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).     

The Effects of Meperidine and Sufentanil on the Shivering Threshold in Postoperative Patients

Background: Meperidine (pethidine) reportedly treats postoperative shivering better than equianalgesic doses of other [micro sign]-receptor agonists. The authors' first goal was to develop a method to accurately determine postoperative shivering threshold, and then to determine the extent to which meperidine and sufentanil inhibit postoperative shivering.

Methods: A computer-controlled infusion was started before operation in 30 patients, with target plasma concentrations of 0.15, 0.30, or 0.60 [micro sign]g/ml meperidine or 0.1, 0.15, or 0.2 ng/ml sufentanil targeted; patients were randomly assigned to each drug and concentration. The infusion was continued throughout surgery and recovery. Anesthesia was maintained with nitrous oxide and isoflurane. Core temperatures were [almost equal to] 34 [degree sign]C by the end of surgery. The compensated core temperature at which visible shivering and a 20% decrease in steady-state oxygen consumption was recorded identified the shivering threshold. A blood sample for opioid concentration was obtained from each patient at this time. The ability of each opioid to reduce the shivering threshold was evaluated using linear regression.

Results: End-tidal isoflurane concentrations were <0.2% in each group at the time of extubation, and shivering occurred [almost equal to] 1 h later. Meperidine linearly decreased the shivering threshold: threshold ([degree sign]C) = -2.8 [middle dot] [meperidine ([micro sign]g/ml)] + 36.2; r2 = 0.64, P = 0.0005. Sufentanil also linearly decreased the shivering threshold: threshold ([degree sign]C) = -7.8 [middle dot] [sufentanil (ng/ml)] + 36.9; r (2) = 0.46, P = 0.02.     

Epidural Anesthesia Reduces the Gain and Maximum Intensity of Shivering

Background: Shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase), and maximum intensity. The gain of shivering might be preserved during epidural or spinal anesthesia if control mechanisms compensate for lower-body paralysis by augmenting the activity of upper-body muscles. Conversely, gain will be reduced approximately by half if the thermoregulatory system fails to compensate. Similarly, appropriate regulatory feedback might maintain maximum shivering intensity during regional anesthesia. Accordingly, the gain and maximum intensity of shivering during epidural anesthesia were determined.

Methods: Seven volunteers participated on two randomly ordered study days. On one day (control), no anesthesia was administered; on the other, epidural anesthesia was maintained at a T8 sensory level. Shivering, at a mean skin temperature near 33 [degree sign] Celsius, was provoked by central-venous infusion of cold fluid; core cooling continued until shivering intensity no longer increased. Shivering was evaluated by systemic oxygen consumption and electromyography of two upper-body and two lower-body muscles. The core temperature triggering an increase in oxygen consumption identified the shivering threshold. The slopes of the oxygen consumption versus core temperature and electromyographic intensity versus core temperature regressions identified systemic and regional shivering gains, respectively.

Results: The shivering threshold was reduced by epidural anesthesia by [nearly =] 0.4 [degree sign] Celsius, from 36.7 +/- 0.6 to 36.3 +/- 0.5 [degree sign] Celsius (means +/- SD; P < 0.05). Systemic gain, as determined by oxygen consumption, was reduced from -581 +/- 186 to -215 +/- 154 ml [center dot] min sup -1 [center dot] [degree sign] Celsius sup -1 (P < 0.01). Lower-body gain, as determined electromyographically, was essentially obliterated by paralysis during epidural anesthesia, decreasing from -0.73 +/- 0.85 to -0.04 +/- 0.06 intensity units/[degree sign] Celsius (P < 0.01). However, upper-body gain had no compensatory increase: -1.3 +/- 1.1 units/[degree sign] Celsius control versus -2.0 +/- 2.1 units/[degree sign] Celsius epidural. Maximum oxygen consumption was decreased by one third during epidural anesthesia: 607 +/- 82 versus 412 +/- 50 ml/min (P < 0.05).     

