil in a regional vascular bed without significantly altering systemic levels.
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Methods
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After approval by the Human Research Review Committee, written informed consent was obtained from 10 volunteers. A 20-gauge catheter was placed in the brachial artery of the non-dominant arm for drug infusion and for arterial blood pressure monitoring. Other monitors included heart rate (HR) via surface electrocardiogram, end-tidal carbon dioxide (ETco2), respiration rate (RR, breaths/min) via nasal cannula, and pulse oximetry. Simultaneous determinations of forearm blood flow (FBF) were made by venous occlusion plethysmography in both arms. The underlying principle of venous occlusion plethysmography is that if venous return from the arm is obstructed and arterial inflow continues unimpeded, the forearm expands at a rate proportional to the rate of arterial inflow (13). In the supine position the elbows were slightly flexed and supported underneath and at the wrists to be above heart level to ensure adequate venous drainage between measurements. Inflatable blood pressure cuffs were placed about the wrists and upper arms and a double-stranded, mercury-in-Silastic, temperature-compensated strain gauge (DE Hokanson, Issaquah, WA) was placed around each forearm at its largest girth. The wrist cuffs were manually inflated to 200 mm Hg to exclude hand circulation. Forearm blood flow was measured over 90 s by calculating the rate of the increase in forearm volume during intermittent (8 s on, 8 s off) inflations of the arm cuffs to 50 mm Hg. Consecutive inflation tracings were averaged for each 90-s period. Forearm vascular resistance was calculated by dividing mean arterial blood pressure (MAP) by FBF (14). By infusing small doses of drug into one arm and comparing the vascular response to the noninfusion (control) arm, the direct effects of sufentanil could be monitored while the systemic effects were negligible.
After baseline measurements were taken, sufentanil (Abbott Laboratories, North Chicago, IL) was infused at rates of 0.083, 0.167, 0.333, and 0.833 µg/min into the experimental arm. Total external flow into the forearm was maintained at 50 mL/h, with saline adjusted downward as the sufentanil concentrations were increased. After 5 min of infusion at each dose, hemodynamic data were recorded and simultaneous FBF measurements were taken in each arm. The patient was then asked to report any feelings of relaxation, drowsiness, or nausea. Effluent venous blood samples from the experimental arm were taken from three subjects to determine forearm plasma sufentanil concentrations. All blood samples were obtained at steady state, collected in EGTA tubes, and spun at 0°C for 10 min. The plasma was removed and stored at –70°C until later analysis by a core biochemical laboratory using high-performance liquid chromatography.
Consecutive measurements were compared over time (increasing doses) and between arms (control versus infusion arm) with repeated measures analysis of variance (each variable separately). Post hoc analysis was done using Scheffé's test. A value of P < 0.05 was considered significant.
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Results
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All subjects were young (18–28 yr) and healthy with an ASA physical status 1. There were no significant changes in HR, MAP, RR, or ETco2 throughout the course of the study (Fig. 1). FBF increased progressively and significantly in the infused arm with a maximal change from baseline of 63.6% ± 15% compared with no significant change in the control (noninfused) arm. Figure 2 shows the FBF for the infusion arm and the control arm, as well as a ratio between the two. There were significant increases in the FBF ratio with each infusion dose. The infusion doses chosen for this study established regional concentrations of sufentanil of 1.02, 2.27, 4.50, and 8.03 ng/mL in the subset of 3 subjects selected for these measurements.
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Figure 1. Hemodynamic responses to increasing, local, intraarterial doses of sufentanil. This technique minimizes systemic effects, and indeed, there were no significant changes in heart rate (HR), mean arterial blood pressure (MAP), respiratory rate (RR), or end-tidal carbon dioxide (ETco2).
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Figure 2. Changes in forearm blood flow (FBF) with increasing, local, intraarterial doses of sufentanil. The upper panel shows the absolute blood flow from the control and infused arms. There is a significant, dose-dependent increase in FBF in the infused arm and no significant change in the control (noninfused) arm (P < 0.05). Repeated measures analysis of variance confirmed significance (P < 0.05) between arms ( ), over time (*), and of the interaction term. The lower panel shows the ratio of the response of FBF in the infused arm divided by the response in the control arm. There were significant dose effects.
