Free
Clinical Science  |   October 1997
Alfentanil Blocks Reflex Pupillary Dilation in Response to Noxious Stimulation But Does Not Diminish the Light Reflex 
Author Notes
  • (Larson) Professor, Department of Anesthesia, University of California, San Francisco.
  • (Kurz) Assistant Professor, Department of Anesthesia, University of California, San Francisco; Attending Anesthesiologist, Associate Director Outcomes Research, Department of Anesthesia and Intensive Care, University of Vienna.
  • (Sessler) Professor of Anesthesia, Department of Anesthesia, University of California, San Francisco; Professor and Vice-Chair, Director Outcomes Research, Department of Anesthesia and Intensive Care, University of Vienna.
  • (Dechert) Staff Research Associate, Department of Anesthesia, University of California, San Francisco.
  • (Bjorksten) Research Scientist, Department of Anaesthesia, Royal Melbourne Hospital, Parkville, Victoria, Australia.
  • (Tayefeh) Research Fellow, Department of Anesthesia, University of California, San Francisco.
  • Received from the Department of Anesthesia, University of California, San Francisco, California; the Outcomes Research Laboratory, Department of Anesthesia and Intensive Care, University of Vienna, Vienna, Austria; and the Department of Anaesthesia, Royal Melbourne Hospital, Parkville, Victoria, Australia. Submitted for publication November 1, 1996. Accepted for publication June 13, 1997. Supported by Fairville Medical Optics, Inc., Amersham, UK; National Institutes of Health grant GM49670; and the Max Kade (New York, New York) Joseph Drown (Los Angeles, California), and Erwin-Schrodinger (Vienna, Austria) Foundations. Mallinckrodt Anesthesiology Products (St. Louis, Missouri) donated the thermocouples. Datex Medical Instruments (Tewksbury, Massachusetts) loaned us a Capnomac Ultima. The authors do not consult for, accept honoraria from, or own stock or stock options in any anesthesia-related company.
  • Address correspondence to Dr. Larson: Department of Anesthesia, University of California, 521 Parnassus Avenue, Room C450, Box 0648, San Francisco, CA 94143–0648. Reprints will not be available.
Article Information
Clinical Science
Clinical Science   |   October 1997
Alfentanil Blocks Reflex Pupillary Dilation in Response to Noxious Stimulation But Does Not Diminish the Light Reflex 
Anesthesiology 10 1997, Vol.87, 849-855. doi:
Anesthesiology 10 1997, Vol.87, 849-855. doi:
Surgical trauma produces well-defined hormonal and metabolic responses, primarily by activating midbrain and hypothalamic centers that control autonomic function. [1 ] Based on Crile's original theories, [2 ] an anesthetic is incomplete unless it contains both hypnotic and analgesic components that are designed to limit this stress response. Although volatile anesthetics often fail to eliminate the stress response to surgery, [3 ] it can be markedly attenuated by supplements including epidural analgesia and intravenous opioids. [1,4,5 ]
Measuring the efficacy of these analgesic supplements in anesthetized and paralyzed patients is often imprecise. Analgesia may be inferred when the hemodynamic response to surgery is attenuated. However, circulatory responses can be altered by a host of unrelated factors, including vasoactive drugs, beta-adrenergic blockade, [6 ] and vascular volume shifts.
We recently showed that pupillary dilation in response to noxious stimulation during anesthesia is not a spinal sympathetic reflex. [7 ] Pupillary dilation after stimulation implies activity of central pathways as high as the rostral mesencephalon, where the pupilloconstrictor nucleus is located. [8 ] This dilation is not depressed by beta-adrenergic blockade or by high concentrations of volatile anesthetics. [9 ] In contrast, epidural analgesia, which fails to fully block somatosensory-evoked potentials, [10 ] obliterates reflex dilation of the pupil during isoflurane anesthesia. [11 ]
Thus we wondered whether another analgesic, alfentanil, would also attenuate pupillary reflex dilation during isoflurane anesthesia. We also wanted to determine how well attenuation of the pupillary responses to noxious stimulation would compare with the attenuation of hemodynamic responses. Our hypothesis was that alfentanil would attenuate reflex dilation in a dose-dependent manner and correlate better with opioid effect than heart rate and blood pressure. Volatile anesthetics depress the light reflex. [12 ] However, the effect of opioids on the human pupillary light reflex during anesthesia has been curiously unexplored. Therefore, we simultaneously measured the effect of alfentanil on the small residual light reflex that remained during isoflurane anesthesia.