Isoflurane Alters Shivering Patterns and Reduces Maximum Shivering Intensity

Background: Shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core hypothermia), and maximum response intensity. Isoflurane produces a clonic muscular activity that is not a component of normal shivering. To the extent that clonic activity is superimposed on normal thermoregulatory shivering, the gain of shivering might be increased during isoflurane anesthesia. Conversely, volatile anesthetics decrease systemic oxygen consumption and peripherally inhibit skeletal muscle strength, which might limit maximum intensity despite central activation. The purpose of the present study was, therefore, to evaluate the effect of isoflurane shivering patterns and the gain and maximum intensity of shivering.

Methods: Ten volunteers were each studied in two separate protocols: (1) control (no drug) and (2) 0.7% end-tidal isoflurane. On each day, the mean skin temperature was maintained at 31 [degree sign] Celsius. Core temperature was then reduced by infusion of cold fluid until shivering intensity no longer increased. The core temperature triggering the initial increase in oxygen consumption defined the shivering threshold. The gain of shivering was defined by the slope of the core temperature versus oxygen consumption regression. Pectoralis and quadriceps electromyography was used to evaluate anesthetic-induced facilitation of clonic (5-7 Hz) muscular activity.

Results: Isoflurane significantly decreased the shivering threshold from 36.4 +/- 0.3 to 34.2 +/- 0.8 [degree sign] Celsius. The increase in oxygen consumption was linear on the control day and was followed by sustained high-intensity activity. During isoflurane administration, shivering was characterized by bursts of intense shivering separated by quiescent periods. Isoflurane significantly increased the gain of shivering (as calculated from the initial increase), from -684 +/- 266 to -1483 +/- 752 ml [center dot] min sup -1 [center dot] [degree sign] Celsius sup -1. However, isoflurane significantly decreased the maximum intensity of shivering, from 706 +/- 144 to 489 +/- 80 ml/min. Relative electromyographic power in frequencies associated with clonus increased significantly when the volunteers were given isoflurane.     

Propofol Linearly Reduces the Vasoconstriction and Shivering Thresholds

Background: Skin temperature is best kept constant when determining response thresholds because both skin and core temperatures contribute to thermoregulatory control. In practice, however, it is difficult to evaluate both warm and cold thresholds while maintaining constant cutaneous temperature. A recent study shows that vasoconstriction and shivering thresholds are a linear function of skin and core temperatures, with skin contributing 20 plus/minus 6% and 19 plus/minus 8%, respectively. (Skin temperature has long been known to contribute [nearly equal] 10% to the control of sweating.) Using these relations, we were able to experimentally manipulate both skin and core temperatures, subsequently compensate for the changes in skin temperature, and finally report the results in terms of calculated core- temperature thresholds at a single designated skin temperature.

Methods: Five volunteers were each studied on 4 days: (1) control; (2) a target blood propofol concentration of 2 micro gram/ml; (3) a target concentration of 4 micro gram/ml; and (4) a target concentration of 8 micro gram/ml. On each day, we increased skin and core temperatures sufficiently to provoke sweating. Skin and core temperatures were subsequently reduced to elicit peripheral vasoconstriction and shivering. We mathematically compensated for changes in skin temperature by using the established linear cutaneous contributions to the control of sweating (10%) and to vasoconstriction and shivering (20%). From these calculated core-temperature thresholds (at a designated skin temperature of 35.7 degrees Celsius), the propofol concentration- response curves for the sweating, vasoconstriction, and shivering thresholds were analyzed using linear regression. We validated this new method by comparing the concentration-dependent effects of propofol with those obtained previously with an established model.

Results: The concentration-response slopes for sweating and vasoconstriction were virtually identical to those reported previously. Propofol significantly decreased the core temperature triggering vasoconstriction (slope = 0.6 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.98 plus/minus 0.02) and shivering (slope = 0.7 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.95 plus/minus 0.05). In contrast, increasing the blood propofol concentration increased the sweating threshold only slightly (slope = 0.1 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.46 plus/minus 0.39).     

