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ANESTHETIC PHARMACOLOGY

Neither Nalbuphine nor Atropine Posses Special Antishivering Activity

Robert Greif, MD^*, Sonja Laciny, MD^*, Angela M. Rajek, MD^*, Merlin D. Larson, MD^*, Andrew R. Bjorksten, PhD, Anthony G. Doufas, MD^*, Maryam Bakhshandeh, MD^*, Masoud Mokhtarani, MD^*, and Daniel I. Sessler, MD^||

*Department of Anesthesia and Perioperative Care, University of California–San Francisco, San Francisco, California; Department of Anesthesiology and Intensive Care Medicine, Donauspital/SMZO-Vienna, Austria; Department of Cardiothoracic and Vascular Anesthesia, University of Vienna, Vienna, Austria; Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia; and ||Outcomes Research^TM Institute and Department of Anesthesiology, University of Louisville, Kentucky, and Ludwig Boltzmann Institute, University of Vienna, Austria

Address correspondence and reprint requests to Dr. Sessler, University of Louisville, Abell Administration Center, Room 217, 323 East Chestnut St., Louisville, KY 40202-3866. Address e-mail to sessler{at}louisville.edu

	Abstract

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The special antishivering action of meperidine may be mediated by its or anticholinergic actions. We therefore tested the hypotheses that nalbuphine or atropine decreases the shivering threshold more than the vasoconstriction threshold. Eight volunteers were each evaluated on four separate study days: 1) control (no drug), 2) small-dose nalbuphine (0.2 µg/mL), 3) large-dose nalbuphine (0.4 µg/mL), and 4) atropine (1-mg bolus and 0.5 mg/h). Body temperature was increased until the patient sweated and then decreased until the patient shivered. Nalbuphine produced concentration-dependent decreases (mean ± SD) in the sweating (-2.5 ± 1.7°C · µg^-1 · mL; r² = 0.75 ± 0.25), vasoconstriction (-2.6 ± 1.7°C · µg^-1 · mL; r² = 0.75 ± 0.25), and shivering (-2.8 ± 1.7°C · µg^-1 · mL; r² = 0.79 ± 0.23) thresholds. Atropine significantly increased the thresholds for sweating (1.0°C ± 0.4°C), vasoconstriction (0.9°C ± 0.3°C), and shivering (0.7°C ± 0.3°C). Nalbuphine reduced the vasoconstriction and shivering thresholds comparably. This differs markedly from meperidine, which impairs shivering twice as much as vasoconstriction. Atropine increased all thresholds and would thus be expected to facilitate shivering. Our results thus fail to support the theory that activation of -opioid or central anticholinergic receptors contribute to meperidine’s special antishivering action.

IMPLICATIONS: The activation of neither -opioid nor central anticholinergic receptors contributes to meperidine’s special antishivering action. Some other aspect of meperidine’s pharmacology is thus responsible for the drug’s special antishivering action.

	Introduction

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Core temperature in humans is well maintained because even small deviations trigger effective thermoregulatory defenses, such as sweating and vasoconstriction (1). Because the normal sweating and vasoconstriction thresholds differ by only 0.2°C (2), normal body temperature is sometimes referred to as a "set point." Opioids (3), like general anesthetics, impair thermoregulatory defenses, producing a characteristic increase in the sweating threshold (triggering core temperature) combined with a synchronous reduction in the vasoconstriction and shivering thresholds. The result is a marked increase in the sweating-to-vasoconstriction interthreshold range—the temperatures between which autonomic thermoregulatory defenses are not triggered.

Meperidine is a far more effective treatment for shivering than pure µ-receptor agonists, such as morphine (4). The special efficacy of meperidine is manifested by a disproportionate reduction in the shivering threshold (5) without any reduction in the gain of shivering (6). Meperidine thus reduces the shivering thresholds twice as much as the vasoconstriction threshold at any given concentration (5). This is in distinct contrast to general anesthetics and pure µ-receptor opioids that comparably reduce the thresholds for each major cold defense (7).

The special antishivering action of meperidine may in part be mediated by its agonist activity at receptors; activity constitutes approximately 10% of meperidine’s total opioid action (8). A clinically important contribution of receptors is supported by the observation that meperidine reduces the intensity of cold-induced shivering even in the presence of moderate doses of naloxone, which presumably block µ receptors while having little effect on the relatively resistant receptors (9). Agonists also produce hypothermia and inhibit cold defenses under a variety of circumstances (10). Furthermore, nalbuphine reportedly treats postoperative shivering as effectively as meperidine (11).

