Merlin D. Larson

Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold

Background: Meperidine administration is a more effective treatment for shivering than equianalgesic doses of other opioids. However, it remains unknown whether meperidine also profoundly impairs other thermoregulatory responses, such as sweating or vasoconstriction. Proportional inhibition of vasoconstriction and shivering suggests that the drug acts much like alfentanil and anesthetics but possesses greater thermoregulatory than analgesic potency. In contrast, disproportionate inhibition would imply a special antishivering mechanism. Accordingly, the authors tested the hypothesis that meperidine administration produces a far greater concentration‐dependent reduction in the shivering than vasoconstriction threshold. Methods: Nine volunteers were each studied on three days: 1) control (no opioid); 2) a target total plasma meperidine concentration of 0.6 micro gram/ml (40 mg/h); and 3) a target concentration of 1.8 micro gram/ml (120 mg/h). Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core‐temperature thresholds (at a designated skin temperature of 34 degrees Celsius) were computed using established linear cutaneous contributions to control sweating (10%) and vasoconstriction and shivering (20%). The dose‐dependent effects of unbound meperidine on thermoregulatory response thresholds was then determined using linear regression. Results are presented as means +/‐ SDs. Results: The unbound meperidine fraction was [nearly equal] 35%. Meperidine administration slightly increased the sweating threshold (0.5 +/‐ 0.8 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r2 = 0.51 +/‐ 0.37) and markedly decreased the vasoconstriction threshold (‐3.3 +/‐ 1.5 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r sup 2 = 0.92 +/‐ 0.08). However, meperidine reduced the shivering threshold nearly twice as much as the vasoconstriction threshold (‐6.1 +/‐ 3.0 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r2 = 0.97 +/‐ 0.05; P = 0.001). Conclusions: The special antishivering efficacy of meperidine results at least in part from an uncharacteristically large reduction in the shivering threshold rather than from exaggerated generalized thermoregulatory inhibition. This pattern of thermoregulatory impairment differs from that produced by alfentanil, clonidine, propofol, and the volatile anesthetics, all which reduce the vasoconstriction and shivering thresholds comparably.

Alfentanil Slightly Increases the Sweating Threshold and Markedly Reduces the Vasoconstriction and Shivering Thresholds

Background Hypothermia is common in surgical patients and victims of major trauma; it also results from environmental exposure and drug abuse. In most cases, hypothermia results largely from drug-induced inhibition of normal thermoregulatory control. Although opioids are given to a variety of patients, the thermoregulatory effects of opioids in humans remain unknown. Accordingly, the hypothesis that opioid administration impairs thermoregulatory control was tested.

Naloxone, Meperidine, and Shivering

BackgroundMeperidine, which binds both μ and k opioid receptors, is reportedly more effective in treating shivering than are equianalgesic doses of morphine (a nearly pure μ-receptor agonist). Furthermore, butorphanol, a k-receptor agonist/antagonist, treats shivering better than does fentanyl, which mostly binds μ receptors. These data Indicate that much of meperidines special antishivering activity may be mediated by its k activity. Accordingly, the authors tested the hypothesis that the antishivering activity of meperidine will be minimally Impaired by low-dose naloxone (blocking most μ-receptors), but largely prevented by high-dose naloxone (blocking all μ and most k receptors). MethodsTwelve volunteers each participated on 2 days. On both days, shivering was induced by central venous Infusion of cold fluid. Twenty minutes later, six volunteers were given a placebo infusion of saline on one day, or an Infusion of 0.5 μg ± kg−1 ± min−1 naloxone hydrochloride (“low-dose,” designed to block μ receptors) on the other. The second group of six volunteers was given a saline bolus and infusion on one day, or a bolus of 11.5 μg/kg naloxone hydrochloride followed by an infusion of naloxone at 5 μg ± kg−1 ± min−1 (“high-dose,” designed to block both μ and k receptors) on the other day. The infusions were continued for the duration of the study. The order of the treatment days (saline vs. naloxone) was randomly assigned, and the study was double blinded. Fifteen minutes after the test infusion was started, all 12 volunteers were given an intravenous bolus of 1 mg/kg meperidine hydrochloride. Pupillary diameter and light reflex amplitude were used to quantify opioid-receptor agonist activity; shivering intensity was evaluated using oxygen consumption. ResultsAdministration of naloxone alone did not alter oxygen consumption, pupil size, or the pupillary light reflex. No pupillary constriction was detected in either group when naloxone and meperidine were combined; in contrast, meperidine alone decreased pupil size and amplitude of the light reflex 30%. The meperidine bolus decreased oxygen consumption nearly to control values when the volunteers were given saline placebo. Combined administration of meperidine and low-dose naloxone also significantly reduced oxygen consumption, but the reduction and the duration of the reduction was less than during saline. When the volunteers were given high-dose naloxone, meperidine only slightly reduced oxygen consumption, and the values rapidly returned to premeperidine levels. ConclusionsThese data Indicate that the antishivering property of meperidine is not fully mediated by μ-receptors. Although meperidine has well-known nonopioid actions, stimulation of k receptors seems a likely alternative explanation for much of the drugs antishivering action.