Methods 
With approval of the University of California, San Francisco, Committee on Human Research and written informed consent, we studied six male volunteers. Their age was 28 +/- 6 (mean +/- SD) yr; weight was 70 +/- 9 kg, and height was 177 +/- 7 cm. All were young, healthy, free of eye disease, and taking no medications.
Treatment Protocol 
Six volunteers each participated on four different study days, separated by at least 48 h. On each occasion, anesthesia was induced with propofol (2 mg/ml) and maintained with isoflurane via a laryngeal mask. After a separate thermoregulatory study lasting 4 +/- 1 h, [13 ] vecuronium bromide was administered, and the trachea was intubated. The end-tidal isoflurane concentration was adjusted to 0.8% and ventilation was controlled to maintain end-tidal partial pressure of carbon dioxide (PCO2) at 35–40 mmHg.
After at least 15 min, a blinded computer-controlled infusion of alfentanil or saline placebo was started to randomly assigned target plasma concentrations of 0, 25, 50, or 100 ng/ml. Alfentanil was administered using a computer-controlled syringe pump (Ohmeda 9000; Ohmeda, Steeton, UK). The infusion profile was based on plasma efflux, with coefficients estimated from published pharmacokinetic data. [14 ] A targeted alfentanil infusion lasting 15 min should exceed by several minutes the time for equilibration between plasma and site-effect concentrations. [15 ]
After at least 15 min of drug or saline infusion, a 60- to 70-MA, 100-Hz, 5-s noxious electrical stimulus (Digistim 2, NeuroTechnology, Houston, TX) was administered to the T-9 dermatome via steel needle electrodes. Venous samples to determine total plasma alfentanil concentration were obtained before the infusion was started and before and 8 min after administration of the tetanic stimulus. Plasma samples were stored at -20 [degree sign] Celsius until analysis.
Measurements 
Routine anesthetic monitors were used in all cases. Oscillometric blood pressure and heart rate were evaluated before and every minute after stimulation using a Dinamap 1846 SX (Critikon, Tampa, FL). End-tidal gas concentrations were determined using a Capnomac II (Datex Medical Instrumentation, Tewksbury, MA). Core temperature was measured in the distal esophagus (Mon-a-Therm, Mallinckrodt, St. Louis, MO).
Pupil size, light reflex, and reflex dilation were measured using a portable infrared pupillometer (Fairville Medical Optics, Amersham, UK). [9,11,12 ] This device displays the pupil on a liquid crystal display as a void in the center of an area of infrared light reflected from the iris. At the release of a button, the infrared scan begins with a flash of visible light (130 candelas/m2). Individual pupillary diameters during anesthesia can vary as much as 0.2 mm, presumably because of noise within the pupillometer system or hand movement. [16 ] When two or three scans are averaged, as is usual, the light reflex can be measured to within 0.05 mm, which is the resolution of the instrument. The pupillometer we used was controlled by an external laptop computer. A newer version integrates all required electronics into the hand-piece of the instrument.
For the current study, we measured pupil size and light reflex amplitude before the start of the alfentanil infusion and then immediately before, during (elapsed time zero), and 0.25, 0.5, 1, 2, 2.5, 4, and 8 min after noxious stimulation. We covered the measured right eye with a rubber cup to exclude ambient light and taped the left eye closed. Scans lasted 2 s, and the light stimulus was 0.2 s. Except for the scan taken at elapsed time zero, we recorded two or three scans and used the averaged scan for each measurement.
For each alfentanil infusion rate, we compared maximum constriction velocity and light reflex amplitude for the averaged scans before the infusion was started, with the averaged scan taken just before the noxious stimulus. We also measured the difference between the starting diameter and the final diameter 2 s after the start of the stimulus (Figure 1). This difference was taken as a measure of the early dilation (dilation at 2 s) of the pupil at each alfentanil plasma concentration.