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Discussion
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The purpose of this study was to determine whether the hypotension often associated with the use of sufentanil could be caused, in part, by a direct vascular effect (1–3). The data suggest a potent direct effect of sufentanil that causes forearm vascular dilation, resulting in increases in FBF. This finding is not without precedent. The same technique was used in our laboratory to show a similar direct effect of remifentanil on forearm vascular tone (12), suggesting that we have identified a class effect for µ-opioid agonists in clinical use.
The study design for this research used a standard technique of microinfusions of vasoactive drug into the brachial artery of volunteers (13,14). This model permitted the attainment of regional concentrations of sufentanil that were clinically relevant (1–8 ng/mL) and similar to those seen with systemic infusions. For example, a 1.5- or 5-µg/kg bolus of sufentanil results in a peak plasma concentration of 
4 or 40 ng/mL, respectively (15,16), and during cardiac surgery, prebypass concentrations from targeted infusions ranged from 1.7 to 3.3 ng/mL (17). In the present research, the local infusions appeared to be without systemic and secondary autonomic effects. Had these occurred, the noninfused, control arm might have shown vasodilation, but none was noted. The absence of slowing of RR and increases in the ETco2 lends further support for lack of a significant systemic effect of opioid spillover from the infused arm. Might the observed vasodilation from sufentanil be from sympathetic withdrawal to the forearm? This could have occurred if venous outflow from the perfused forearm resulted in systemic concentrations that acted centrally in the central nervous system (brain or spinal cord). However, centrally mediated sympathetic inhibition should have resulted in effects in both arms, which was not the case. Taken together, these observations suggest a local direct effect of sufentanil rather than a centrally mediated sympathoinhibition.
The literature is remarkably unclear as to the mechanism of the vasodilation response to opioids, particularly sufentanil. O'Keefe et al. (10) used an isolated limb technique in a canine model to demonstrate vasodilation from sufentanil but noted that the effect could be abolished by denervation of the limb. However, in a more recent study using a similar model, White et al. (11) found that denervation did nothing to reduce the vasodilation to sufentanil and that the mechanism was probably direct in nature. White et al. theorized that the difference between studies was attributable to a difference in the way the legs of the dogs were perfused; constant pressure by O'Keefe et al. versus constant flow by White et al. Indeed, this study, which was more similar to a constant flow protocol than a constant pressure protocol, agrees with the work of White et al., suggesting that sufentanil results in directly mediated vascular relaxation.
In clinical use, it is unlikely that sufentanil, or any other opioid, would be the sole cause of hypotension. It appears that combining opioids with benzodiazepines is more commonly associated with hypotension (18–20). However, this study provides evidence of a direct vasodilation in response to administration of opioids, and this response almost certainly plays a role in the genesis of the hypotension. The exact receptor or vascular mechanism causing the vasodilation is still unclear and warrants further study. Several investigations have excluded histamine release as a mechanism (5,6). Others have considered peripheral µ-receptor activation as a mechanism, although this appears questionable, as White et al. showed that pretreatment with naloxone (a µ-antagonist) did not attenuate the vasodilation from sufentanil or fentanyl in dogs (11). Other possible mechanisms might involve endothelial actions that enhance nitric oxide production or presynaptic modulation of transmitter release from sympathetic terminals.
The limitations of this study were that only moderate doses of sufentanil were infused in young, healthy individuals to avoid the systemic effects of larger doses that may have mandated airway control and complicated interpretation of the data. However, as the forearm venous effluent blood samples indicate, the chosen brachial artery infusion doses of sufentanil were sufficient to achieve clinically relevant local concentrations. Manifestation of greater vasodilation in patients with other complicating pathological factors or vasodilation leading to significant hypotension in patients with a reduced intravascular volume status might be observed in the clinical setting. The study was underpowered to adequately define the observed effects as a dose-related vasodilation.
In conclusion, there was a direct, local vasodilation in response to sufentanil. This vasodilation likely contributes to the infrequent but often profound hypotension noted with systemic administration of both small and larger doses of sufentanil in patients.
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Footnotes
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Supported, in part, by the Zablocki VAMC, Milwaukee and a VA Merit Award.
Accepted for publication June 21, 2005.