Pupillary response to noxious stimulation during isoflurane and propofol anesthesia

We studied the effects of noxious stimuli on arterial blood pressure, heart rate, pupil size, and the pupillary light reflex in 13 volunteers anesthetized with either isoflurane or propofol. Those given isoflurane (n = 8) were anesthetized twice, in a randomly selected order, once at an end-tidal concentration of 0.8% and once at 1.2%. An intense noxious stimulus was provided by electrical stimulation applied to skin of the abdominal wall (65–70 mA, 100 Hz). Hemodynamic values and pupillary responses were recorded immediately before stimulation and at 15–60-s intervals during 8 subsequent min. In the volunteers given isoflurane (both concentrations), stimulation significantly increased pupil size (265 ± 244%) and the amplitude of the light reflex (233 ± 23%). In contrast, mean heart rate and systolic blood pressure increased only 19 ± 7% and 13 ± 7% after stimulation. Five additional volunteers were anesthetized twice with propofol (≈ 3 μg/mL plasma concentration) and 60% nitrous oxide. The same electrical stimulus was applied, and hemodynamic and pupillary measurements were obtained. During one propofol anesthetic, an esmolol infusion (100 μg·kg−1·min−1) was started 10 min before stimulation to determine whether this agent would blunt the pupillary response. The pupillary light reflex increased more than 200% during both propofol anesthetics with or without esmolol; once again, heart rate and blood pressure changed little. We conclude that with these experimental conditions, the pupil is a more sensitive measure of noxious stimulation than the commonly used variables of arterial blood pressure and heart rate.

Alfentanil blocks reflex pupillary dilation in response to noxious stimulation but does not diminish the light reflex

Background: Estimation of the micro‐agonist opioid effect in anesthetized and paralyzed patients is often imprecise and can be obscured by concomitant administration of drugs that affect the sympathetic nervous system, such as beta‐adrenergic blocking agents. As an alternative to hemodynamic measures of opioid effect, the authors tested the hypothesis that the pupillary light reflex or pupillary reflex dilation correlated with alfentanil concentrations during isoflurane anesthesia. Methods: Six volunteers were anesthetized on 4 days with 0.8% isoflurane. Alfentanil was administered intravenously to target total plasma concentrations of 0, 25, 50, and 100 ng/ml. A 5‐s tetanic electrical stimulus was applied to the skin. Pupil size and the pupillary light reflex were recorded before and after alfentanil administration, and before and for 8 min after the stimulus. Results: Alfentanil exponentially impaired reflex pupillary dilation, decreasing the maximum 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 mm at 100 ng/ml. In contrast, only the highest concentration of alfentanil depressed the dilation of the pupil in the first 2 s after the stimulus. Alfentanil administration had no effect on the pupillary light reflex. Conclusions: Dilation of the pupil in response to a noxious stimulus is a measure of opioid effect in isoflurane‐anesthetized volunteers. 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.

