Meperidine Decreases the Shivering Threshold Twice as Much as the Vasoconstriction Threshold
Kurz, Andrea MD; Ikeda, Takehiko MD; Sessler, Daniel I. MD; Larson, Merlin D. MD; Bjorksten, Andrew R. PhD; Dechert, Martha BS; Christensen, Richard BS
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.
General anesthetics markedly impair thermoregulatory control, producing a characteristic slight increase in the sweating threshold (triggering core temperature) combined with a marked and comparable reduction in the vasoconstriction and shivering thresholds. [1–3
] Alfentanil, a nearly pure micro‐receptor agonist, produces a similar pattern of thermoregulatory inhibition, although the magnitude is somewhat less. [4
Meperidine possesses special antishivering properties. That is, meperidine prevents or manages shivering far better than roughly equianalgesic doses of other opioids. [5–7
] Meperidine possesses numerous nonopioid effects, including electroencephalographic (EEG) activation, [8
] lethal hyperthermia when combined with monoamine oxidase inhibitors, [9
] positive inotropy, [10
] local anesthetic properties, [11
] and a central anticholinergic action. [8
] Nonetheless, the special antishivering effect of meperidine appears related to its [nearly equal] 10% activity at kappa opioid receptors. [12
] This theory is supported by observations that moderate‐dose naloxone only partially blocks the antishivering effect of meperidine and that butorphanol (also a partial kappa‐receptor agonist) stops shivering better than fentanyl. [13
Despite clinical observations that meperidine possesses special antishivering efficacy, [5–7
] the drug's thermoregulatory physiology remains unexplored. For example, it is unknown whether meperidine also profoundly impairs other thermoregulatory responses such as sweating or vasoconstriction. The issue is important because the drug's efficacy could be mediated by general thermoregulatory impairment or by a special action on shivering.
Proportional inhibition of thermoregulatory control suggests that the drug acts much like an anesthetic, [14–16
] but possesses greater thermoregulatory than analgesic potency. In contrast, disproportionate inhibition of shivering would imply a special antishivering mechanism. Accordingly, we tested the hypothesis that meperidine administration produces a far greater concentration‐dependent reduction in the shivering than vasoconstriction threshold.
With approval from the Committee on Human Research at the University of California in San Francisco and informed consent, we studied nine healthy male volunteers. Morphometric characteristics included age, 31 +/‐ 6 yr; weight, 72 +/‐ 6 kg; height, 177 +/‐ 4 cm; and body fat, 20 +/‐ 2%. [17
] The volunteers fasted 8 hours before arriving at the laboratory, which was maintained near 22 or 23 degrees Celsius. They were minimally clothed during the protocol and rested supine on a standard operating room table. The studies were conducted from July through October 1994. Five of the volunteers participated in a similar, near‐simultaneous evaluation of alfentanil. [4
The volunteers were each evaluated on three separate study days. To avoid circadian fluctuations, studies were scheduled so that thermoregulatory responses were triggered at similar times on each of the days. An intravenous catheter was inserted in the left forearm for fluid and meperidine administration. Fluid was administered as necessary to maintain mean arterial blood pressure > 60 mmHg. A 14‐g catheter was inserted in a right antecubital vein and used for blood sampling.
Meperidine was administered intravenously using a computer‐controlled syringe pump (Ohmeda 9000, Ohmeda Inc., Steeton, England). The infusion profile was based on plasma efflux, [18
] with coefficients estimated from published pharmacokinetic data. [19,20
] The pump was adjusted to provide a target total meperidine plasma concentration of 0.6 micro gram/ml ([nearly equal] 40 mg/h) on the first study day. The second study day served as a control (no drug infusion), and a meperidine plasma concentration of 1.8 micro gram/ml ([nearly equal] 120 mg/h) was targeted on the final study day. To minimize the effects of tolerance, [21
] the lower meperidine dose was always studied first, and at least 2 weeks were allowed between the two meperidine days.
Thermal manipulation started after 15 min of meperidine administration. Before warming, the volunteers were wrapped in plastic to minimize evaporative heat loss. Throughout the protocol, arms were protected from active warming and cooling to avoid locally mediated vasomotion. [22
] 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 then were gradually decreased using the circulating‐water mattress and a forced‐air cooler. [23
] As in previous studies, [2,3
] 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 sweating threshold. The study ended each day when shivering was detected. Skin and core temperature changes were restricted to less than 2 degrees Celsius/h because this rate is unlikely to trigger dynamic thermoregulatory responses. [24
Heart rate and oxyhemoglobin saturation (SpO2) were measured continuously using pulse oximetry, and blood pressure was determined oscillometrically at 5‐min intervals at the left ankle. Expiratory carbon dioxide concentrations were measured from a catheter inserted into one nostril using a Rascal(R) monitor (Ohmeda Inc., Salt Lake City, UT); exhaust gas from this monitor was returned to a DeltaTrac(TM) oxygen consumption monitor (SensorMedics Corp., Yorba Linda, CA).