Dantrolene reduces the threshold and gain for shivering

Dantrolene is used for treatment of life-threatening hyperthermia, yet its thermoregulatory effects are unknown. We tested the hypothesis that dantrolene reduces the threshold (triggering core temperature) and gain (incremental increase) of shivering. Healthy volunteers were evaluated on 2 random days: control and dantrolene (approximately 2.5 mg/kg plus a continuous infusion). In Study 1, 9 men were warmed until sweating was provoked and then cooled until arteriovenous shunt constriction and shivering occurred. Sweating was quantified on the chest using a ventilated capsule. Absolute right middle fingertip blood flow was quantified using venous-occlusion volume plethysmography. A sustained increase in oxygen consumption identified the shivering threshold. In Study 2, 9 men were given cold lactated Ringer's solution i.v. to reduce core temperature approximately 2 degrees C/h. Cooling was stopped when shivering intensity no longer increased with further core cooling. The gain of shivering was the slope of oxygen consumption versus core temperature regression. In Study 1, sweating and vasoconstriction thresholds were similar on both days. In contrast, shivering threshold decreased 0.3 +/- 0.3 degrees C, P = 0.004, on the dantrolene day. In Study 2, dantrolene decreased the shivering threshold from 36.7 +/- 0.2 to 36.3 +/- 0.3 degrees C, P = 0.01 and systemic gain from 353 +/- 144 to 211 +/- 93 mL.min(-1).degrees C(-1), P = 0.02. Thus, dantrolene substantially decreased the gain of shivering, but produced little central thermoregulatory inhibition. IMPLICATIONS: Dantrolene substantially decreases the gain of shivering but produces relatively little central thermoregulatory inhibition. It thus seems unlikely to prove more effective than conventional muscle relaxants for treatment of life-threatening hyperthermia.     

Neither nalbuphine nor atropine possess special antishivering activity

The special antishivering action of meperidine may be mediated by its kappa 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 microg/mL), 3) large-dose nalbuphine (0.4 microg/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 degrees C. microg(-1). mL; r(2) = 0.75 +/- 0.25), vasoconstriction (-2.6 +/- 1.7 degrees C. microg(-1). mL; r(2) = 0.75 +/- 0.25), and shivering (-2.8 +/- 1.7 degrees C. microg(-1). mL; r(2) = 0.79 +/- 0.23) thresholds. Atropine significantly increased the thresholds for sweating (1.0 degrees C +/- 0.4 degrees C), vasoconstriction (0.9 degrees C +/- 0.3 degrees C), and shivering (0.7 degrees C +/- 0.3 degrees 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 kappa-opioid or central anticholinergic receptors contribute to meperidine's special antishivering action.     

The effects of urapidil on thermoregulatory thresholds in volunteers

In a previous study we have shown that the antihypertensive drug, urapidil, stops postanesthetic shivering. One possible mechanism in the inhibition of postanesthetic shivering by urapidil may be alterations in thermoregulatory thresholds. We therefore studied the effects of urapidil on vasoconstriction and shivering thresholds during cold-induced shivering in volunteers. Seven healthy male volunteers were cooled by an infusion of saline at 4 degrees C on two study days separated by 48 h. Thermoregulatory vasoconstriction was estimated using forearm minus fingertip skin-temperature gradients, and values exceeding 0 degrees C were considered to represent significant vasoconstriction. The rectal core temperatures at the beginning of shivering and at vasoconstriction were considered the thermoregulatory thresholds. Before cooling, either 25 mg of urapidil or placebo was administered randomly and blindly to each volunteer. When shivering occurred continuously for 10 min, another 25 mg of urapidil was administered IV to completely stop shivering. Urapidil led to a decrease in core temperature at vasoconstriction and shivering threshold by 0.4 degrees C plus/minus 0.2 degrees C (P < 0.001) and 0.5 degrees C plus/minus 0.3 degrees C (P < 0.01), respectively. Oxygen consumption increased during shivering by 70% plus/minus 30% (P < 0.01) in comparison with baseline and decreased levels after shivering stopped, despite the continued low core temperature. Our investigation shows that urapidil stops postanesthetic shivering by decreasing important thermoregulatory thresholds. This means that shivering, not hypothermia, is treated, and hypothermia will need more attention in the postanesthesia care unit. IMPLICATIONS: In this study we show that the antihypertensive drug urapidil stops cold-induced shivering and decreases normal thermoregulatory responses, i.e., the thresholds for vasoconstriction and shivering, in awake volunteers.     