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References
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- West JM, Estrada S, Heerdt M. Sudden hypotension associated with midazolam and sufentanil. Anesth Analg 1987;66:693–4.
- Spiess BD, Sathoff RH, El-Ganzouri ARS, et al. High-dose sufentanil: four cases of sudden hypotension on induction. Anesth Analg 1986;65:703–5.[Free Full Text]
- Starr NJ, Sethna DH, Estafanous FG. Bradycardia and asystole following the rapid administration of sufentanil with vecuronium. Anesthesiology 1986;64:521–3.[ISI][Medline]
- Sareen J, Hudson RJ, Rosenbloom M, et al. Dose-response to anaesthetic induction with sufentanil: haemodynamic and electroencephalographic effects. Can J Anaesth 1997;44:19–25.[Abstract/Free Full Text]
- Flacke JW, Flacke WE, Bloor BC, et al. Histamine release by four narcotics: a double-blind study in humans. Anesth Analg 1987;66:723–30.[Abstract/Free Full Text]
- Rosow CE, Philbin DM, Keegan CR, et al. Hemodynamics and histamine release during induction with sufentanil or fentanyl. Anesthesiology 1984;60:489–91.[ISI][Medline]
- Reitan JA, Stengert KB, Wymore ML, et al. Central vagal control of fentanyl-induced bradycardia during halothane anesthesia. Anesth Analg 1978;57:31–6.[Abstract/Free Full Text]
- Flacke JW, Davis LJ, Flacke WE, et al. Effects of fentanyl and diazepam in dogs deprived of autonomic tone. Anesth Analg 1985;64:1053–9.[Abstract/Free Full Text]
- Laubie M, Schmitt H, Drouillat M. Central sites and mechanisms of the hypotensive and bradycardic effects of the narcotic analgesic agent fentanyl. Arch Pharmacol 1977;296:255–61.
- O'Keefe RJ, Domalik-Wawrzynski L, Guerrero JL, et al. Local and neurally mediated effects of sufentanil on canine muscle vascular resistance. J Pharmacol Exp Ther 1987;242:699–706.[Abstract/Free Full Text]
- White DA, Reitan JA, Kien ND, et al. Decrease in vascular resistance in the isolated canine hindlimb after graded doses of alfentanil, fentanyl, and sufentanil. Anesth Analg 1990;71:29–34.[Abstract/Free Full Text]
- Noseir RK, Ficke DJ, Kundu A, et al. Sympathetic and vascular consequences from remifentanil in humans. Anesth Analg 2003;96:1645–50.[Abstract/Free Full Text]
- Benjamin N, Calver A, Collier J, et al. Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension 1995;25:918–23.[Abstract/Free Full Text]
- Robinson BJ, Ebert TJ, O'Brien TJ et al. Mechanisms whereby propofol mediates peripheral vasodilation in humans. Anesthesiology 1997;86:64–72.[ISI][Medline]
- Weldon ST, Perry DF, Cork RC, et al. Detection of picogram levels of sufentanil by capillary gas chromatography. Anesthesiology 1985;63:684–7.[ISI][Medline]
- Bovill JG, Sebel PS, Blackburn CL, et al. The pharmacokinetics of sufentanil in surgical patients. Anesthesiology 1984;61:502–6.[ISI][Medline]
- Thomson IR, Moon M, Hudson RJ, et al. Does sufentanil concentration influence isoflurane requirements during coronary artery bypass grafting? J Cardiothorac Vasc Anesth 1999;13:9–14.[ISI][Medline]
- Liu WS, Bidwal AV, Lunn JK, et al. Urine catecholamine excretion after large doses of fentanyl, fentanyl and diazepam and fentanyl, diazepam and pancuronium. Can Anaesth Soc J 1977;24:371–9.[ISI][Medline]
- Tomicheck RC, Rosow CE, Philbin DM, et al. Diazepam-fentanyl interaction: hemodynamic and hormonal effects in coronary artery surgery. Anesth Analg 1983;62:881–4.[Abstract/Free Full Text]
- Stanley TH, Berman L, Green O, et al. Plasma catecholamine and cortisol responses to fentanyl-oxygen anesthesia for coronary-artery operations. Anesthesiology 1980;53:250–3.[ISI][Medline]
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Abstract
Introduction