Sympathetic nervous system does not mediate reflex pupillary dilation during desflurane anesthesia

Background Pupil size is determined by an interaction between the sympathetic and parasympathetic divisions of the autonomic nervous system. Noxious stimulation dilates the pupil in both unanesthetized and anesthetized humans. In the absence of anesthesia, dilation is primarily mediated by the sympathetic nervous system. In contrast, pupillary dilation in cats given barbiturate or cloralose anesthesia is mediated solely by inhibition of the midbrain parasympathetic nucleus. The mechanism by which noxious stimuli dilate pupils during anesthesia in humans remains unknown. Accordingly, the authors tested the hypothesis that the pupillary dilation in response to noxious stimulation during desflurane anesthesia is primarily a parasympathetic reflex. Methods In six volunteers, the alpha‐1 adrenergic receptors of the iris musculature were blocked by unilateral administration of topical dapiprazole; six other volunteers were given unilateral topical tropicamide to block the muscarinic receptors in the iris. Desflurane anesthesia was subsequently induced in all volunteers. Sympathetic nervous system activation, with reflex dilation of the pupil, was produced by noxious electrical stimulation during 4% and 8% end‐tidal desflurane, and by a rapid 4%‐to‐8% step‐up in the desflurane concentration. Pupil diameter and the change in pupil size induced by a light stimulus (light reflex amplitude) were measured with infrared pupillometry. Results Dapiprazole drops produced a Horners miosis, but pupils were equally small after induction of anesthesia. Pupillary dilation after noxious stimulation and desflurane step‐up was identical in the unblocked and dapiprazole‐blocked pupils. After tropicamide administration, the pupil was dilated and the light reflex was completely inhibited. Noxious stimulation nonetheless produced a slight additional dilation. Conclusions During desflurane anesthesia, pupillary dilation in response to noxious stimulation or desflurane step‐up is not mediated by the sympathetic nervous system (as it is in unanesthetized persons). Although inhibition of the pupillo‐constrictor nucleus may be the cause of this dilation, the mechanism remains unknown.

Pupillary assessment of sensory block level during combined epidural/general anesthesia

BackgroundCurrently, no reliable method exists to determine the level of sensory block during combined epidural/general anesthesia. However, the pupil dilates markedly in response to noxious electrical stimulation during general anesthesia. Presumably, sensory block produced by epidural anesthesia decreases or obliterates this autonomic response. Accordingly, we tested the hypothesis that pupillary dilation in response to noxious stimulation would predict the level of sensory block achieved during combined epidural/general anesthesia. MethodsWe studied eight volunteers and ten patients during combined epidural/general anesthesia. The volunteers were given an epidural infusion of 2% 2-chloroprocaine while general anesthesia was maintained with 0.8% isoflurane and 60% N2O. In the patients, an epidural infusion of 0.25% bupivacaine was combined with isoflurane and vecuronium. Noxious electrical stimulation was administered to dermatomal segments in a caudal-to-rostral progression. A twofold increase in pupil size following electrical stimulation was considered the predicted block level in volunteers. In patients, an increase in pupil size exceeding 50% was considered the predicted level. After general anesthesia was discontinued, observers blinded to the pupillary measurements independently determined the actual epidural block level using pain in response to a pinprick as the criterion. ResultsThe level predicted by pupillary responses was within two dermatomal segments of the actual level in all the volunteers. The predicted and actual block levels were within two segments in eight of the ten patients and never differed by more than four dermatomes. ConclusionsWe conclude that dilation of the pupil in response to electrical stimulation is an accurate test of the sensory block level during combined epidural/general anesthesia.

Meperidine and alfentanil do not reduce the gain or maximum intensity of shivering.