There is thus considerable reason to believe that -receptor agonists possess special antishivering activity. However, the specific thermoregulatory effects of -receptor agonists have yet to be evaluated, and it remains unknown whether activity is sufficient to explain meperidine’s special antishivering action. We therefore tested the hypothesis that the relatively specific agonist nalbuphine substantially and disproportionately decreases the shivering threshold. (There is no specific agonist approved for human use.) Specifically, we determined whether nalbuphine decreases the shivering threshold more than it increases the vasoconstriction threshold.

Meperidine produces numerous pharmacologic actions in addition to its opioid effects. Among the most important is the drug’s central anticholinergic action (12). The extent to which central anticholinergic activity contributes to meperidine’s antishivering action remains unknown. We therefore also tested the hypothesis that the central anticholinergic drug atropine disproportionately decreases the shivering threshold.

	Methods

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With approval from the Committee on Human Research at the University of California in San Francisco and informed consent, we studied eight healthy male volunteers. Volunteers had a light breakfast before arriving at the laboratory, but they refrained from coffee and tea intake during the 8 h before each investigation. During the study, they were allowed to drink water and to eat crackers. Ambient temperature in the laboratory was maintained at 22.0°C ± 0.2°C, with a relative humidity of 42% ± 5%. The volunteers were minimally clothed during the protocol and rested supine on a standard operating room table.

The volunteers were each evaluated on four separate study days: 1) control (no drug), 2) small-dose nalbuphine (target plasma concentration of 0.2 µg/mL), 3) large-dose nalbuphine day (0.4 µg/mL), and 4) atropine (1-mg bolus, followed by an infusion of 0.5 mg/h). To avoid circadian fluctuations, studies were scheduled so that thermoregulatory responses were triggered at similar times on each of the 4 days. An IV catheter was inserted into the left forearm for fluid, nalbuphine, and atropine administration. Lactated Ringer’s solution was given as necessary to maintain mean arterial blood pressure >60 mm Hg. A 14-gauge catheter was inserted into a right antecubital vein and used for blood sampling.

Nalbuphine was administered IV by using a computer-controlled syringe pump. The infusion profile was based on use of a modification of the Kruger-Thiemer method (13), with coefficients estimated from published pharmacokinetic data (14). To minimize the effects of tolerance, the smaller nalbuphine dose was always studied first, and at least 1 wk elapsed between the two nalbuphine days. The control day was either between or after the other two study days. Atropine was always studied last; the drug was given as a 1-mg bolus, followed by an infusion of 0.5 mg/h.

Thermal manipulation began 15 min after the study drug was started. To minimize redistribution hypothermia, we prewarmed the volunteers for half an hour with a full-body forced-air warmer (Augustine Medical, Inc., Eden Prairie, MN) on "low" and a circulating-water mattress (Cincinnati Sub-Zero, Cincinnati, OH) set at 37°C. Throughout the protocol, arms were protected from active warming and cooling to avoid locally mediated vasomotion. However, all other skin below the neck was similarly manipulated throughout each study day.

Skin and core temperatures were first gradually increased with a forced-air warmer and circulating-water mattress until sweating was observed. Skin and core temperatures were then gradually decreased, by using the circulating-water mattress and a prototype forced-air cooler (Augustine Medical, Inc.). As in previous studies (7), the sweating threshold was determined first because this threshold deviates least from normal body temperature. This protocol allowed a considerably shorter study day than if we had first cooled to the shivering and then rewarmed all the way to the sweating threshold. The study ended each day when shivering was detected. Skin and core temperature changes were restricted to 2°C/h because this rate is unlikely to trigger dynamic thermoregulatory responses (2).

Heart rate and oxyhemoglobin saturation were measured continuously by using pulse oximetry, and blood pressure was determined oscillometrically at 5-min intervals at the left ankle. End-tidal carbon dioxide concentrations were measured from a catheter inserted into one nostril, by using a Rascal monitor (Ohmeda Inc., Salt Lake City, UT); exhaust gas from this monitor was returned to a DeltaTrac oxygen consumption monitor (SensorMedics Corp., Yorba Linda, CA).

