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Anesth Analg 2003;96:456-462 © 2003 International Anesthesia Research Society
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Abstract |
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Determining the effects of analgesia on the microcirculation is difficult because the surgery needed to allow in vivo observation often requires anesthesia. In this study, we used the dorsal microcirculatory chamber (DMC) to determine the effects of large (LF) and small (SF) dose IV fentanyl on the microcirculation compared with a conscious control. Male Wistar rats (130 g, n = 5) were implanted with the DMC to enclose a single layer of striated muscle. Animals were allowed 3 wk to recover from surgery and then, over the following 2 wk (1 infusion/wk) using intravital microscopy, the microcirculation was viewed in conscious animals (t = 0–30 min), followed by an induction bolus dose (t = 40–45 min), then a "step-up" maintenance infusion of one of the following, LF (40–90 µg · kg-1 · h-1), SF (10–60 µg · kg-1 · h-1), or saline (5–10 µg · kg-1 · h-1) (t = 45–105 min). Small arterioles (<30 µm) dilated (23.6% ± 7.1%) after induction with LF, but constricted (-21.3% ± 7.1%) with SF (P < 0.05). During maintenance, constriction increased with increasing dose of LF (-21.9% ± 4.0%) and SF (-16.7% ± 9.1%) (t = 105 min, P < 0.05). Similar patterns were observed in all arterioles (10–120 µm) and venules (15–250 µm). We conclude that the DMC provides an excellent technique for observing microcirculatory responses to fentanyl, and in rat skeletal muscle in vivo, an IV infusion of fentanyl produces significant constriction of arterioles.
IMPLICATIONS: Fentanyl is used as a pain killing drug during surgery, but its effects on small blood vessels are uncertain. We implanted chambers into a skin flap in rats to study skeletal muscle microcirculation. Fentanyl caused a decrease in blood vessel diameter that could potentially reduce blood flow to tissues during surgery.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Fentanyl is generally associated with stable hemodynamics (1), but with larger doses, or after prolonged use, hypotension or an alteration in cardiac performance may occur (2,3). Little is known about the effects of fentanyl on the microcirculation. Determining the response of analgesia on the microcirculation is difficult because the surgery needed to allow in vivo observation often requires anesthesia. This may be overcome with the use of the dorsal microcirculatory chamber (DMC), chronically implanted in rats (4,5), which allows observation of the skeletal muscle microcirculation in conscious animals. We have previously used this model to determine the effects of IV anesthesia on skeletal muscle microcirculation compared with a conscious control (6). It is important to determine the effects of analgesics, such as fentanyl, on the peripheral circulation because reduced perfusion of tissues could result in ischemia and tissue damage, which may affect their recovery from surgery.
Fentanyl acts as a µ-opioid (OP3) receptor agonist (7), which is also thought to be present on the vascular endothelium (8). Activation of µ-opioid receptors can inhibit the release of norepinephrine, modulating the effector response to sympathetic nerves, both centrally and peripherally (9,10), which would be expected to result in generalized vasodilation and a decrease in mean arterial blood pressure (MAP). Injection of a selective µ-opioid receptor agonist into the hypothalamus of conscious rats, however, causes MAP to decrease (9,11,12). Fentanyl administered systemically also constricts small cerebral arterioles (approximately 100 µm) and decreases blood flow with larger doses (>25 µg/kg) (13,14). However, the direct effects of systemically administered fentanyl on skeletal muscle microcirculation are unknown and studies measuring changes in blood flow to skeletal muscle after an IV infusion of fentanyl have not reported consistent findings (15–17). Cerebral arterioles constrict and exhibit decreased blood flow with larger doses of IV fentanyl (>25 µg/kg), but with smaller doses, no such changes occur (13). Perhaps, therefore, fentanyl also produces differential effects on skeletal muscle microcirculation in a dose-dependent manner. Our aim was to use intravital microscopy to determine the effects of "large" and "small" dose fentanyl on skeletal muscle microcirculation in vivo compared with a conscious control. This will enable study of the full range of microvascular effects of fentanyl that occur at levels of light analgesia through to sedation and unconsciousness when respiratory depression may occur.