Background Thermoregulatory shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core temperature deviation), and maximum intensity. Meperidine (a combined micro‐ and kappa‐agonist) treats shivering better than equianalgesic doses of pure micro‐opioid agonists. Meperidines special antishivering action is mediated, at least in part, by a disproportionate decrease in the shivering threshold. That is, meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold, whereas alfentanil (a pure micro‐agonist) decreases the vasoconstriction and shivering thresholds comparably. However, reductions in the gain or maximum shivering intensity might also contribute to the clinical efficacy of meperidine. Accordingly, we tested the hypothesis that meperidine reduces the gain and maximum intensity of shivering much more than alfentanil does. Methods Ten volunteers were each studied on three separate days: (1) control (no drug); (2) a target total plasma meperidine concentration of 1.2 micro gram/ml; and (3) a target plasma alfentanil concentration of 0.2 micro gram/ml. Skin temperatures were maintained near 31 [degree sign] Celsius, and core temperatures were decreased by central‐venous infusion of cold lactated Ringers solution until maximum shivering intensity was observed. Shivering was evaluated using oxygen consumption and electromyography. A sustained increase in oxygen consumption identified the shivering threshold. The gain of shivering was calculated as the slope of the oxygen consumption versus core temperature regression, and as the slope of electromyographic intensity versus core temperature regression. Results Meperidine and alfentanil administration significantly decreased the shivering thresholds. However, neither meperidine nor alfentanil reduced the gain of shivering, as determined by either oxygen consumption or electromyography. Opioid administration also failed to significantly decrease the maximum intensity of shivering. Conclusions The authors could not confirm the hypothesis that meperidine reduces the gain or maximum intensity of shivering more than alfentanil does. These results suggest that meperidines special antishivering effect is primarily mediated by a disproportionate reduction in the shivering threshold.

Portable infrared pupillometry: a review.

Portable infrared pupillometers provide an objective measure of pupil size and pupillary reflexes, which for most clinicians was previously only a visual impression. But despite the fact that pupillometry can uncover aspects of how the human pupil reacts to drugs and noxious stimulation, the use of pupillometry has not gained widespread use among anesthesiologists and critical care physicians. The present review is an introduction to the physiology of pupillary reflexes and the currently established clinical applications of infrared pupillometry, which will hopefully encourage physicians to use this diagnostic tool in their clinical practice. Portable infrared pupillometry was introduced in 1989. The technology involves flooding the eye with infrared light and then measuring the reflected image on an infrared sensor. Pupil size, along with variables of the pupillary light reflex and pupillary reflex dilation, is calculated by the instrument and displayed on a screen immediately after each time-stamped measurement. Use of these instruments has uncovered aspects of how the human pupil reacts to drugs and noxious stimulation. The primary clinical applications for portable pupillometry have been in the assessment of brainstem function. Portable pupillometry is useful in the management of pain because it allows for assessments of the effect of opioids and in the titration of combined regional–general anesthetics.

Mechanism of opioid-induced pupillary effects☆

OBJECTIVE This study tested the hypothesis that increased activity in the pupilloconstrictor nucleus by the addition of ambient light and by the administration of fentanyl, sufficient to block pupillary reflex dilation, constricts the pupil of anesthetized patients. METHODS Pupil diameter was measured in 10 anesthetized patients during noxious stimulation above an epidural block level, in darkness and then with light directed into the left eye. Two measurements were taken from the right eye separated by 5 min. Following the second measurement, fentanyl (1 mcg/kg) was administered and the measures in light and dark were repeated. The effect of light and fentanyl on pupil size and pupillary reflex dilation were analyzed. RESULTS An increase in light directed into the left eye constricted the pupil from 2.15+/-0.38 to 1.87+/-0.40 mm before fentanyl. Fentanyl did not constrict the pupil either in darkness or light but it did decrease pupillary reflex dilation by 49%. CONCLUSIONS The miotic pupil during general anesthesia is not maximally constricted. Increased excitation of the pupilloconstrictor nucleus does not account for blockade of pupillary reflex dilation after fentanyl administration during desflurane anesthesia. SIGNIFICANCE This study does not support the hypothesis that opioid effects on the human pupil are brought about by a direct excitatory action on the pupilloconstrictor nucleus.