Core temperature was recorded from the tympanic membrane by using Mon-a-Therm thermocouples (Mallinckrodt Anesthesiology Products, Inc., St. Louis, MO). The aural probes were inserted by the volunteers until they felt the thermocouple touch the tympanic membrane; appropriate placement was confirmed when volunteers easily detected a gentle rubbing of the attached wire. The aural canal was occluded with cotton, the probe securely taped in place, and a gauze bandage positioned over the external ear. Mean skin-surface temperature was calculated from measurements at 15 area-weighted sites (15). Temperatures were recorded at 1-min intervals from thermocouples connected to calibrated Iso-Thermex thermometers having an accuracy of 0.1°C and a precision of 0.01°C (Columbus Instruments Corp., Columbus, OH).

Sweating was continuously quantified on the left upper chest, just below the clavicle, by using a ventilated capsule (16). As in previous studies (3), sustained sweating >40 g · m^-2 · h^-1 defined the sweating threshold. Absolute right middle fingertip blood flow was quantified with venous-occlusion volume plethysmography at 1-min intervals (17); as in our previous evaluation of opioids (3), a decrease in finger blood flow to <1.0 mL/min was defined as the threshold for vasoconstriction.

Shivering was evaluated with oxygen consumption, as measured by the DeltaTrac metabolic monitor. The system was used in canopy mode, and measurements were averaged over 1-min intervals and recorded every 5 min. As in numerous previous studies, a sustained increase in oxygen consumption to 30% of baseline values identified significant shivering.

Venous blood was sampled for nalbuphine concentrations before drug administration and at the time of sweating, vasoconstriction, and shivering. Blood components were separated in a refrigerated centrifuge for 30 min, and the plasma samples were isolated and then stored at -20°C for subsequent analysis with high-performance liquid chromatography.

One-milliliter aliquots of plasma for nalbuphine analysis were alkalinized with 1.5 mL of 0.5 M Na₃PO₄ in a polypropylene centrifuge tube and extracted into 5 mL of ethyl acetate, along with 0.1 mL of 25 mg/L naloxone, which served as the internal standard. The ethyl acetate layer was transferred to a second polypropylene tube and evaporated to dryness under nitrogen at 40°C. It was reconstituted in 0.1 mL mobile phase. The mobile phase was 300:700:0.6 acetonitrile/20 mM KH₂PO₄/triethylamine running through a 150- by 3.9-mm-long Novapak C-18 column (Waters Associates, Milford, MA) at a rate of 1.2 mL/min with detection by ultraviolet absorbance at 205 nm. The response was linear to at least 5000 ng/mL, with a detection limit of 10 ng/mL and a within-day coefficient of variation of 5.1% at 400 ng/mL.

Pupil diameter and light-reflex amplitude (the difference between the prestimulus diameter and the minimum diameter in the 2 s after a pulse of visible light) are both inversely correlated with opioid effect (18). We therefore used pupillary responses to evaluate the pharmacodynamic effects of nalbuphine and atropine. A portable infrared pupillometer (Fairville Medical Optics, Inc., Amersham, Buckinghamshire, England) was used to measure the pupillary response. The pupillometer was programmed to provide a 0.5-s duration, 130 candela/m² pulse of visible light and scan the pupil at a rate of 10 Hz for 2 s from the beginning of the light stimulus. Pupillary diameter and light reflex amplitude from the right eye were measured at baseline and three times in succession at each threshold, and the resulting values were averaged. Ambient light was maintained near 150 lux, and the left eye was kept covered during the measurements. We have previously described the use of this pupillometer (19).

Sedation was assessed with the Observer’s Assessment of Alertness/Sedation Score (OAA/S). The OAA/S test consists of four components (Table 1); as described by Chernik et al. (20), we summed the component scores. Sedation was evaluated at the time of sweating, vasoconstriction, and shivering.

Ambient temperature and humidity on each study day were first averaged for each volunteer; the resulting values were then averaged among the volunteers. Pupillary, hemodynamic, and respiratory responses and mean skin temperature at baseline and each thermoregulatory threshold were similarly averaged first for each volunteer on each treatment day and subsequently among the volunteers. Results for each study day were compared by use of repeated-measures analysis of variance, with the Scheffé F test for post hoc intragroup comparison.