Figure 1. The light reflex is defined by the difference between the initial diameter and the minimum diameter after a short light stimulus. Maximum constriction velocity is the maximum speed (measured in millimeters per second) attained during the constriction phase of the light reflex. Reflex dilation is the difference between the initial diameter and the diameter at the end of a 2-s scan. The data shown are the mean scans taken before and after alfentanil administration (25 ng/ml). See Table 1for the statistical analysis.
Figure 1. The light reflex is defined by the difference between the initial diameter and the minimum diameter after a short light stimulus. Maximum constriction velocity is the maximum speed (measured in millimeters per second) attained during the constriction phase of the light reflex. Reflex dilation is the difference between the initial diameter and the diameter at the end of a 2-s scan. The data shown are the mean scans taken before and after alfentanil administration (25 ng/ml). See Table 1for the statistical analysis.
Figure 1. The light reflex is defined by the difference between the initial diameter and the minimum diameter after a short light stimulus. Maximum constriction velocity is the maximum speed (measured in millimeters per second) attained during the constriction phase of the light reflex. Reflex dilation is the difference between the initial diameter and the diameter at the end of a 2-s scan. The data shown are the mean scans taken before and after alfentanil administration (25 ng/ml). See Table 1for the statistical analysis.
×
Table 1. Pupillary Size, Blood Pressure, and Heart Rate After Stimulation at Each Alfentanil Concentration 
Image not available
Table 1. Pupillary Size, Blood Pressure, and Heart Rate After Stimulation at Each Alfentanil Concentration 
×
Total plasma alfentanil concentrations were determined by high-performance liquid chromatography, using a modification of a previously described technique. This assay is linear to at least 10,000 ng/ml, with a detection limit of 2 ng/ml, and within-day coefficient of variation of 4.1%(n = 6) at 250 ng/ml. [17 ]
Statistical Analysis 
Alfentanil concentrations, core temperatures, isoflurane concentrations, pupillary measures (light reflex amplitude, constriction velocity, and dilation in the first 2 s), heart rates, and systolic blood pressures at each alfentanil target concentration were compared using repeated-measures analysis of variance and Scheffe's F tests.
Maximum poststimulus values of heart rate, systolic blood pressure, pupillary light reflex, and pupil size were compared with the prestimulus values using two-tailed, paired t tests. As suggested by Matthews et al., [18 ] statistical analysis was restricted to curve descriptors.
Based on inspection of the data, the relation between plasma alfentanil concentration and stimulus-evoked change in pupillary size was fit to an exponential equation. Results are presented as mean +/- SD; P < 0.05 was considered significant.
Results 
According to the protocol, plasma alfentanil concentrations at the time of stimulation on each of the study days differed significantly but were near the target concentrations (Table 1). Typical responses are illustrated in Figure 1. Alfentanil concentrations did not change significantly in the 8 min after stimulation. Alfentanil infusion did not alter prestimulus pupil size (Table 1and Table 2).
Table 2. The Pupillary Light Reflex and Early Dilation at Each Alfentanil Concentration 
Image not available
Table 2. The Pupillary Light Reflex and Early Dilation at Each Alfentanil Concentration 
×
Alfentanil impaired reflex pupillary dilation, decreasing the response amplitude from 5 mm at 0 ng/ml, to 2.3 mm at 25 ng/ml, to 1.0 mm at 50 ng/ml, and finally to 0.2 mg at 100 ng/ml (Figure 2). The relation between plasma alfentanil and the poststimulus change in pupil size measured in millimeters was exponentially related to total plasma alfentanil concentration in nanograms per milliliter: size = 4 [center dot] e sup -0.0327[Alfentanil], r2= 0.78. Pupillary dilation thus was 50% inhibited at a plasma alfentanil concentration of only about 20 ng/ml. In contrast, the correlation between plasma alfentanil concentration and the change in heart rate or systolic blood pressure was relatively poor (Figure 3). Alfentanil administration also markedly reduced the time required for pupil size to return to baseline values. For example, a plasma alfentanil concentration of 25 ng/ml decreased recovery time from 7.6 min to 2.3 min (Table 1).
Figure 2. Alfentanil infusion did not alter prestimulus pupil size but produced a substantial and dose-dependent inhibition of stimulus-induced pupillary dilation, with dilation nearly obliterated at the 100 ng/ml target concentration. The background anesthetic was 0.8% isoflurane. Results are presented as mean +/- SD. See Table 1for statistical analysis and measured alfentanil concentrations at each target concentration.