Effect of meperidine on oxygen consumption, carbon dioxide production, and respiratory gas exchange in postanesthesia shivering

Meperidine has been used to suppress postanesthesia shivering. However, its efficacy to date has only been assessed by observation of visible shivering. We measured the effect of meperidine on oxygen consumption (VO2), carbon dioxide production (VCO2) and pulmonary gas exchange in 14 otherwise healthy patients shivering after general anesthesia. Meperidine successfully suppressed visible shivering in all patients and was associated with significant decreases in VO2, and VCO2 and minute ventilation (VE) but not with return to basal levels. Arterial PCO2 levels remained unchanged at normal, whereas significant improvements occurred in pH and bicarbonate levels. Meperidine is an effective method of reducing the elevated metabolic demand of shivering.     

Differential Effects of [alpha]2-adrenoceptors in the Modulation of the Thermoregulatory Response in Mice Induced by Meperidine

Background: Meperidine proved to be more effective in treatment of shivering than equianalgesic doses of other opioids, especially pure [mu]-agonists. Further, meperidine has well known nonopioid actions including agonistic effects at [alpha]2-adrenoceptors in vitro. Accordingly, the authors investigated nonopioid receptor-mediated effects of meperidine on thermoregulation using a mice model of nonshivering thermogenesis. To differentiate conceivable [alpha]2-adrenoceptor subtype specific interactions the authors analyzed wild-type mice and knock-out mice with deletion of the [alpha]2A-, [alpha]2B-, or [alpha]2C-adrenoceptor.

Methods: Ten mice per group (n = 60) were injected with saline, meperidine (20 mg/kg), saline plus naloxone (125 [mu]g/kg), meperidine plus naloxone, fentanyl (50 [mu]g/kg) plus naloxone, or meperidine plus atipamezole (2 mg/kg) intraperitoneally. Each mouse was subjected to the six different treatments. Then they were positioned into a plexiglas chamber where rectal temperature and mixed expired carbon dioxide were measured while whole body cooling was performed. Maximum response intensity and thermoregulatory threshold temperature of nonshivering thermogenesis were analyzed.

Results: Meperidine decreased the thermoregulatory threshold temperature in wild-type mice and [alpha]2B- and [alpha]2C-adrenoceptor knock-out mice. This effect ended after injection of the [alpha]2-adrenoceptor antagonist atipamezole. In wild-type and [alpha]2B-adrenoceptor knock-out mice, the decrease of thermoregulatory threshold was not reversible by administration of the opioid receptor antagonist naloxone. In contrast, in [alpha]2A-adrenoceptor knock-out mice, no decline of thermoregulatory threshold following meperidine injection was detectable. Maximum response intensity of nonshivering thermogenesis was comparable in all groups.     

Isoflurane Produces Marked and Nonlinear Decreases in the Vasoconstriction and Shivering Thresholds

Background: Desflurane decreases the vasoconstriction and shivering thresholds disproportionately at high anesthetic concentrations. This result contrasts with the authors' previous report that isoflurane decreases the vasoconstriction threshold linearly. It is surprising that the basic shape of the concentration-response curve should differ with these two otherwise similar anesthetics. Therefore, the hypothesis that isoflurane produces a nonlinear reduction in the vasoconstriction threshold was tested. Because the effect of isoflurane on shivering remains unknown, the extent to which isoflurane reduces the shivering threshold also was determined.