Thermoregulatory response thresholds were determined by arithmetically compensating for alterations in skin temperature by using a previously described model (21). The coefficient of cutaneous contribution (ß) was taken as 0.1 for sweating (22) and 0.2 for vasoconstriction and shivering (23). The designated skin temperature was set at 34°C because that is a typical intraoperative value.

From the calculated core temperature thresholds on each study day, nalbuphine concentration-response curves for the sweating, vasoconstriction, and shivering thresholds were determined with linear regression. The average slopes and correlation coefficients (r²) for the individual volunteers were then computed from these values. Additionally, a single regression for each thermoregulatory response was determined from the combined data from all eight volunteers. The control pupillary and thermoregulatory responses were compared with those reported on the atropine day with two-tailed, paired t-tests. We thus considered the nalbuphine and atropine portions of the study to be distinct from an analysis point of view, although the two protocols shared a common control group.

	Results

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Morphometric characteristics of the volunteers included age (29 ± 4 yr), weight (76 ± 8 kg), height (173 ± 6 cm), body fat (19% ± 3%), and lean body mass (59 ± 4 kg) (mean ± SD). Ambient temperature (22.0°C), relative humidity (42%), and sedation scores were comparable with each treatment. Even at the largest nalbuphine dose, the volunteers were only minimally sedated. Atropine did not cause sedation. Nalbuphine administration had no clinically important hemodynamic effects. However, nalbuphine and atropine both significantly increased end-tidal PCO₂. Atropine also significantly increased heart rate.

By design, plasma nalbuphine concentrations differed significantly on the small- and the large-dose days, being 0.2 and 0.4 µg/mL, respectively. The concentrations, though, were similar at the sweating, vasoconstriction, and shivering thresholds within each study day (Table 2).

View larger version (17K): [in this window] [in a new window]   Figure 1. The sweating, vasoconstriction, and shivering thresholds (triggering core temperatures) as a function of plasma nalbuphine concentrations. The solid line shows the linear regression for each response. Data are presented as mean ± SD.

View larger version (34K): [in this window] [in a new window]   Figure 2. Heart rate and the sweating, vasoconstriction, and shivering thresholds before ( and after (•) the administration of atropine. Atropine was given as a 1-mg bolus, followed by an infusion of 0.5 mg/h. The squares show the mean values for each response. Data are presented as mean ± SD; *P < 0.05 compared with control.

Parasympathetic side effects, including dry mouth, made the volunteers uncomfortable on the atropine study day. Furthermore, the volunteers had the highest discomfort scores during atropine. However, they had difficulty articulating why they felt poorly and made comments such as "it is a strange feeling" and "I don’t like it." However, all reported feeling normal by the subsequent day.

	Discussion

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Opioids, anesthetics, and most sedatives increase the sweating threshold while simultaneously decreasing the vasoconstriction and shivering thresholds. Divergent thresholds thus increase the sweating-to-vasoconstriction interthreshold range, which is analogous to a decrease in the precision of thermoregulatory control. The combination of an increased sweating threshold and reduced vasoconstriction threshold makes the patient poikilotherm over a wider range of core temperatures, thus decreasing the ability to maintain normothermia over a normal range of ambient temperatures. In contrast, nalbuphine slightly decreased the sweating threshold while decreasing the vasoconstriction and shivering thresholds even more. Nalbuphine thus decreased the set point, but it also somewhat reduced the precision of thermoregulatory control. This pattern has previously been reported only twice, with midazolam (24) and tramadol (25). This reduction might impair rewarming from hypothermia in a postoperative patient because vasoconstriction normally decreases cutaneous heat loss and facilitates core rewarming by constraining metabolic heat to the core compartment.

However, nalbuphine reduced the vasoconstriction and shivering thresholds comparably. The vasoconstriction-to-shivering range thus remained unchanged during drug administration. A synchronous reduction in the major autonomic cold-response thresholds differs markedly from meperidine, which impairs shivering twice as much as vasoconstriction. It is thus apparent that meperidine’s -receptor activity does not explain its special antishivering action. This conclusion is inconsistent with a report that nalbuphine and meperidine are comparable treatments for postoperative shivering (11). The most likely reason is that Wang et al. (11) simply evaluated the fraction of patients that stopped shivering with each drug. This approach is inherently risky because it does not include established methodology (4) for evaluating dose dependence and compensating for kinetic differences to ensure steady-state drug concentrations.