Core temperature was recorded from the tympanic membrane using Mon‐a‐Therm(R) 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. [25,26
] Temperatures were recorded at 5‐min intervals from thermocouples connected to calibrated Iso‐Thermex(R) thermometers having an accuracy of 0.1 degree Celsius and a precision of 0.01 degree Celsius (Columbus Instruments, Corp., Columbus, OH).
Sweating was continuously quantified on the left upper chest, just below the clavicle, using a ventilated capsule. [27,28
] As in previous studies, [4
] sustained sweating more than 40 g [center dot] m sup ‐2 [center dot] h sup ‐1 defined the sweating threshold. Absolute right middle fingertip blood flow was quantified using venous‐occlusion volume plethysmography at 5‐min intervals; [29
] as in our previous evaluation of opioids, [4
] a sustained decrease in fingertip blood flow to less than 0.25 ml/min identified intense vasoconstriction.
Shivering was evaluated using oxygen consumption as measured by the DeltaTrac(TM) metabolic monitor. The system was used in canopy‐mode, and measurements were averaged for 1‐min intervals and recorded every 5 min. (In this mode, 40 l/min is aspirated by the metabolic monitor from a plastic bubble surrounding the head and upper chest.) A sustained increase in oxygen consumption to 130% of baseline values identified significant shivering.
Venous blood was sampled at the time of sweating, vasoconstriction, and shivering for measurement of meperidine blood concentrations. To determine the concentration of unbound meperidine and normeperidine, 1 ml of fresh plasma from each blood sample was centrifuged using the Micro‐partition System MPS‐1 with YM‐T membrane (Amicon, Inc., Beverly, MA) for 30 min. The ultrafiltrate and the plasma samples were stored at ‐20 degrees Celsius until meperidine concentrations were determined using high‐performance liquid chromatography.
To evaluate meperidine concentrations, plasma (800 micro liter) or ultrafiltrate (150–250 micro liter) were alkalinized with 100 micro liter 3 M NaOH and extracted into 6 ml pentane, along with 25 micro liter/ml of ropivacaine as an internal standard, and back extracted into 125 micro liter 1.5 mM orthophosphoric acid. The mobile phase was 100:10:1 acetonitrile: methanol 20 mM K2 HPO4 at pH 7.0, running through a 150 mm x 3.9 mm micro Bondapac CN column (Waters Associates, Milford, MA) at a rate of 1.5 ml/min with detection by ultraviolet absorbance at 205 nm. This assay is linear to at least 10 micro gram/ml, with a detection limit of 0.005 micro gram/ml with an 80‐micro liter injection and within‐day coefficient of variation of 4.1% (n = 6) at 0.25 micro gram/ml.
Pupil diameter and light‐reflex amplitude correlate well with opioid effect. [30
] Consequently, pupillary responses were used to evaluate pharmacodynamic effects of meperidine. 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, 130 candela/m2
pulse of green light and to 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 three times in succession at each threshold, and the resulting values averaged. Ambient light was maintained near 150 lux, and the left eye was kept covered during the measurements. We previously have described use of this pupillometer. [31
Hemodynamic responses and ambient temperature and humidity on each study day were first averaged within each volunteer; the resulting values then were averaged among volunteers. Results are presented as mean +/‐ SD. All the physiologic effects of meperidine are reported in terms of unbound (active) concentrations. Results for each study day were compared using repeated‐measures analysis of variance and Scheffe's F test. Mean skin temperatures, end‐tidal PCO2, and pupillary responses at the sweating, vasoconstriction, and shivering thresholds were similarly compared. Meperidine blood concentrations and unbound meperidine fraction were compared at the thresholds using two‐tailed, paired t tests.
Core‐temperature response thresholds were determined by arithmetically compensating for alterations in skin temperature using a previously described model. [3
] The coefficient of cutaneous contribution (beta) was taken as 0.1 for sweating [32
] and 0.2 for vasoconstriction and shivering. [33
] The designated skin temperature was set at 34 degrees Celsius because that is a typical intraoperative value.