Figure 2. Alfentanil infusion did not alter prestimulus pupil size but produced a substantial and dose-dependent inhibition of stimulus-induced pupillary dilation, with dilation nearly obliterated at the 100 ng/ml target concentration. The background anesthetic was 0.8% isoflurane. Results are presented as mean +/- SD. See Table 1for statistical analysis and measured alfentanil concentrations at each target concentration.
Figure 2. Alfentanil infusion did not alter prestimulus pupil size but produced a substantial and dose-dependent inhibition of stimulus-induced pupillary dilation, with dilation nearly obliterated at the 100 ng/ml target concentration. The background anesthetic was 0.8% isoflurane. Results are presented as mean +/- SD. See Table 1for statistical analysis and measured alfentanil concentrations at each target concentration.
×
Figure 3. The relation between plasma alfentanil and the post-stimulus change in pupil size in millimeters was exponentially related to plasma alfentanil concentration expressed as nanograms per milliliter: size = 4 [center dot] e sup -0.0327[Alfentanil], r2= 0.78. Pupillary dilation was thus 50% inhibited at a total plasma alfentanil concentration of about 20 ng/ml. There was a poor relation between alfentanil concentration and the increase in heart rate (DeltaHR): DeltaHR = 10 [center dot] e sup -0.0213[Alfentanil], r2= 0.39. The relation between alfentanil concentration and the increase in systolic blood pressure (DeltaBP) was even worse: DeltaBP = 10 [center dot] e sup -0.0081[Alfentanil], r2= 0.05.
Figure 3. The relation between plasma alfentanil and the post-stimulus change in pupil size in millimeters was exponentially related to plasma alfentanil concentration expressed as nanograms per milliliter: size = 4 [center dot] e sup -0.0327[Alfentanil], r2= 0.78. Pupillary dilation was thus 50% inhibited at a total plasma alfentanil concentration of about 20 ng/ml. There was a poor relation between alfentanil concentration and the increase in heart rate (DeltaHR): DeltaHR = 10 [center dot] e sup -0.0213[Alfentanil], r2= 0.39. The relation between alfentanil concentration and the increase in systolic blood pressure (DeltaBP) was even worse: DeltaBP = 10 [center dot] e sup -0.0081[Alfentanil], r2= 0.05.
Figure 3. The relation between plasma alfentanil and the post-stimulus change in pupil size in millimeters was exponentially related to plasma alfentanil concentration expressed as nanograms per milliliter: size = 4 [center dot] e sup -0.0327[Alfentanil], r2= 0.78. Pupillary dilation was thus 50% inhibited at a total plasma alfentanil concentration of about 20 ng/ml. There was a poor relation between alfentanil concentration and the increase in heart rate (DeltaHR): DeltaHR = 10 [center dot] e sup -0.0213[Alfentanil], r2= 0.39. The relation between alfentanil concentration and the increase in systolic blood pressure (DeltaBP) was even worse: DeltaBP = 10 [center dot] e sup -0.0081[Alfentanil], r2= 0.05.
×
Dilation of the pupil during the first 2 s of noxious electrical stimulation was only slightly decreased, even by the highest alfentanil concentration. Light reflex amplitude and maximum constriction velocity were not significantly altered at any alfentanil concentration (Table 2, Figure 4). Power analysis indicated that we had a greater than 80% chance of detecting a difference in the light reflex of 0.05 mm and in the maximum constriction velocity of 0.25 mm/s.
Figure 4. Pupillary light reflex before and after alfentanil. The superimposed scans are averages showing the size of the pupil after a 0.2-s light stimulus. The target alfentanil concentration was 100 ng/ml, and the background anesthetic was 0.8% isoflurane. See Table 2for statistical comparisons of the light reflex at different alfentanil concentrations.
Figure 4. Pupillary light reflex before and after alfentanil. The superimposed scans are averages showing the size of the pupil after a 0.2-s light stimulus. The target alfentanil concentration was 100 ng/ml, and the background anesthetic was 0.8% isoflurane. See Table 2for statistical comparisons of the light reflex at different alfentanil concentrations.