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Materials and Methods |
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Male Wistar rats (n = 5) were obtained from the Sheffield Field Laboratories at the University of Sheffield. Food in the form of a standard pelleted commercial diet (Diet, CRM; Labsure, Poole, UK) and tap water were available ad libitum and animals were exposed to a 12/12-h light/dark cycle. All procedures were performed with Home Office approval, project license number PPL 40/2110.
Rats weighing 130–140 g were anesthetized with 0.1 mL/100 g Hypnorm/diazepam (1:1, Hypnorm [0.315 mg/mL fentanyl citrate, 10 mg/mL fluanisone] [Janssen-Cilag Ltd., High Wycome, Bucks, UK] Diazemuls [10 mg/mL] [Dumex Ltd., Tring, Herts, UK]) administered intraperitoneally. The DMC was then implanted according to methods previously described in detail (4,5) and modified by the authors (6). The DMC consists of two halves of light weight polycarbonate (Carolina Medical Electronics, King, NC), which when implanted into the dorsal skinfold allows sufficient space between to enclose one layer of cutaneous maximus muscle.
Animals weighing 80–90 g commenced daily training in the use of a restraining device for 2 wk before sterile surgery (Weeks 1 and 2). Training times were increased gradually from a few minutes to 2.5 h. This was to ensure that any hemodynamic changes observed in conscious animals were not stress induced. Animals were then allowed 1 wk to recover after surgery (Week 3) before recommencing training for a further 2 wk (Weeks 4 and 5). Therefore, 3 wk after implantation of the DMC (Week 6), animals were entered into the experimental protocol, randomly receiving one of the following: saline (S), large-dose fentanyl (LF), or small-dose fentanyl (SF) over a 2-wk period (Weeks 6–8 when animals weighed 220–320 g). Drugs administered first were: S (n = 2), SF (n = 2), and LF (n = 1). One week was allowed between each drug for "washout" and recovery from analgesia.
The same experimental protocol was adhered to for each study. On each study day, the rat was placed in the restrainer while cannulation of the tail vein was performed. Care was taken not to damage the vein. Fluorescein isothiocyanate-bovine serum albumin 2% (0.25 mL/100 g) was immediately administered via this route. This was followed by a 30-min "preanalgesic" baseline with no infusion (t = 0–30 min, baseline). Fentanyl or S was then administered IV at a steady rate over a 5-min period (t = 40–45 min, induction), followed by 60 min of continuous infusion (t = 45–105 min, maintenance). For each experiment, animals were randomly administered with sterile solutions of one of the following: SF (10 µg/kg IV bolus dose for induction and a 10–60 µg · kg-1 · h-1 step-up continuous IV infusion for maintenance) (5 experiments), LF (30 µg/kg bolus induction, 40–90 µg · kg-1 · h-1 step-up maintenance) (5 experiments), or S (1 mL/kg bolus, 5–10 mL · kg-1 · h-1 infusion) (5 experiments). The infusion rate was increased every 10 min and the dose given in equal "step-up" increments. These doses were based on those previously used in rats by Carlsson et al. (13). For the purposes of our study, however, it was necessary to reduce these doses to allow spontaneous respiration and full recovery of the animals for further experimentation. Animals always received 1 mL/kg fluid during induction and 5–10 mL · kg-1 · h-1 (step-up) during maintenance. The infusion was then discontinued at t = 105 and variables were monitored every 15 min for 60 min to assess recovery from analgesia (t = 105–165 min, recovery).
During maintenance of analgesia that resulted in loss of consciousness (LF), only air containing 30% oxygen was blown into a chamber over the animal (1–2 L/min). The animal was also placed on a warming pad during unconsciousness to maintain body temperature at 36° to 37°C, which was monitored by using an esophageal thermistor probe. Cardiovascular variables were measured noninvasively by using a tail cuff. The cuff was inflated only once at each time point and excessive inflation avoided to prevent damage to the tail vasculature. After the final experiment at Week 8, rats were killed with a lethal dose of IV thiopental.