Methods: Eight men volunteered to be studied on four randomly ordered days: (1) a target end-tidal isoflurane concentration of 0.55%, (2) a target concentration of 0.7%, (3) control (no anesthesia) and a target end-tidal concentration of 0.85%, and (4) a target end-tidal concentration of 1.0%. Volunteers were surface-cooled until peripheral vasoconstriction and shivering were observed. We arithmetically compensated for changes in skin temperature using the established linear cutaneous contributions to control for each response. From the calculated thresholds (core temperatures triggering responses at a designated skin temperature of 34 degrees C), the concentration-response relation was determined.

Results: Isoflurane administration produced a dose-dependent reduction in the vasoconstriction and shivering thresholds, decreasing each [nearly equal] 4.6 degrees C at an end-tidal concentration of 1%. Residual analysis indicated that the vasoconstriction and shivering thresholds were decreased in a nonlinear fashion during isoflurane administration. The vasoconstriction-to-shivering range was 1.5+/- 0.8 degree C without isoflurane, and did not change significantly during isoflurane administration.     

Physostigmine Prevents Postanesthetic Shivering As Does Meperidine or Clonidine

Background: Postanesthetic shivering develops in as many as one half of patients recovering from isoflurane anesthesia. Cholinergic stimulation of the hypothalamic-pituitary-adrenal axis and adrenal medulla by physostigmine enhances secretion of arginine vasopressin, epinephrine, and norepinephrine. Because the hypothalamus is the dominant thermoregulatory controller in mammals, and these neurotransmitters may be involved in body temperature control, physostigmine administration may influence the incidence of shivering. Accordingly, the authors tested the hypothesis that physostigmine administration inhibits postanesthetic shivering. Its efficacy was compared with that of saline (negative control) and meperidine and clonidine (positive controls).

Methods: Sixty patients having surgery of the ear or nose were tested. General anesthesia was induced with 2 mg/kg propofol, 0.1 mg/kg vecuronium, and 1.5 micro gram/kg fentanyl and maintained with isoflurane (1.5 +/- 0.4%) in 70% nitrous oxide. At the end of surgery, the patients were randomly assigned to receive an intravenous bolus of 0.04 mg/kg physostigmine, isotonic saline, 0.5 mg/kg meperidine, or 1.5 micro gram/kg clonidine. Heart rate, mean arterial blood pressure, oxygen saturation, visual analog pain score, temperature, and postanesthetic shivering were measured during recovery.

Results: Postanesthetic shivering occurred in 6 of 15 (40%) patients given saline. In contrast, postanesthetic shivering was significantly reduced in physostigmine-treated patients (1 of 15, or 7%) and was absent in patients given clonidine or meperidine.     

Nefopam, a nonsedative benzoxazocine analgesic, selectively reduces the shivering threshold in unanesthetized subjects

BACKGROUND: The analgesic nefopam does not compromise ventilation, is minimally sedating, and is effective as a treatment for postoperative shivering. The authors evaluated the effects of nefopam on the major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering. METHODS: Nine volunteers were studied on three randomly assigned days: (1) control (saline), (2) nefopam at a target plasma concentration of 35 ng/ml (low dose), and (3) nefopam at a target concentration of 70 ng/ml (high dose, approximately 20 mg total). Each day, skin and core temperatures were increased to provoke sweating and then reduced to elicit peripheral vasoconstriction and shivering. The authors determined the thresholds (triggering core temperature at a designated skin temperature of 34 degrees C) by mathematically compensating for changes in skin temperature using the established linear cutaneous contributions to control of each response. RESULTS: Nefopam did not significantly modify the slopes for sweating (0.0 +/- 4.9 degrees C. microg-1. ml; r2 = 0.73 +/- 0.32) or vasoconstriction (-3.6 +/- 5.0 degrees C. microg-1. ml; r2 = -0.47 +/- 0.41). In contrast, nefopam significantly reduced the slope of shivering (-16.8 +/- 9.3 degrees C. microg-1. ml; r2 = 0.92 +/- 0.06). Therefore, high-dose nefopam reduced the shivering threshold by 0.9 +/- 0.4 degrees C (P < 0.001) without any discernible effect on the sweating or vasoconstriction thresholds. CONCLUSIONS: Most drugs with thermoregulatory actions-including anesthetics, sedatives, and opioids-synchronously reduce the vasoconstriction and shivering thresholds. However, nefopam reduced only the shivering threshold. This pattern has not previously been reported for a centrally acting drug. That pharmacologic modulations of vasoconstriction and shivering can be separated is of clinical and physiologic interest.     