Figure 4. Pupillary light reflex before and after alfentanil. The superimposed scans are averages showing the size of the pupil after a 0.2-s light stimulus. The target alfentanil concentration was 100 ng/ml, and the background anesthetic was 0.8% isoflurane. See Table 2for statistical comparisons of the light reflex at different alfentanil concentrations.
×
Discussion 
Volatile and intravenous anesthetics are often combined with opioids because it is widely appreciated that synergy between these drug classes permits administration of lower doses of each, and consequently reduced overall toxicity. Often a standard dose of each drug is given, and adjustments are made in reaction to hemodynamic changes that occur during the operation. One difficulty with this approach, however, is that variability in individual responsiveness may result in excessive or inadequate administration of either drug type. Thus we sought a more precise measure of opioid effect during isoflurane anesthesia.
Alfentanil produced a substantial dose-dependent depression of pupillary dilation after a noxious stimulus: dilation was reduced to 50% of control values at alfentanil concentrations near 20 ng/ml, and was nearly abolished at concentrations approaching 100 ng/ml. Although we could not directly measure pain in these anesthetized, paralyzed volunteers, opioids produce analgesia and there was a good correlation between plasma alfentanil concentration and magnitude of reflex dilation. Pupillary dilation correlated better with alfentanil concentration than with increases in either systolic blood pressure or heart rate. Our data thus suggest that pupillary dilation can be used to assess the effect of active micro opioids. This measure may be especially useful when newer opioids with short plasma half-lives are used.
Our finding that alfentanil had no effect on the light reflex, but essentially blocked reflex dilation, was unexpected. In unanesthetized persons, Pickworth et al. [19,20 ] showed that buprenorphine, morphine, heroin, codeine, oxycodone, and hydrocodone all depressed both the magnitude of the light reflex and maximum constriction velocity. The studies of Pickworth et al. were confounded by simultaneous drug-induced changes in pupillary size. Pupillary constriction reduces the mechanical range available for iris movement. [21 ] Further, the optical stimulus for constriction is reduced because retinal light flux decreases as the pupil becomes mitotic. Our study, in contrast, was performed in anesthetized persons whose pupils were consistently mitotic and did not change size after opioid administration. Under these circumstances, the pupillary light reflex was well maintained after alfentanil administration. Our findings are consistent with a previous study that found no effect of bolus injections of fentanyl on the light reflex during the stable miosis of desflurane anesthesia. [22 ]
We targeted alfentanil concentrations known to have respiratory and analgesic effects. Substantial respiratory depression is produced by alfentanil concentration of only 108 ng/ml, and 100 ng/ml provides adequate postoperative analgesia for most patients. [23,24 ] Alfentanil at these concentrations also has significant effects during isoflurane anesthesia. An alfentanil concentration of only 29 ng/ml reduces the minimum alveolar concentration (MAC) of isoflurane by 50%; 100 ng/ml reduces this value by approximately 70%. [25 ] The volunteers who received our largest alfentanil dose (100 ng/ml) were also receiving 0.8% isoflurane. This end-tidal concentration, combined with 100 ng/ml alfentanil, is reported to be approximately twice that concentration required to prevent movement in 50% of patients after a painful stimulus (2 MAC). [25 ] That we failed to detect opioid-induced depression of the light reflex, even with a sensitive electronic pupillometer, suggests that the light reflex is well preserved at typical clinical doses of alfentanil.
The effects of alfentanil and the volatile anesthetics on pupillary reflexes thus differ significantly. For example, increasing end-tidal isoflurane concentration from 0.7 MAC to 1.0 MAC decreases the light reflex by about 50% without any significant change in pupil size. [9 ] Although there is considerable interindividual variability in the magnitude of the light reflex at any given end-tidal concentration, [9,12,26 ] regression analysis indicates that the light reflex is usually absent at concentrations exceeding 1.5 MAC. [12 ] Reflex dilation, in contrast, is not diminished as isoflurane concentration is increased from 0.7 MAC to 1.0 MAC [9 ] or desflurane is increased from 0.6 MAC to 1.1 MAC. [7 ] Presumably a higher concentration could be attained in which all transmission through the spinal cord would fail, but such concentrations would rarely be required in clinical practice.