From the calculated core‐temperature thresholds on each of the three study days, unbound meperidine concentration‐response curves for the sweating, vasoconstriction, and shivering thresholds were determined using linear regression. The average slopes and correlation coefficients (r2) for the nine volunteers then were computed from these values. The effect of unbound meperidine on pupillary responses was similarly computed using linear regression. Additionally, a single regression for each thermoregulatory response was determined from the combined data from all nine volunteers.
The concentration‐dependence of pupillary and thermoregulatory responses in our current volunteers was compared with those previously given alfentanil using linear regression. [34
] The ratio of the slopes, therefore, evaluated the relative potency of each opioid for each response.
Volunteers typically were mildly sedated when the target total plasma meperidine concentration was 0.6 micro gram/ml and deeply sedated when the target concentration was 1.8 micro gram/ml. Total plasma meperidine concentrations were essentially constant during the study. In contrast, normeperidine concentrations increased throughout the infusion. None of the volunteers required mechanical ventilatory assistance. However, most required verbal reminders to breathe at the lower target meperidine concentration, and all required frequent reminders at the higher target concentration. Ambient temperatures and blood pressures were comparable on each of the study days. Expired PCO2
differed significantly at the highest meperidine concentration, but neither difference was clinically important. Heart rate also increased significantly at the highest dosage, by [nearly equal] 10 beats/min (Table 1
Mean skin and core temperatures at sweating, vasoconstriction, and shivering, and the thresholds calculated from these values are shown in Table 2
. The sweating‐to‐vasoconstriction interthreshold range increased progressively as the meperidine concentration was increased. Unbound plasma meperidine decreased the core temperature triggering vasoconstriction by 3.3 +/‐ 1.5 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml (r2
= 0.92 +/‐ 0.08) and shivering by 6.1 +/‐ 3.0 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml (r2
= 0.97 +/‐ 0.05). Shivering was thus inhibited nearly twice as much as vasoconstriction (P = 0.001). In contrast, increasing meperidine blood concentration increased the sweating threshold only slightly (slope = 0.5 +/‐ 0.8 degrees Celsius [center dot] micro gram sup ‐1 [center dot] ml; r2
= 0.51 +/‐ 0.37; Figure 1
). Figure 2
shows the regressions for each threshold in terms of unbound plasma meperidine concentration, this time calculated using the combined data from all volunteers.
Pupil size and reflex amplitude decreased progressively as a function of meperidine concentration; however, the concentrations were similar at the sweating, vasoconstriction, and shivering thresholds on each study day (Table 2
). Absolute reflex amplitude also was markedly reduced from 2.2 to 1.3 to 0.5 mm as the meperidine concentration increased. In contrast, reflex amplitude, expressed as a percentage of pupil size, was similar on the control and 0.6 micro gram/ml day and decreased only [nearly equal] 35% at the highest meperidine concentration. Pupillary responses at each target concentration were virtually identical in our current volunteers and in those given alfentanil in a previous, similar study. [4
The ratio of the concentration‐dependence slopes for vasoconstriction, pupil size, and absolute reflex amplitude were [nearly equal] 20. In contrast, the ratio for shivering was 10, indicating that meperidine inhibits shivering far more than vasoconstriction and more than roughly equivalent concentrations of alfentanil (Table 3
Meperidine slightly increased the sweating threshold while markedly reducing the threshold for vasoconstriction. The sweating‐to‐vasoconstriction interthreshold range [1
] increased sevenfold from its control values of 0.3 degree Celsius to [nearly equal] 2.1 degrees Celsius at the highest meperidine concentration. This pattern of thermoregulatory impairment is similar to that produced by propofol [3
] and volatile anesthetics. [2
] Further, the extent to which sweating and vasoconstriction were inhibited was similar in our current volunteers given meperidine and in those who were previously given roughly equianalgesic plasma concentrations of alfentanil. [4
] Meperidine, like alfentanil and anesthetics, thus markedly impairs thermoregulatory control.
] alfentanil, [4
] propofol, [3
] and the volatile anesthetics [1,2
] comparably decrease the vasoconstriction and shivering thresholds. In marked contrast, meperidine decreased the shivering threshold twice as much as the vasoconstriction threshold. The special antishivering action of meperidine does not, therefore, result simply from a generalized thermoregulatory effect exceeding that expected from the drug's analgesic potency. Instead, shivering appears specifically targeted. It is likely that other kappa‐receptor opioids manifest similar special antishivering activity.