A comparison between meperidine, clonidine and urapidil in the treatment of postanesthetic shivering

Postanesthetic shivering can be treated with many types of drugs. We compared the effects of meperidine, clonidine, and urapidil on postanesthetic shivering. Sixty patients shivering during recovery from general anesthesia were treated in a randomized, double-blinded fashion with 25 mg meperidine IV, 0.15 mg clonidine IV, or 25 mg urapidil IV in three separate groups of 20 patients each. If shivering did not stop within 5 min, the treatment was repeated once; clonidine was replaced with saline for the second dose. Rectal temperature, arterial blood pressure, heart rate, SaO(2) and vigilance were monitored. Clonidine stopped shivering in all 20 patients. A single dose of meperidine stopped the shivering in 18 of 20 patients, with the other 2 patients needing a second dose. Urapidil was less effective: the first dose stopped the shivering in only six patients; the second dose was effective in another six; the drug was ineffective in 8 of 20 patients. Meperidine and clonidine were both nearly 100% effective in treating postanesthetic shivering without negative side effects. By comparison, urapidil was only effective in 60% of patients treated (P <0.01). Implications: Patients shivering during recovery from general anesthesia were treated in a randomized double-blinded fashion with meperidine, clonidine, or urapidil. Meperidine and clonidine were both very effective, whereas urapidil was only effective in 60% of patients treated.     

Dexmedetomidine Does Not Alter the Sweating Threshold, But Comparably and Linearly Decreases the Vasoconstriction and Shivering Thresholds

Background: Clonidine decreases the vasoconstriction and shivering thresholds. It thus seems likely that the alpha2 agonist dexmedetomidine will also impair control of body temperature. Accordingly, the authors evaluated the dose-dependent effects of dexmedetomidine on the sweating, vasoconstriction, and shivering thresholds. They also measured the effects of dexmedetomidine on heart rate, blood pressures, and plasma catecholamine concentrations.

Methods: Nine male volunteers participated in this randomized, double-blind, cross-over protocol. The study drug was administered by computer-controlled infusion, targeting plasma dexmedetomidine concentrations of 0.0, 0.3, and 0.6 ng/ml. Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core-temperature thresholds were computed using established linear cutaneous contributions to control of sweating, vasoconstriction, and shivering. The dose-dependent effects of dexmedetomidine on thermoregulatory response thresholds were then determined using linear regression. Heart rate, arterial blood pressures, and plasma catecholamine concentrations were determined at baseline and at each threshold.

Results: Neither dexmedetomidine concentration increased the sweating threshold from control values. In contrast, dexmedetomidine administration reduced the vasoconstriction threshold by 1.61 +/- 0.80 [degree sign] Celsius [center dot] ng sup -1 [center dot] ml (mean +/- SD) and the shivering threshold by 2.40 +/- 0.90 [degree sign] Celsius [center dot] ng sup -1 [center dot] ml. Hemodynamic responses and catecholamine concentrations were reduced from baseline values, but they did not differ at the two tested dexmedetomidine doses.     