We tested only a single background isoflurane concentration (0.8%). Although we have previously shown that the pupillary response to noxious stimulation is similar at 0.8% and 1.2% end-tidal isoflurane, [9 ] it is not known what effect other isoflurane concentrations might have on opioid-induced depression of reflex dilation. It is likely that alfentanil will prove less effective in reducing reflex dilation at lower isoflurane concentrations. We also studied only young men. The elderly are more sensitive to opioids, [27 ] and women respond somewhat differently than men do to certain opioid agonists. [28 ] Reflex pupillary dilation might, therefore, be abolished at different alfentanil concentrations in the elderly or in women. We also anticipate that persons who are tolerant to opioids would be resistant to suppression of reflex dilation by opioid agonists. Our study followed a separate thermoregulatory study during which isoflurane was administered for about 4 h and core temperatures were manipulated. [13 ] Although it seems unlikely, results may differ in persons given shorter anesthetics.
Opioids produce a dose-dependent attenuation of reflex dilation in response to noxious stimulation. In contrast, the pupillary light reflex is unaffected by alfentanil during isoflurane anesthesia. These data suggest that stimulus-induced pupillary dilation may be used to evaluate the analgesic component of a combined volatile and opioid anesthetic.
References 
References 
Weissman C: The metabolic response to stress: An overview and update. Anesthesiology 1990; 73:308-27.
Crile GW, Lower WE: Anoci-Association: Chapter V Anoci-Association. Philadelphia, WB Saunders, 1914:108-21.
Lacoumenta S, Paterson JL, Burrin J, Causon RC, Brown MJ, Hall GM: Effects of two differing halothane concentrations on the metabolic and endocrine responses to surgery. Br J Anaesth 1986; 58:844-50.
Engquist A, Fog-Moller F, Christiansen C, Thode J, Anderson T, Nistrup-Madsen S: Influence of epidural analgesia on the catecholamine and cyclic AMP response to surgery. Acta Anaesthesiol Scand 1980; 24:17-21.
George JM, Reier CE, Lanese RR, Rower MJ: Morphine anaesthesia blocks cortisol and growth hormone response to surgical stress in humans. J Clin Endocrinol Metab 1974; 38:736-41.
Smith I, Van Hemelrijck J, White PF: Efficacy of esmolol versus alfentanil as a supplement to proopofol-nitrous oxide anesthesia. Anesth Analg 1991; 73:540-6.
Larson MD, Tayefeh F, Sessler DI, Daniel M, Noorani M: Sympathetic nervous system does not mediate reflex pupillary dilation during propofol-desflurane anesthesia. Anesthesiology 1996; 85:748-54.
Loewenfeld IE: Mechanisms of reflex dilation of the pupil. Historical review and experimental analysis. Docum Ophthalmol 1958; 12:185-448.
Larson MD, Sessler DI, Washington DE, Merrifield BR, Hynson JA, McGuire J: Pupillary response to noxious stimulation during isoflurane and propofol anesthesia. Anesth Analg 1993; 76:1072-8.
Lund C, Selmar P, Hansen OB, Hjortso N, Kehlet H: Effect of epidural bupivacaine on somatosensory evoked potentials after dermatomal stimulation. Anesth Analg 1987; 66:34-8.
Larson MD, Sessler DI, Ozaki M, McGuire J, Schroeder M: Pupillary assessment of sensory block level during combined epidural/general anesthesia. Anesthesiology 1993; 79:42-8.
Larson MD, Sessler DI, McGuire J, Hynson JM: Isoflurane, but not mild hypothermia, depresses the human pupillary light reflex. Anesthesiology 1991; 75:62-7.
Xiong J, Kurz A, Sessler DI, Plattner O, Christensen R, Dechert M, Ikeda T: Isoflurane produces marked and non-linear decreases in the vasoconstriction and shivering thresholds. Anesthesiology 1996; 85:240-5.
Crankshaw DP, Morgan DJ, Beemer GH, Karasawa F: Preprogrammed infusion of alfentanil to constant arterial plasma concentration. Anesth Analg 1993; 76:556-61.
Scott JC, Ponganis KV, Stanski DR: EEG quantitation of narcotic effect: The comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 1985; 62:234-41.
Stark L, Campbell FW, Alwood J: Pupillary unrest: An example of noise in a biological servo-mechanism. Nature 1958; 182:857-8.