Because only systemic responses were evaluated, we cannot determine the site at which meperidine acts on shivering. However, kappa receptors are mostly located in the spinal cord. Further, shivering‐more than other thermoregulatory responses‐appears to be controlled at the level of the spinal cord. [36–38
] The special antishivering activity of meperidine may thus be mediated by the spinal cord. This site contrasts with thermoregulatory inhibition routinely produced by micro‐receptor agonists, which is presumably largely hypothalamic. Meperidine, having micro and kappa activity, will act at each site. We thus can postulate that meperidine reduces the vasoconstriction threshold via micro effect in the hypothalamus, whereas the shivering threshold is reduced by hypothalamic micro effect and by kappa activity at the level of the cord. To the extent that this paradigm is correct, it suggests that the drug's antishivering action is comparable at each site, thus producing twice the effect of a pure micro‐receptor agonist.
Bound and unbound normeperidine concentrations increased throughout the infusion period. This is a natural consequence of the drug's relatively slow metabolism and occurs even when the meperidine concentration is kept constant by a computer‐controlled infusion. Normeperidine concentrations were thus significantly greater at the shivering threshold than at the vasoconstriction and sweating thresholds‐although the levels never exceeded 10% of the total plasma concentration of meperidine. High concentrations of normeperidine can cause seizures, [39,40
] but the drug probably has weak opioid properties. Further, pupillary responses were comparable at the beginning and end of each study, despite the progressive increase in the normeperidine concentration. It therefore seems unlikely that normeperidine has substantial thermoregulatory consequences. A limitation of our protocol is that we did not independently evaluate the thermoregulatory effects of meperidine and normeperidine.
We used pupil size as a measure of opioid effect. Pupil size is easily obtained with infrared pupillometry, and this convenient measure obviates some of the difficulties surrounding other measures of opioid effect, such as CO2
‐response curves and qualitative scores of mental function. Our goal was to provide equianalgesic doses of meperidine and alfentanil. Pupillary constriction correlates poorly with analgesia when meperidine is given orally. [41
] After parenteral administration, pupil size and analgesia are similarly affected by meperidine. [2
] This correlation has not been studied with alfentanil, but the degree of pupillary constriction correlates well with analgesia during administration of other micro‐receptor agonists, such as heroin, morphine, and methadone. [30,42
] Similar degrees of pupillary constriction with meperidine and alfentanil thus indicate that plasma concentrations of each drug were at least roughly equianalgesic.
Interestingly, the light reflex, expressed as a percentage of pupil size, was only minimally affected by meperidine or alfentanil, [4
] whereas the reflex was markedly reduced by isoflurane [31
] and enflurane. [43
] It thus appears that the percentage reflex amplitude is relatively well maintained during opioid administration, despite markedly reduced pupil size. In contrast, volatile anesthetics reduce the reflex amplitude more than pupil size. Differing effects on pupil size and the reflex amplitude with these two classes of drugs could possibly be exploited to independently evaluate “depth‐of‐anesthesia” (volatile anesthetic effect) and analgesia (opioid effect).
Development of tolerance is dose‐ and time‐dependent, but it is similar with opioids of differing potencies. [44
] The amount of meperidine required when the target plasma concentration was 0.6 micro gram/ml was far less than at the higher concentration and was given for less than half the time. We minimized the chance of developing significant tolerance by always administering the lower dose first. The time required for opioid‐naive humans to recover normal pharmacodynamic responses after several hours of narcotic administration remains unclear, although it seems likely that the 2 weeks we allowed between the lower and higher target meperidine concentrations was adequate. [21
As in previous investigations, [3,4
] we always initially warmed subjects to sweating and only subsequently cooled to vasoconstriction and shivering. We chose this order because the sweating threshold deviates from normal temperature far less than the cold‐response thresholds. The studies were much shorter using initial warming than had we cooled subjects to shivering and then rewarmed to sweating. Although we lost the benefits of randomization with this strategy, it allowed us to complete the studies more quickly and to limit potential for opioid tolerance.
The validity of our comparison between the thermoregulatory effects of alfentanil and meperidine is potentially limited because the studies were not exactly contemporaneous and because only half the volunteers participated in both. However, it is unlikely that relevant characteristics of the volunteers changed significantly: all were young, healthy men who avoided opioids and recreational drugs.
Another factor limiting comparison between our current and previous studies is that the equianalgesic plasma concentrations of meperidine and alfentanil remain unclear. Previous work on clinical analgesic efficacy suggests an [nearly equal] 6:1 total concentration ratio between meperidine and alfentanil. [45,46
] The actual total meperidine‐to‐alfentanil ratio in our two studies was only [nearly equal] 4:1. However, pupillary responses‐a reliable measure of opioid effect [30
]‐were virtually identical in the two studies. Additionally sedation levels, evaluated informally, also were similar. It seems likely that the meperidine and alfentanil doses in our two studies were roughly equianalgesic.