Increasing Mean Skin Temperature Linearly Reduces the Core- temperature Thresholds for Vasoconstriction and Shivering in Humans

Background: The contribution of mean skin temperature to the thresholds for sweating and active precapillary vasodilation has been evaluated in numerous human studies. In contrast, the contribution of skin temperature to the control of cold responses such as arteriovenous shunt vasoconstriction and shivering is less well established. Accordingly, the authors tested the hypothesis that mean skin and core temperatures are linearly related at the vasoconstriction and shivering thresholds in men. Because the relation between skin and core temperatures might vary by gender, the cutaneous contribution to thermoregulatory control also was determined in women.

Methods: In the first portion of the study, six men participated on 5 randomly ordered days, during which mean skin temperatures were maintained near 31, 34, 35, 36, and 37 degrees Celsius. Core hypothermia was induced by central venous infusion of cold lactated Ringer's solution sufficient to induce peripheral vasoconstriction and shivering. The core-temperature thresholds were then plotted against skin temperature and a linear regression fit to the values. The relative skin and core contributions to the control of each response were calculated from the slopes of the regression equations. In the second portion of the study, six women participated on three randomly ordered days, during which mean skin temperatures were maintained near 31, 35, and 37 degrees Celsius. At each designated skin temperature, core hypothermia sufficient to induce peripheral vasoconstriction and/or shivering was again induced by central venous infusion of cold lactated Ringer's solution. The cutaneous contributions to control of each response were then calculated from the skin- and core-temperature pairs at the vasoconstriction and shivering thresholds.

Results: There was a linear relation between mean skin and core temperatures at the response thresholds in the men: r = 0.90 plus/minus 0.06 for vasoconstriction and r = 0.94 plus/minus 0.07 for shivering. Skin temperature contributed 20 plus/minus 6% to vasoconstriction and 19 plus/minus 8% to shivering. Skin temperature in the women contributed to 18 plus/minus 4% to vasoconstriction and 18 plus/minus 7% to shivering, values not differing significantly from those in men. There was no apparent correlation between the cutaneous contributions to vasoconstriction and shivering in individual volunteers.     

Intrathecal meperidine decreases shivering during cesarean delivery under spinal anesthesia

Shivering associated with spinal anesthesia is uncomfortable and may interfere with monitoring. We performed this prospective, double-blinded, and randomized study to determine whether intrathecal meperidine (0.2 mg/kg) decreases the incidence and intensity of shivering after spinal anesthesia for cesarean delivery. Forty parturients scheduled for nonemergent cesarean delivery were enrolled in two groups. Spinal anesthesia consisted of hyperbaric bupivacaine (0.75%; 10.5 mg), morphine 0.15 mg, and, in the experimental group, meperidine (0.2 mg/kg) or, in the control group, normal saline. Data collection, including sensory block level, blood pressure, core temperature, and shivering intensity, was performed every minute for 10 min, every 3 min for 33 min, and then every 5 min until the sensory level receded to L4. Time to highest sensory level, maximum number of blocked segments, sensory and motor blockade regression, and systolic blood pressure showed no difference between groups. The incidence of shivering was less (P < 0.02) in the meperidine group, as was its intensity (P < 0.003). Intrathecal meperidine (0.2 mg/kg) is effective in reducing the incidence and intensity of shivering associated with spinal anesthesia for cesarean delivery. IMPLICATIONS: Previous studies have suggested that IV meperidine is helpful for treating intraoperative shivering. This study was undertaken to evaluate spinal meperidine and found that it decreases the incidence and intensity of shivering associated with spinal anesthesia for cesarean delivery.     