The animals were placed in the Perspex restrainer fixed to the stage of a modified horizontally mounted Nikon Optiphot microscope, equipped with transmitted light and an excitation broadband pass filter cube (B-2A) that allowed blue fluorescent light (450–490 nm) to be selected and observe the microcirculation (emission 510 nm). The power output of the blue light was consistent between experiments (1.76 mV). The observation window of the DMC protruded through a longitudinal slot and was held in position by an adjustable optical rod, allowing observation of the intravascular space. Images of the preparation were viewed by using fluorescent light (to activate fluorescein isothiocyanate-albumin) and a x10 objective and displayed on a high-resolution monitor (Sony PVM-1443) via a black and white CCD camera (Hitachi KP161, UK).
Before commencing the experimental protocol, 3–5 areas of interest were preselected within the skeletal muscle microcirculation that contained no connective tissue. These areas included A1–A4 arterioles (10–120 µm) and V1–V4 venules (15–250 µm), classified according to their order of branching (18). The areas were then recorded every 10 min for 30 s during exposure to fluorescent light, on VHS videotape (JVC E180-SX) via a video-recorder for later off-line analysis of diameter and macromolecular leak.
Physiological variables were recorded every 15 min during baseline, every 10 min for the duration of the IV maintenance infusion, and every 15 min during recovery. Vessel diameters and macromolecular leak were determined by using computerized image analysis (CapiScope; KK Technology, Devon, UK), and the assessor was blinded to the drug administered. The system was calibrated to produce values in microns and diameter then measured in arterioles and venules from the outside edge of the vessel wall. By using 
2 contingency table analysis in previous studies within our laboratory, we have determined that there is no significant difference between measurements made by two blinded independent assessors (P < 0.05). For the present study, on a 45-µm vessel, we repeated the same diameter measurement 5 times by the assessor and then 5 times with each of 5 inexperienced independent assessors. The percentage increase from the minimal (m) to maximal (M) measurement was then determined (M - m/m x 100), thus giving an indication of the variability of this method. Macromolecular leak from postcapillary venules (V3 and V4, <40 µm) was measured by placing 3 boxes (3 mm2) just outside the vessel wall and determining the mean of the gray levels obtained. Gray levels were determined by using a software package (Capiscope) that assigned an integer value to the brightness of interstitial fluorescence (0 = black, 255 = white). The postcapillary venules are the vessels from which macromolecular leak occurs (19). This provided an indication of vessel integrity after long-term implantation of the DMC and/or after 60 min of anesthesia.
Cardiovascular and microvascular data were presented as mean (±SEM) percentage change from baseline (t = 30 min), because stability of all variables was achieved by this time point. In each group (n = 5, 15 experiments), S and fentanyl, both LF and SF dose, were compared with their preinfusion baseline (t = 30 min) by using a one-way analysis of variance for repeated measures and with conscious controls (5 experiments, S) by using a two-way analysis of variance. Post hoc analysis was performed by using the Students-Newman-Keuls test. Results were considered statistically significant at P < 0.05. A commercially available software package was used to perform the relevant statistical tests, including linear regression and determination of r2 values (Sigmastat 2000).
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Results |
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In control animals (S), cardiovascular variables remained stable, with no changes in heart rate or MAP during the induction, maintenance, or recovery periods (Fig. 1). Microvascular variables were also stable with no change in the diameter of arterioles or venules after induction or maintenance, and there was no increase in macromolecular leak (Figs. 2–4).
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), or saline (
) infusion (t = 45–105 min), followed by recovery (no infusion, t = 105–165 min). *P < 0.05 versus t = 30 min, #P < 0.05 versus control (saline).
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), and small venules (After induction (t = 45 min) and during maintenance (t = 55–105 min), SF animals remained conscious. However, at faster infusion rates, LF animals became unconscious (t = 85–105 min). LF animals regained consciousness almost immediately after cessation of the fentanyl infusion (<5 min).
