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.     

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).     

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.     

Doxapram produces a dose-dependent reduction in the shivering threshold in rabbits

Dopamine is a thermoregulatory neurotransmitter that provokes hypothermia when injected in or near the hypothalamus. Doxapram stimulates release of dopamine from carotid bodies, but is known to have central effects that are probably, at least in part, similarly mediated. We thus tested the hypothesis that doxapram produces a substantial, dose-dependent reduction in the shivering threshold in rabbits. Twenty-four rabbits, anesthetized with isoflurane, were randomly assigned to 1) saline (control), 2) 0.25 mg x kg(-1) x h(-1) doxapram, or 3) 0.50 mg x kg(-1) x h(-1) doxapram. These doses are within the recommended range for humans. Body temperature was reduced at a rate of 2 degrees to 3 degrees C/h by perfusing water at 10 degrees C through a U-shaped thermode positioned in the colon. Core temperatures were recorded from the distal esophagus. A blinded observer evaluated shivering. Core temperature at the onset of shivering defined the threshold. Data were analyzed with a one-way analysis of variance; P < 0.05 was considered statistically significant. Hemodynamic and respiratory responses were comparable in the groups. The control rabbits shivered at 36.3 degrees +/- 0.3 degrees C, those given 0.25 mg x kg(-1) x h(-1) doxapram shivered at 34.8 degrees +/- 0.5 degrees C, and those given 0.50 mg x kg(-1) x h(-1) shivered at 33.7 degrees +/- 0.6 degrees C. All the shivering thresholds significantly (P < 0.001) differed from one another. The magnitude of this inhibition, if similar in humans, would be clinically important.     

Local saline infusion into ischemic territory induces regional brain cooling and neuroprotection in rats with transient middle cerebral artery occlusion

OBJECTIVE: The neuroprotective effect of hypothermia has long been recognized. Use of hypothermia for stroke therapy, which is currently being induced by whole-body surface cooling, has been limited primarily because of management problems and severe side effects (e.g., pneumonia). The goal of this study was to determine whether local infusion of saline into ischemic territory could induce regional brain cooling and neuroprotection. METHODS: A novel procedure was used to block the middle cerebral artery of rats for 3 hours with a hollow filament and locally infuse the middle cerebral artery-supplied territory with 6 ml cold saline (20 degrees C) for 10 minutes before reperfusion. RESULTS: The cold saline infusion rapidly and significantly reduced temperature in cerebral cortex from 37.2 +/- 0.1 to 33.4 +/- 0.4 degrees C and in striatum from 37.5 +/- 0.2 to 33.9 +/- 0.4 degrees C. The significant hypothermia remained for up to 60 minutes after reperfusion. Significant (P < 0.01) reductions in infarct volume (approximately 90%) were evident after 48 hours of reperfusion. In ischemic rats that received the same amount of cold saline systemically through a femoral artery, a mild hypothermia was induced only in the cerebral cortex (35.3 +/- 0.2 degrees C) and returned to normal within 5 minutes. No significant reductions in infarct volume were observed in this group or in the ischemic group with local warm saline infusion or without infusion. Furthermore, brain-cooling infusion significantly (P < 0.01) improved motor behavior in ischemic rats after 14 days of reperfusion. This improvement continued for up to 28 days after reperfusion. CONCLUSION: Local prereperfusion infusion effectively induced hypothermia and ameliorated brain injury from stroke. Clinically, this procedure could be used in acute stroke treatment, possibly in combination with intra-arterial thrombolysis or mechanical disruption of clot by means of a microcatheter.     

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.     

Meperidine and Alfentanil Do Not Reduce the Gain or Maximum Intensity of Shivering

Background: Thermoregulatory shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core temperature deviation), and maximum intensity. Meperidine (a combined micro- and kappa-agonist) treats shivering better than equianalgesic doses of pure micro-opioid agonists. Meperidine's special antishivering action is mediated, at least in part, by a disproportionate decrease in the shivering threshold. That is, meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold, whereas alfentanil (a pure micro-agonist) decreases the vasoconstriction and shivering thresholds comparably. However, reductions in the gain or maximum shivering intensity might also contribute to the clinical efficacy of meperidine. Accordingly, we tested the hypothesis that meperidine reduces the gain and maximum intensity of shivering much more than alfentanil does.

Methods: Ten volunteers were each studied on three separate days: (1) control (no drug); (2) a target total plasma meperidine concentration of 1.2 micro gram/ml; and (3) a target plasma alfentanil concentration of 0.2 micro gram/ml. Skin temperatures were maintained near 31 [degree sign] Celsius, and core temperatures were decreased by central-venous infusion of cold lactated Ringer's solution until maximum shivering intensity was observed. Shivering was evaluated using oxygen consumption and electromyography. A sustained increase in oxygen consumption identified the shivering threshold. The gain of shivering was calculated as the slope of the oxygen consumption versus core temperature regression, and as the slope of electromyographic intensity versus core temperature regression.