The effect of meperidine on thermoregulation in mice: involvement of alpha2-adrenoceptors

Meperidine has potent antishivering properties. The underlying mechanisms are not fully elucidated, but recent investigations suggest that alpha2-adrenoceptors are likely to be involved. We performed the current study to investigate the effects of meperidine on nonshivering thermogenesis in a model of thermoregulation in mice. After injection (0.1 mL/kg intraperitoneally) of saline, meperidine (20 mg/kg), the specific alpha2-adrenoceptor antagonist atipamezole (2 mg/kg), plus saline or atipamezole plus meperidine, respectively, mice were positioned in a Plexiglas chamber. Rectal temperature and mixed expired carbon dioxide were measured after provoking thermoregulatory effects by whole body cooling. Maximum response intensity of nonshivering thermogenesis and the thermoregulatory threshold for nonshivering thermogenesis, which was defined as the temperature at which a sustained increase in expiratory carbon dioxide can be measured, were investigated. Meperidine significantly decreased the threshold of nonshivering thermogenesis (36.6 degrees C +/- 0.7 degrees C) versus saline (37.9 degrees C +/- 0.6 degrees C) and versus atipamezole plus saline (37.8 degrees C +/- 0.4 degrees C; P <0.01). This effect was abolished after administration of meperidine combined with atipamezole (37.7 degrees C +/- 0.6 degrees C; P <0.05). Meperidine did not decrease the maximum intensity of nonshivering thermogenesis. The results suggest a major role of alpha2-adrenoceptors in the inhibition of thermoregulation by meperidine in mice.     

Doxapram only slightly reduces the shivering threshold in healthy volunteers

We determined the effects of doxapram on the major autonomic thermoregulatory responses in humans. Nine healthy volunteers were studied on 2 days: control and doxapram (IV infusion to a plasma concentration of 2.4 +/- 0.8, 2.5 +/- 0.9, and 2.6 +/- 1.1 microg/mL at the sweating, vasoconstriction, and shivering thresholds, respectively). Each day, skin and core temperatures were increased to provoke sweating, then reduced to elicit peripheral vasoconstriction and shivering. We determined the sweating, vasoconstriction, and shivering thresholds with compensation for changes in skin temperature. Data were analyzed with paired t-tests and presented as mean +/- sd; P < 0.05 was considered statistically significant. Doxapram did not change the sweating (control: 37.5 degrees +/- 0.4 degrees C, doxapram: 37.3 degrees +/- 0.4 degrees C; P = 0.290) or the vasoconstriction threshold (36.8 degrees +/- 0.7 degrees C versus 36.4 degrees +/- 0.5 degrees C; P = 0.110). However, it significantly reduced the shivering threshold from 36.2 degrees +/- 0.5 degrees C to 35.7 degrees +/- 0.7 degrees C (P = 0.012). No sedation or symptoms of panic were observed on either study day. The observed reduction in the shivering threshold explains the drug's efficacy for treatment of postoperative shivering; however, a reduction of only 0.5 degrees C is unlikely to markedly facilitate induction of therapeutic hypothermia as a sole drug.     

Nefopam, a Nonsedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold in Unanesthetized Subjects

Background: The analgesic nefopam does not compromise ventilation, is minimally sedating, and is effective as a treatment for postoperative shivering. The authors evaluated the effects of nefopam on the major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering.

Methods: Nine volunteers were studied on three randomly assigned days: (1) control (saline), (2) nefopam at a target plasma concentration of 35 ng/ml (low dose), and (3) nefopam at a target concentration of 70 ng/ml (high dose, approximately 20 mg total). Each day, skin and core temperatures were increased to provoke sweating and then reduced to elicit peripheral vasoconstriction and shivering. The authors determined the thresholds (triggering core temperature at a designated skin temperature of 34[degrees]C) by mathematically compensating for changes in skin temperature using the established linear cutaneous contributions to control of each response.

Results: Nefopam did not significantly modify the slopes for sweating (0.0 +/- 4.9[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = 0.73 +/- 0.32) or vasoconstriction (-3.6 +/- 5.0[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = -0.47 +/- 0.41). In contrast, nefopam significantly reduced the slope of shivering (-16.8 +/- 9.3[degrees]C [middle dot] [mu]g-1 [middle dot] ml; r2 = 0.92 +/- 0.06). Therefore, high-dose nefopam reduced the shivering threshold by 0.9 +/- 0.4[degrees]C (P < 0.001) without any discernible effect on the sweating or vasoconstriction thresholds.