An additional limitation of this study is that we evaluated neither the gain nor the maximal intensity of shivering. Gain is defined by the rate at which shivering increases, once triggered, with additional core cooling. Maximum intensity is the largest increase in metabolic rate that can be induced by body cooling. Reduced gain or maximum intensity of shivering could contribute to the remarkable clinical efficacy of meperidine.
In summary, meperidine slightly increased the threshold for sweating and markedly reduced the vasoconstriction and shivering thresholds. The shivering threshold was reduced nearly twice as much as the vasoconstriction threshold. The special antishivering efficacy of meperidine thus results at least in part from a special and uncharacteristically large reduction in the shivering threshold rather than from exaggerated generalized thermoregulatory inhibition. This pattern of impairment differs from that produced by alfentanil, clonidine, propofol, and the volatile anesthetics, all which reduce the vasoconstriction and shivering thresholds comparably. Disproportionate inhibition of shivering by meperidine possibly results from kappa‐receptor agonist at the level of the spinal cord.
The authors thank Charles Hackman, F.A.N.Z.C.A. (assisted by an Australian and New Zealand College of Anaesthetists Research Project Grant) for programming the computer‐controlled infusion.
1. Sessler DI: Perianesthetic thermoregulation and heat balance in humans. FASEB J 1993; 7:638-44.
2. Annadata RS, Sessler DI, Tayefeh F, Kurz A, Dechert M: Desflurane slightly increases the sweating threshold, but produces marked and non-linear decreases in the vasoconstriction and shivering thresholds. Anesthesiology 1995; 83:1205-11.
3. Matsukawa T, Kurz A, Sessler DI, Bjorksten AR, Merrifield B, Cheng C: Propofol linearly reduces the vasoconstriction and shivering thresholds. Anesthesiology 1995; 82:1169-80.
4. Kurz A, Go JC, Sessler DI, Kaer K, Larson M, Bjorksten AR: Alfentanil slightly increases the sweating threshold and markedly reduces the vasoconstriction and shivering thresholds. Anesthesiology 1995; 83:293-9.
5. Pauca AL, Savage RT, Simpson S, Roy RC: Effect of pethidine, fentanyl and morphine on post-operative shivering in man. Acta Anaesthesiol Scand 1984; 28:138-43.
6. Guffin A, Girard D, Kaplan JA: Shivering following cardiac surgery: Hemodynamic changes and reversal. J Cardiothorac Vasc Anesth 1987; 1:24-8.
7. Nikki P: Influence of some cholinomimetic and cholinolytic drugs on halothane shivering in mice. Ann Med Exp Biol Fenn 1968; 46:521-30.
8. Votava Z, Elliott HW: The effect of morphine, meperidine, and methadone on the cholinergic EEG and behavioral activation in rabbits, Chemical Modulation of Brain Function, Edited by Sabelli HC. New York, Raven Press, 1973, pp 123-35.
9. Mackenzie JE, Frank LW: Influence of pretreatment with a monoamine oxidase inhibitor (phenelzine) on the effects of buprenorphine and pethidine in the conscious rabbit. Br J Anaesth 1988; 60:216-21.
10. Helgesen KT, Ellingsen O, Ilebekk A: Inotropic effect of meperidine: Influence of receptor and ion channel blockers in the rat atrium. Anesth Analg 1990; 70:499-506.
11. Kaya K, Babacan A, Beyazova M, Bolukbasi N, Akcabay M, Karadenizli Y: Effects of perineural opioids on nerve conduction of N. suralis in man. Acta Neurol Scand 1992; 85:337-9.
12. Magnan J, Paterson SJ, Tavani A, Kosterlitz HW: The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties. Naunyn-Schmiedeberg's Arch Pharmacol 1982; 319:197-205.
13. Kurz M, Belani K, Sessler DI, Kurz A, Larson M, Blanchard D, Schroeder M: Naloxone, meperidine, and shivering. Anesthesiology 1993; 79:1193-201.
14. Farber NE, Schmidt JE, Kampine JP, Schmeling WT: Halothane modulates thermosensitive hypothalamic neurons in rat brain slices. Anesthesiology 1995; 83:1241-53.
15. Farber NE, Poterack KA, Kampine JP, Schmeling WT: The effects of halothane, isoflurane, and enflurane on thermoregulatory responses in the neuraxis of cats. Anesthesiology 1994; 80:879-91.