Kumar K, Morgan DJ, Crankshaw DP: Determination of fentanyl and alfentanil in plasma by high-performance liquid chromatography with ultraviolet detection. J Chromatogr 1987; 419:464-8.
Matthews JNS, Altman DG, Campbell MJ, Royston P: Analysis of serial measurements in medical research. BMJ 1990; 300:230-5.
Pickworth WB, Welch P, Henningfield JE, Cone EJ: Opiate-Induced pupillary effects in humans. Meth Find Exp Clin Pharmacol 1989; 11:759-63.
Pickworth WB, Lee H, Fudala J: Buprenorphine-induced pupillary effects in human volunteers. Life Sciences 1990; 47:1269-77.
Loewenfeld IE, Newsome DA. Iris mechanics I: Influence of pupil size on dynamics of pupillary movements. Am J Ophthal 1971; 71:347-62.
Daniel M, Larson MD, Eger EI, Noorani M, Weisdopf RB: Fentanyl, clonidine, and repeated increases in desflurane concentration, but not nitrous oxide or esmolol, block the transient mydriasis caused by rapid increases in desflurane concentration. Anesth Analg 1995; 81:372-8.
O'Connor M, Escarpa A, Prys-Roberts C: Ventilatory depression during and after infusion of alfentanil in man. Br J Anaesth 1983; 55:2175-225.
van den Nieuwenhuyzen MCO, Engbers FHM, Burm AGL, Lemmens HJM, Vletter AA, van Kleef JW, Bovill JG: Computer-controlled infusion of alfentanil for postoperative analgesia. A pharmacokinetic and pharmacodynamic evaluation. Anesthesiology 1993; 79:481-92.
Westmoreland CL, Sebel PS, Gropper A: Fentanyl or alfentanil decreases the minimum alveolar anesthetic concentration of isoflurane in surgical patients. Anesth Analg 1994; 78:23-8.
Belani KG, Sessler DI, Larson MD, Lopez MA, Washington DE, Ozaki M, McGuire J, Merrifield B, Schroeder M: The pupillary light reflex: Effects of anesthetics and hyperthermia. Anesthesiology 1993; 79:23-7.
Scott JC, Stanski DR: Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther 1987; 240:159-65.
Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD: Kappa opioids produce significantly greater analgesia in women than in men. Nature Medicine 1996; 2:1248-50.
Figure 1. The light reflex is defined by the difference between the initial diameter and the minimum diameter after a short light stimulus. Maximum constriction velocity is the maximum speed (measured in millimeters per second) attained during the constriction phase of the light reflex. Reflex dilation is the difference between the initial diameter and the diameter at the end of a 2-s scan. The data shown are the mean scans taken before and after alfentanil administration (25 ng/ml). See Table 1for the statistical analysis.
Figure 1. The light reflex is defined by the difference between the initial diameter and the minimum diameter after a short light stimulus. Maximum constriction velocity is the maximum speed (measured in millimeters per second) attained during the constriction phase of the light reflex. Reflex dilation is the difference between the initial diameter and the diameter at the end of a 2-s scan. The data shown are the mean scans taken before and after alfentanil administration (25 ng/ml). See Table 1for the statistical analysis.
Figure 1. The light reflex is defined by the difference between the initial diameter and the minimum diameter after a short light stimulus. Maximum constriction velocity is the maximum speed (measured in millimeters per second) attained during the constriction phase of the light reflex. Reflex dilation is the difference between the initial diameter and the diameter at the end of a 2-s scan. The data shown are the mean scans taken before and after alfentanil administration (25 ng/ml). See Table 1for the statistical analysis.
×
Figure 2. Alfentanil infusion did not alter prestimulus pupil size but produced a substantial and dose-dependent inhibition of stimulus-induced pupillary dilation, with dilation nearly obliterated at the 100 ng/ml target concentration. The background anesthetic was 0.8% isoflurane. Results are presented as mean +/- SD. See Table 1for statistical analysis and measured alfentanil concentrations at each target concentration.
Figure 2. Alfentanil infusion did not alter prestimulus pupil size but produced a substantial and dose-dependent inhibition of stimulus-induced pupillary dilation, with dilation nearly obliterated at the 100 ng/ml target concentration. The background anesthetic was 0.8% isoflurane. Results are presented as mean +/- SD. See Table 1for statistical analysis and measured alfentanil concentrations at each target concentration.