There was no change in heart rate after induction or maintenance with SF or LF, and there was no significant change from the baseline values of 350 ± 32 (LF) and 365 ± 34 (SF) bpm (t = 30 min) throughout the study. After induction and during maintenance, LF and SF caused a decrease in MAP (P < 0.05) (Fig. 1). In the recovery period, MAP returned to baseline.
The mean (±SEM) diameters of arterioles and venules in micrometers before analgesia (t = 30 min) were as follows: 110 ± 8.5 (A1), 53.3 ± 5.0 (A2), 23.2 ± 2.9 (A3), 11.7 ± 1.4 (A4), 165.5 ± 12.5 (V1), 81.2 ± 8.6 (V2), 36.4 ± 2.3 (V3), and 16.6 ± 1.3 (V4). Data were subsequently presented as a percentage change in "large" arterioles and venules (first and second order) and "small" arterioles and venules (third and fourth order), because the magnitude of responses were similar between these orders of vessels. The percentage of variability of repeated measurement of vessel diameter was 2.3% by the assessor and 4.0% ± 0.7% (n = 5) by the independent assessors.
Large and small arterioles dilated after the induction of LF, by 12.9% ± 5.0% and 23.6% ± 7.7%, respectively (P < 0.05 versus t = 30 min). With SF, however, the larger arterioles demonstrated a small dilation (5.1% ± 1.2%, not significant), whereas the small arterioles constricted (-21.4% ± 7.6%, P < 0.05) (Fig. 2, A and B). During maintenance with LF, constriction of large and small arterioles increased with increasing dose (P < 0.05), whereas with SF, large and small arterioles remained constricted during maintenance (P < 0.05) (Fig. 2, A and B), an effect more marked in the smaller vessels. During the recovery period, the diameters of arterioles tended toward baseline, but were not stable by the end of the study.
The responses in venular diameters essentially followed the same pattern as the arterioles, but were of reduced magnitude. Large and small venules dilated after the induction of LF and constricted during maintenance (P < 0.05) (Fig. 3, A and B). During maintenance with LF, constriction increased with increasing dose (P < 0.05) (Fig. 3, A and B). Diameters of venules tended toward baseline, but were not stable by the end of the recovery period.
During maintenance, the effect of increasing infusion rate for both LF and SF on the diameter of all four vessel groups is shown in Figure 4, A and B,. Linear regression demonstrated a consistent significant decrease in diameter with increasing infusion rate for all vessel types. This was of greater magnitude in the larger-dose study. r2 values were 0.97 and 0.18 in larger arterioles, 0.81 and 0.45 in small arterioles, 0.93 and 0.44 in large venules, and 0.95 and 0.57 in small venules for LF and SF, respectively.
There was no significant macromolecular leak from postcapillary venules after induction or during maintenance of LF or SF (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The DMC model has successfully allowed the effects of fentanyl on the skeletal muscle microcirculation in spontaneously ventilating rats to be determined, and compared with a conscious control. Both LF and SF IV infusions caused a decrease in MAP. Within the microcirculation, however, only the LF resulted in dilation of arterioles and venules. A continuous infusion of both LF and SF caused constriction of arterioles and venules. This constriction was of a large magnitude in arterioles (20%–30%) and much less pronounced in venules (approximately 10%). Thus, it is probably reasonable to conclude that only the arterioles are exhibiting significant constriction. Nevertheless, the accuracy of vessel diameter measurements lies within 2.3% for the assessor, and is only 4% with assessors who used this technique for the first time. It would seem, therefore, that venules also display constriction in response to fentanyl. With LF, constriction of arterioles and venules seemed to be dose-dependent because constriction increased with increasing dose. This was confirmed graphically by the liner relationship we identified between dose and constriction. The degree of change found with the faster rates of infusion in the SF study was also comparable to that found with the slower rates of infusion in the LF study. This is the first study to demonstrate that fentanyl has dose-dependent effects on vessel diameter in the microcirculation of skeletal muscle in vivo.