Results: Meperidine and alfentanil administration significantly decreased the shivering thresholds. However, neither meperidine nor alfentanil reduced the gain of shivering, as determined by either oxygen consumption or electromyography. Opioid administration also failed to significantly decrease the maximum intensity of shivering.     

Comparison of meperidine and pancuronium for the treatment of shivering after cardiac surgery

Shivering after cardiac surgery can produce adverse haemodynamic and metabolic sequelae. In this study, the metabolic effects of shivering and the efficacy of treatment with meperidine or pancuronium were studied, using a metabolic cart, in 61 patients who had undergone cardiac surgery. The patients received premedication with morphine, perphenazine and diazepam or lorazepam, and were anaesthetised with fentanyl or sufentanil and diazepam. Muscle relaxation was achieved with pancuronium. Patients were monitored with a radial arterial line, pulmonary artery catheter and oesophageal and urinary bladder temperature probes. Rewarming to an oesophageal temperature of 38 degrees C was achieved before the termination of CPB and was maintained for a minimum of 15 min reperfusion time. Every 15 min after surgery, the patients' temperature at three sites (pulmonary artery, oesophagus, bladder) and shivering scores were monitored. Hourly measurements were made of haemodynamic variables (MAP, PAOP, CVP, SVR, PVR, CI), carbon dioxide production, oxygen consumption and respiratory quotient. If the patient shivered, the measurements were recorded prior to drug treatment and repeated 30 min later following randomization to either: meperidine 0.25 mg.kg-1 (Group 1), meperidine 0.5 mg.kg-1 (Group 2) or pancuronium 0.06 mg.kg-1 intravenously (Group 3). Thirty-two patients shivered and mean VO2 and VCO2 values were greater in the shivering group than in the nonshivering patients (VO2 334.8 +/- 17.6 vs. 240.5 +/- 8.8 ml.min-1; VCO2 238.8 +/- 17.2 vs 199.2 +/- 8.4 ml.min-1, P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Single-dose parenteral pharmacological interventions for the prevention of postoperative shivering: a quantitative systematic review of randomized controlled trials

Shivering is a frequent complication in the postoperative period. The relative efficacy of pharmacological interventions to prevent this phenomenon is not well understood. We performed a systematic search for full reports of randomized comparisons of prophylactic, parenteral, single-dose antishivering interventions with inactive control (placebo or no treatment). Variable doses were converted to fixed doses. Dichotomous data on the absence of shivering were analyzed by using relative benefit (RB) and number needed to treat (NNT) with 95% confidence intervals (CI). Data from 27 trials (1348 adults received an antishivering intervention; 931 were controls) were analyzed. The average incidence of shivering in controls was extremely frequent (52%). Clonidine 65-300 microg (1078 patients), meperidine 12.5-35 mg (250 patients), tramadol 35-220 mg (250 patients), and nefopam 6.5-11 mg (204 patients) were tested in at least 3 trials each. All were more effective than control. For clonidine, meperidine, and nefopam, there was some weak evidence of dose responsiveness. For small-dose clonidine (65-110 microg), the RB compared with control was 1.32 (95% CI, 1.16-1.51); for medium-dose clonidine (140-150 microg), the RB was 1.83 (95% CI, 1.47-2.27); and for large-dose clonidine (220-300 microg), the RB was 1.52 (95% CI, 1.30-1.78). For all clonidine regimens combined, the RB was 1.58 (95% CI, 1.43-1.74), with an NNT of 3.7. For all meperidine regimens combined, the RB was 1.67 (95% CI, 1.37-2.03), with an NNT of 3. For all tramadol regimens combined, the RB was 1.93 (95% CI, 1.56-2.39), with an NNT of 2.2. For all nefopam regimens combined, the RB was 2.62 (95% CI, 2.02-3.40), with an NNT of 1.7. Methylphenidate, midazolam, dolasetron, ondansetron, physostigmine, urapidil, and flumazenil were tested in no more than 3 trials each, with a limited number of patients.     