Our results suggest that some other aspect of meperidine’s pharmacology is responsible for the drug’s special antishivering action. Unlike other opioids, meperidine produces generalized electroencephalographic activation, apparently via the inhibition of central cholinergic receptors (12). Monoamine oxidase inhibitors combined with meperidine, but not other opioids, produce a potentially lethal hyperthermia syndrome (26). -Aminobutyric acid-mimetic drugs reduce the antinociceptive effect of meperidine but enhance the potency of fentanyl (27). Finally, meperidine has local anesthetic properties not shared by other opioids (28).

However, one of the most important nonopioid actions of meperidine is the drug’s central anticholinergic activity (12). We thus tested the theory that atropine-induced central cholinergic inhibition contributes to meperidine’s special antishivering action. Our results, though, fail to support this hypothesis: instead, atropine increased all three major autonomic response thresholds. Furthermore, the threshold increases were synchronous; that is, each was comparably increased. Atropine thus increased the "set point," rather than decreasing the precision of thermoregulatory control. This thermoregulatory pattern shares some characteristics of fever but differs from all other perioperative drugs that have been formally evaluated.

Atropine premedication increases the incidence of postoperative shivering (29), as does glycopyrrolate (30). Anticholinergic toxicity can also be associated with severe or even lethal hyperthermia, a condition known as the "central cholinergic syndrome" (31). In contrast, physostigmine induces cold defenses at neutral temperature and provokes hyperthermia (32). Furthermore, postanesthetic shivering is prevented by the application of central cholinergic agonists in mice (33). Consistent with these observations, physostigmine is an effective treatment for shivering in humans (34).

Our results do not support the theory that activation of -opioid or central anticholinergic receptors contributes to meperidine’s special antishivering action. Meperidine must therefore block shivering via some other pharmacologic action. Among the likely possibilities is the activation of -2b adrenoreceptors (35). This is important because _2-receptor agonists such as clonidine (36) and dexmedetomidine (37) synchronously reduce the vasoconstriction and shivering thresholds. As might be expected, ₂ agonists are thus effective treatments for postoperative shivering (38). Meperidine’s special antishivering action may be similarly mediated. Alternatively, it may result from another aspect of meperidine pharmacology—or from a combination of factors.

In contrast to µ-receptor agonists, the pupillary effects of opioids remain poorly understood. Nalbuphine slightly increased end-tidal PCO₂ and also caused pupillary constriction. This is analogous to the well known association between miosis and respiratory depression with µ-receptor agonists (39). Both respiratory and pupillary effects were maximal with small-dose nalbuphine and did not increase with additional drug. This ceiling effect is curious and remains unexplained. Larger concentrations of nalbuphine do produce psychomimetic side effects, but these are apparently mediated by different central mechanisms, because pupil diameter remains unchanged as symptoms develop (40).

The OAA/S score remained normal even after large-dose atropine administration. As might be expected, atropine produced parasympathetic side effects. It also produced dysphoria, and the volunteers thus considered atropine to be the worst of the four study days. In contrast, dysphoria was rare during nalbuphine. Many of the volunteers given nalbuphine became nauseated, but nausea started well after completion of the thermoregulatory measurements and is thus unlikely to have altered our threshold determinations.

In summary, nalbuphine reduced the vasoconstriction and shivering thresholds comparably. The vasoconstriction-to-shivering range thus remained unchanged. This differs markedly from meperidine, which impairs shivering twice as much as vasoconstriction. Atropine increased all thresholds and would thus be expected to facilitate shivering. Our results thus fail to support the theory that activation of -opioid or central anticholinergic receptors contributes to meperidine’s special antishivering action. Some other aspect of meperidine’s pharmacology is thus responsible for the drug’s special antishivering action.

	Acknowledgments

 
Supported by National Institutes of Health Grant GM58273 (Bethesda, MD), the Joseph Drown Foundation (Los Angeles, CA), and the Commonwealth of Kentucky Research Challenge Trust (Louisville, KY). Mallinckrodt Anesthesiology Products, Inc. (St. Louis, MO), donated the thermocouples.

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