The decrease in MAP observed in the current study is in agreement with previous studies using large bolus doses of fentanyl (3). This is also consistent with an ability of µ-opioid receptors to cause inhibition of central and peripheral sympathetically mediated responses, which would result in generalized vasodilation (9,10,16). It is perhaps surprising, therefore, that during the continuous infusion of fentanyl, while MAP was decreased, we observed constriction of arterioles and venules in skeletal muscle, particularly because small arterioles in skeletal muscle contribute significantly to peripheral resistance. It is possible that fentanyl exhibits differential effects on the microvasculature of different organs. Indeed, centrally administered µ-opioid receptor agonists induce renal and mesenteric vasoconstriction and at the same time as vasodilation occurs in the hindquarters (9). This raises the possibility that the vasoconstriction observed in skeletal muscle in the current study is a compensatory response to maintain blood pressure when increased perfusion occurs in other organs.
Because surgery is often required to observe the microcirculation, the effects of fentanyl on the skeletal muscle microvascular diameters in vivo have not previously been measured and compared with a conscious control. Pial arterioles have previously been studied using the cranial window preparation, which allows such measurements. In cerebral arterioles (approximately 100 µm), a dose-dependent constriction occurs in response to fentanyl (13,14). Similarly, the maintenance infusion used in our "larger" dose study also seemed to cause dose-dependent arteriolar constriction within skeletal muscle. It is also important to note that the bolus dose in the SF study produced constriction of a magnitude similar to that of the faster infusion rates used in the maintenance phases. Carlsson et al. (13) suggested a direct effect of fentanyl on blood vessels, possibly via µ-opioid receptors. Morphine acts via the µ3 subtype of opioid receptors found on endothelial cells resulting in vasodilation (20), but the possibility of fentanyl interacting with another µ-opioid receptor subtype to cause vasoconstriction has not been studied.
The bolus dose of fentanyl in the LF study produced dilation of the arterioles and venules, which preceded the constriction observed during the maintenance phase. Milde et al. (21) reported a similar biphasic pattern of response to sufentanil in cerebral arterioles. µ-Opioid receptor agonists modulate norepinephrine-induced responses at small concentrations, whereas larger concentrations cause direct contraction of rat aorta (22). In our study, the vasodilation did not seem dose-dependent, because with an increasing maintenance dose of fentanyl, increasing constriction occurred. It is more likely that this is an acute effect of a large dose producing respiratory depression and hypercapnia. Fentanyl causes an increase in PCO2 and hypercapnia results in vasodilation within the microcirculation of skeletal muscle (3,17,23). Increased PCO2 and decreased respiratory rate have been demonstrated after only a 4 µg/kg bolus dose of fentanyl (3). Our smallest bolus dose was 10 µg/kg. Interestingly, we observed the largest dilation in small arterioles, which are most sensitive to changes in local metabolites (23). However, if dilation had occurred because of inhibition of neurotransmitter release from sympathetic nerves, large arterioles would demonstrate the greatest degree of vasodilation, because they receive the greatest sympathetic innervation in skeletal muscle (24), but this was not the case. We have previously determined that the small maintenance dose of fentanyl, administered along with propofol, does not alter systemic pH, PO2, or PCO2 (25). In retrospect, we would have also wished to measure blood gases with the larger dose to provide greater support to our proposal that vasodilation after a large bolus dose of fentanyl results from hypercapnia. This model currently does not allow the continuous measurement of systemic and tissue levels of PCO2.
In conclusion, an IV infusion of fentanyl causes significant constriction of skeletal muscle arterioles, possibly via a direct mechanism. Fentanyl caused vasodilation of arterioles and venules after a large-dose bolus injection.
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Acknowledgments |
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Funded by Trustees of the Former United Hospitals of Sheffield.
We acknowledge funding from trustees of the Former United Sheffield Hospitals. We also thank Helma van Essen and Professor Struijker Boudier, University of Limberg, Maastricht, Netherlands, for their assistance with the DMC technique.
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References |
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