16. Murakami N, Stolwijk AJ, Hardy JD: Responses of preoptic neurons to anesthetics and peripheral stimulation. Am J Physiol 1967; 213:1015-24.
17. Conway JM, Norris KH, Bodwell CE: A new approach for the estimation of body composition: Infrared interactance. Am J Clin Nutr 1984; 40:1123-30.
18. Crankshaw DP, Karasawa F: A method for implementing programmed infusion of theiopentone and methohexitone with a simple infusion pump. Anaesth Int Care 1989; 17:496-9.
19. Mather LE, Tucker GT, Pflug AE, Lindop MJ, Wilkerson C: Meperidine kinetics in man: Intravenous injection in surgical patients and volunteers. Clin Pharmacol Ther 1974; 17:21-30.
20. Austin KL, Stapleton JV, Mather LE: Relationship between blood meperidine concentrations and analgesic response. Anesthesiology 1980; 53:460-6.
21. Carter BD, Medzihradsky F: Receptor mechansims of opioid tolerance in SH-SY5Y human neural cells. Mol Pharmacol 1993; 43:465-73.
22. Wurster RD, McCook RD: Influence of rate of change in skin temperature on sweating. J Appl Physiol 1969; 27:237-40.
23. Kurz A, Sessler DI, Birnbauer F, Illievich U, Spiss C: Thermoregulatory vasoconstriction impairs active core cooling. Anesthesiology 1995; 82:870-6.
24. Lopez M, Sessler DI, Walter K, Emerick T, Ozaki M: Rate and gender dependence of the sweating, vasoconstriction, and shivering thresholds in humans. Anesthesiology 1994; 80:780-8.
25. Sessler DI, McGuire J, Moayeri A, Hynson J: Isoflurane-induced vasodilation minimally increases cutaneous heat loss. Anesthesiology 1991; 74:226-32.
26. Matsukawa T, Sessler DI, Sessler AM, Schroeder M, Ozaki M, Kurz A, Cheng C: Heat flow and distribution during induction of general anesthesia. Anesthesiology 1995; 82:662-73.
27. Washington D, Sessler DI, Moayeri A, Merrifield B, Prager M, McGuire J, Belani K, Hudson S, Schroeder M: Thermoregulatory responses to hyperthermia during isoflurane anesthesia in humans. J Appl Physiol 1993; 74:82-7.
28. Lopez M, Ozaki M, Sessler DI, Valdes M: Physiological responses to hyperthermia during epidural anesthesia and combined epidural/enflurane anesthesia in women. Anesthesiology 1993; 78:1046-54.
29. Rubinstein EH, Sessler DI: Skin-surface temperature gradients correlate with fingertip blood flow in humans. Anesthesiology 1990; 73:541-5.
30. Martin WR: Pharmacology of opioids. Pharmmacol Rev 1983; 35:283-323.
31. Larson M, Sessler DI: Isoflurane, but not mild hypothermia, depresses the human pupillary light reflex. Anesthesiology 1991; 75:62-7.
32. Nadel ER, Metchell JW, Stolwijk JAJ: Control of local and total sweating during exercise transients. Int J Biometeorol 1971; 15:201-6.
33. Cheng C, Matsukawa T, Sessler DI, Kurz A, Merrifield B, Lin H, Olofsson P: Increasing mean skin temperature linearly reduces the core-temperature thresholds for vasoconstriction and shivering thresholds in humans. Anesthesiology 1995; 82:1160-8.
34. Webb WR, deGuzman VC, Grogan JB, Artz CP: Hypothermia: Its effects upon hematologic clearance in experimentally induced staphylococcal bacteremia. Surgery 1962; 52:643-7.
35. Delaunay L, Bonnet F, Liu N, Beydon L, Catoire P, Sessler DI: Clonidine comparably decreases the thermoregulatory thresholds for vasoconstriction and shivering in humans. Anesthesiology 1993; 79:470-4.
36. Simon E: Temperature regulation: The spinal cord as a site of extrahypothalamic thermoregulatory functions. Rev Physiol Biochem Pharmacol 1974; 71:1-76.
37. Klussmann FW: Energy production of rabbits before and after transection of both ventro-lateral funiculi of the spinal cord. J Therm Biol 1983; 8:133-5.
38. Kosaka M, Simon E, Thauer R: Shivering in intact and spinal rabbits during spinal cord cooling. Experientia 1967; 23:385-7.