Figure 2. Alfentanil infusion did not alter prestimulus pupil size but produced a substantial and dose-dependent inhibition of stimulus-induced pupillary dilation, with dilation nearly obliterated at the 100 ng/ml target concentration. The background anesthetic was 0.8% isoflurane. Results are presented as mean +/- SD. See Table 1for statistical analysis and measured alfentanil concentrations at each target concentration.
×
Figure 3. The relation between plasma alfentanil and the post-stimulus change in pupil size in millimeters was exponentially related to plasma alfentanil concentration expressed as nanograms per milliliter: size = 4 [center dot] e sup -0.0327[Alfentanil], r2= 0.78. Pupillary dilation was thus 50% inhibited at a total plasma alfentanil concentration of about 20 ng/ml. There was a poor relation between alfentanil concentration and the increase in heart rate (DeltaHR): DeltaHR = 10 [center dot] e sup -0.0213[Alfentanil], r2= 0.39. The relation between alfentanil concentration and the increase in systolic blood pressure (DeltaBP) was even worse: DeltaBP = 10 [center dot] e sup -0.0081[Alfentanil], r2= 0.05.
Figure 3. The relation between plasma alfentanil and the post-stimulus change in pupil size in millimeters was exponentially related to plasma alfentanil concentration expressed as nanograms per milliliter: size = 4 [center dot] e sup -0.0327[Alfentanil], r2= 0.78. Pupillary dilation was thus 50% inhibited at a total plasma alfentanil concentration of about 20 ng/ml. There was a poor relation between alfentanil concentration and the increase in heart rate (DeltaHR): DeltaHR = 10 [center dot] e sup -0.0213[Alfentanil], r2= 0.39. The relation between alfentanil concentration and the increase in systolic blood pressure (DeltaBP) was even worse: DeltaBP = 10 [center dot] e sup -0.0081[Alfentanil], r2= 0.05.
Figure 3. The relation between plasma alfentanil and the post-stimulus change in pupil size in millimeters was exponentially related to plasma alfentanil concentration expressed as nanograms per milliliter: size = 4 [center dot] e sup -0.0327[Alfentanil], r2= 0.78. Pupillary dilation was thus 50% inhibited at a total plasma alfentanil concentration of about 20 ng/ml. There was a poor relation between alfentanil concentration and the increase in heart rate (DeltaHR): DeltaHR = 10 [center dot] e sup -0.0213[Alfentanil], r2= 0.39. The relation between alfentanil concentration and the increase in systolic blood pressure (DeltaBP) was even worse: DeltaBP = 10 [center dot] e sup -0.0081[Alfentanil], r2= 0.05.
×
Figure 4. Pupillary light reflex before and after alfentanil. The superimposed scans are averages showing the size of the pupil after a 0.2-s light stimulus. The target alfentanil concentration was 100 ng/ml, and the background anesthetic was 0.8% isoflurane. See Table 2for statistical comparisons of the light reflex at different alfentanil concentrations.
Figure 4. Pupillary light reflex before and after alfentanil. The superimposed scans are averages showing the size of the pupil after a 0.2-s light stimulus. The target alfentanil concentration was 100 ng/ml, and the background anesthetic was 0.8% isoflurane. See Table 2for statistical comparisons of the light reflex at different alfentanil concentrations.
Figure 4. Pupillary light reflex before and after alfentanil. The superimposed scans are averages showing the size of the pupil after a 0.2-s light stimulus. The target alfentanil concentration was 100 ng/ml, and the background anesthetic was 0.8% isoflurane. See Table 2for statistical comparisons of the light reflex at different alfentanil concentrations.
×
Table 1. Pupillary Size, Blood Pressure, and Heart Rate After Stimulation at Each Alfentanil Concentration 
Image not available
Table 1. Pupillary Size, Blood Pressure, and Heart Rate After Stimulation at Each Alfentanil Concentration 
×
Table 2. The Pupillary Light Reflex and Early Dilation at Each Alfentanil Concentration 
Image not available
Table 2. The Pupillary Light Reflex and Early Dilation at Each Alfentanil Concentration 
×