39. Goetting MG: Neurotoxicity of meperidine. Ann Emerg Med 1985; 14:1007-9.
40. Szeto HH, Inturrisi CE, Houde R, Saal S, Cheigh J, Reidberg MM: Accumulation of normeperidine, an active metabolite of meperidine in patients with renal failure and cancer. Ann Intern Med 1977; 86:738-41.
41. Fraser HF, Nash TL, Vanhorn GD, Isbell H: Use of miotic effect in evaluating analgesic drugs in man. Arch Int Pharmacodyn 1954; 98:443-51.
42. Jasinski DR: Assessment of the abuse potentiality of morphinelike drugs (methods used in man), Drug Addiction 1: Morphine, Sedative/hypnotic and Alcohol Dependence, Edited by Martin WR. Berlin, Springer-Verlag, 1977, pp 197-258.
43. Belani KB, Sessler DI, Larson M, Lopez M, Washington DE, Ozaki M, McGuire J, Merrifield B, Hynson J, Schroeder M: The pupillary light reflex: Effects of anesthetics and hyperthermia. Anesthesiology 1993; 79:23-7.
44. Kissin I, Brown PT, Bradley EL: Magnitude of acute tolerance to opioids is not related to their potency. Anesthesiology 1991; 75:813-6.
45. Tamsen A, Hartvig P, Fagerlund C, Dahlstrom B: Patient controlled analgesic therapy, part 2: Individual analgesic demand and analgesic plasma concentrations of pethidine in postoperative pain. Clin Pharmacokinet 1982; 7:164-75.
46. Baumann TJ, Smythe MA, Marikis B, Bivins BA: Meperidine serum concentrations and analgesic response in postsurgical patients. Ann Pharmacother 1991; 25:724-6.
This article has been cited 61 time(s).
Journal of Critical CareNonpharmacologic approach to minimizing shivering during surface cooling: A proof of principle studyJournal of Critical Care
Journal of Cardiothoracic and Vascular Anesthesia
The implications of hypothermia for early tracheal extubation following cardiac surgery
Journal of Cardiothoracic and Vascular Anesthesia, 12(6):
Anesthesia and Analgesia
Neither nalbuphine nor atropine posses special antishivering activity
Anesthesia and Analgesia, 93(3):
AnaesthesiaA randomised double-blind controlled study evaluating the hypothermic effect of 150 mu g morphine during spinal anaesthesia for Caesarean sectionAnaesthesia
International Journal of Stroke
Therapeutic hypothermia for acute stroke
International Journal of Stroke, 1(1):
Anesthesia and Analgesia
Hypoxemia decreases the shivering threshold in rabbits anesthetized with 0.2 minimum alveolar anesthetic concentration isoflurane
Anesthesia and Analgesia, 87(6):
Anesthesia and Analgesia
Induction of anesthesia with ketamine reduces the magnitude of redistribution hypothermia
Anesthesia and Analgesia, 93(4):
StrokeDexmedetomidine and meperidine additively reduce the shivering threshold in humansStroke
Journal of the Neurological SciencesProgress in shivering controlJournal of the Neurological Sciences
Neurocritical CareEffect of Shivering on Brain Tissue Oxygenation During Induced Normothermia in Patients With Severe Brain InjuryNeurocritical Care
British Journal of AnaesthesiaNitrous oxide decreases shivering threshold in rabbits less than isofluraneBritish Journal of Anaesthesia
Anesthesia and AnalgesiaDantrolene reduces the threshold and gain for shiveringAnesthesia and Analgesia
Postoperative pain facilitates nonthermoregulatory tremor
Anesthesia and Analgesia
Buspirone and meperidine synergistically reduce the shivering threshold
Anesthesia and Analgesia, 93(5):
Anesthesia and Analgesia
The threshold and gain of thermoregulatory vasoconstriction differs during anesthesia in the dependent and upper arms in the lateral position
Anesthesia and Analgesia, 94(4):
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Best evidence in anesthetic practice - Treatment: meperidine, clonidine, doxapram, ketanserin or alfentanil abolishes short-term postoperative shivering
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 50(7):
Critical CareMeperidine and skin surface warming additively reduce the shivering threshold: a volunteer studyCritical Care
Journal of Clinical Anesthesia
Atropine prevents midazolam-induced core hypothermia in elderly patients
Journal of Clinical Anesthesia, 13(7):
Anesthesia and AnalgesiaIntrathecal meperidine decreases shivering during cesarean delivery under spinal anesthesiaAnesthesia and Analgesia
Physiology and clinical relevance of induced hypothermia
Neurocritical Care, 1(4):
Journal of Pharmacology and Experimental TherapeuticsPharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: Assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical dataJournal of Pharmacology and Experimental Therapeutics
Journal of Theoretical BiologyBrain cooling maintenance with cooling cap following induction with intracarotid cold saline infusion: A quantitative modelJournal of Theoretical Biology
Anesthesia and AnalgesiaThe Shivering Threshold in Rabbits with JM-1232(-), a New Benzodiazepine Receptor AgonistAnesthesia and Analgesia
Endogenous opiates: 1997
Thermoregulatory thresholds for vasoconstriction in patients anesthetized with various 1-minimum alveolar concentration combinations of xenon, nitrous oxide, and isoflurane
International Journal of Obstetric AnesthesiaThe rise in maternal temperature associated with regional analgesia in labour is harmful and should be treatedInternational Journal of Obstetric Anesthesia
Effect of postoperative skin-surface warming on oxygen consumption and the shivering threshold
Journal of Thermal BiologyEffect of tropisetron versus placebo on cold-induced oxygen consumption and shivering in male volunteersJournal of Thermal Biology
American Journal of Medicine
The effects of physical treatment on induced fever in humans
American Journal of Medicine, 106(5):
Annals of Emergency Medicine
Resistive heating is more effective than metallic-foil insulation in an experimental model of accidental hypothermia: A randomized controlled trial
Annals of Emergency Medicine, 35(4):
StrokeNeither arm nor face warming reduces the shivering threshold in unanesthetized humansStroke
Anaesthesia and Intensive Care
Pethidine and skin warming to prevent shivering during endovascular cooling
Anaesthesia and Intensive Care, 32(3):
Anesthesia and AnalgesiaSingle-dose parenteral pharmacological interventions for the prevention of postoperative shivering: A quantitative systematic review of randomized controlled trialsAnesthesia and Analgesia
AnaesthesiaComparison of the effects of intrathecal morphine and pethidine on shivering after Caesarean delivery under combined-spinal epidural anaesthesiaAnaesthesia
NeuropharmacologyNefopam but not physostigmine affects the thermoregulatory response in mice via alpha(2)-adrenoceptorsNeuropharmacology
Anesthesia and Analgesia
Intraoperative phenylephrine infusion decreases the magnitude of redistribution hypothermia
Anesthesia and Analgesia, 89(2):
Anesthesia and Analgesia
Epidural fentanyl reduces the shivering threshold during epidural lidocaine anesthesia
Anesthesia and Analgesia, 87(3):
Perioperative heat balance
Regional Anesthesia and Pain Medicine
Effects of epidural anesthesia on thermal sensation
Regional Anesthesia and Pain Medicine, 26(6):
Journal of NeuroimagingTranscranial Doppler ultrasonographic evaluation of middle cerebral artery hemodynamics during mild hypothermiaJournal of Neuroimaging
StrokeDefeating Normal Thermoregulatory Defenses Induction of Therapeutic HypothermiaStroke
Journal of Internal Medicine
Journal of Internal Medicine, 244(5):
Postanaesthetic shivering - Epidemiology, pathophysiology, and approaches to prevention and management
Journal of AnesthesiaThe effects of remifentanil or acetaminophen with epidural ropivacaine on body temperature during laborJournal of Anesthesia
Anesthesia and Analgesia
Tramadol reduces the sweating, vasoconstriction, and shivering thresholds
Anesthesia and Analgesia, 87(1):
Regional Anesthesia and Pain Medicine
Maternal fever, neonatal sepsis evaluation, and epidural labor analgesia
Regional Anesthesia and Pain Medicine, 25(5):
Regional Anesthesia and Pain MedicineNefopam and tramadol for the prevention of shivering during neuraxial anesthesiaRegional Anesthesia and Pain Medicine
Journal of Clinical Anesthesia
Nonmalignant hyperthermia on induction of anesthesia in a pediatric patient undergoing bi-directional Glenn procedure
Journal of Clinical Anesthesia, 10(5):
AnesthesiologyTemperature Monitoring and Perioperative ThermoregulationAnesthesiology
Current Opinion in Critical CareManagement of cardiac arrest patients to maximize neurologic outcomeCurrent Opinion in Critical Care
Journal of Neurosurgical AnesthesiologyInfrared Pupillometry During Uncal HerniationJournal of Neurosurgical Anesthesiology
Anesthesia; Opioids: alfentanil; meperidine; pethidine; Temperature; Thermoregulation: shivering; sweating; vasoconstriction.
© 1997 American Society of Anesthesiologists, Inc.
Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Highlight selected keywords in the article text.