Upright posture reduces thermogenesis and augments core hypothermia

We recently reported that baroreceptor-mediated reflexes modulate thermoregulatory vasoconstriction during lower abdominal surgery. Accordingly, we examined the hypothesis that postural differences and the related alterations in baroreceptor loading similarly modulate the thermogenic (i.e., shivering) response to hypothermia in humans. In healthy humans (n = 7), cold saline was infused IV (30 mL/kg at 4 degrees C) for 30 min to decrease core temperature. Each participant was studied on 2 separate days, once lying supine and once sitting upright. Tympanic membrane temperature and oxygen consumption were monitored for 40 min after each saline infusion. The decrease in core temperature upon completion of the infusion in the upright posture position was 1.24 degrees C +/- 0.07 degrees C, which was significantly greater than the 1.02 degrees C +/- 0.06 degrees C seen in the supine position. The core temperature was reduced by 0.59 degrees C +/- 0.07 degrees C in the upright position but only by 0.37 degrees C +/- 0.05 degrees C in the supine position when the increase in oxygen consumption signaling thermogenic shivering occurred. Thus, the threshold temperature for thermogenesis was significantly less in the upright than the supine position. The gain of the thermogenic response did not differ significantly between the positions (363 +/- 69 mL. min(-1). degrees C(-1) for upright and 480 +/- 80 mL. min(-1). degrees C(-1) for supine). The skin temperature gradient was significantly larger in the upright than in the supine posture, suggesting that the peripheral vasoconstriction was augmented by upright posture. Plasma norepinephrine concentrations increased in response to cold saline infusion under both conditions, but the increase was significantly larger in the upright than in the supine posture. Baroreceptor unloading thus augments the peripheral vasoconstrictor and catecholamine response to core hypothermia but simultaneously reduces thermogenesis, which consequently aggravated the core temperature decrease in the upright posture. IMPLICATIONS: Upright posture attenuates the thermogenic response to core hypothermia but augments peripheral vasoconstriction. This divergent result suggests that input from the baroreceptor modifies the individual thermoregulatory efferent pathway at a site distal to the common thermoregulatory center or neural pathway.     

Postanaesthetic shivering. Epidemiology,pathophysiology and approaches to prevention and management

Postanaesthetic shivering is one of the leading causes of discomfort for patients recovering from general anesthesia. During EMG records, the distinguishing factor from shivering in fully awake patients is the existence of clonus similar to that recorded in patients with spinal cord transection. They coexist with the classic waxing and waning signals associated with cutaneous vasoconstriction (thermoregulatory shivering). The causes responsible for their appearance primarily include hypothermia, which sets in due to thermoregulation inhibition by anesthetics. However, we also note the existence of shivering associated with cutaneous vasodilatation (non-thermoregulatory shivering) one of the origins of which is postoperative pain. Apart from the discomfort and aggravated pain, postanaesthetic shivering raises metabolic demand proportionally to the solicited muscle mass and the patient's cardiac capacities. No link has been demonstrated between their occurrence and an increase in cardiac morbidity but it is preferable to avoid postanaesthetic shivering since it is oxygen draining. Prevention mainly entails preventing hypothermia by actively rewarming the patient. Postoperative skin surface rewarming is a way of obtaining the threshold shivering temperature while raising the skin temperature and improving the patient's comfort. However, it is less efficient than certain drugs such as meperidine, nefopam or tramadol, which act by reducing the shivering threshold temperature.     

Active warming during cesarean delivery.

We tested the hypothesis that 15 min of forced-air prewarming, combined with intraoperative warming, prevents hypothermia and shivering in patients undergoing elective cesarean delivery. We simultaneously tested the hypothesis that maintaining maternal normothermia increases newborn temperature, umbilical vein pH, and Apgar scores. Thirty patients undergoing elective cesarean delivery were randomly assigned to forced-air warming or to passive insulation. Warming started 15 min before the induction of epidural anesthesia. Core temperature was measured at the tympanic membrane, and shivering was graded by visual inspection. Patients evaluated their thermal sensation with visual analog scales. Rectal temperature and umbilical pH were measured in the infants after birth. Results were compared with unpaired, two-tailed Student's t-tests and chi(2) tests. Core temperatures after 2 h of anesthesia were greater in the actively warmed (37.1 degrees C +/- 0.4 degrees C) than in the unwarmed (36.0 degrees C +/- 0.5 degrees C; P < 0.01) patients. Shivering was observed in 2 of 15 warmed and 9 of 15 unwarmed mothers (P < 0.05). Babies of warmed mothers had significantly greater core temperatures (37.1 degrees C +/- 0.5 degrees C vs 36.2 degrees C +/- 0.6 degrees C) and umbilical vein pH (7.32 +/- 0.07 vs 7.24 +/- 0.07). IMPLICATIONS: Perioperative forced-air warming of women undergoing cesarean delivery with epidural anesthesia prevents maternal and fetal hypothermia, reduces maternal shivering, and improves umbilical vein pH.     

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.     

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.     

A comparison of urapidil, clonidine, meperidine and placebo in preventing postanesthetic shivering

This placebo-controlled study was performed to evaluate the efficacy of urapidil compared with clonidine and meperidine in preventing postanesthetic shivering, which is common after anesthesia administration and may be very distressing. We studied 120 patients undergoing elective abdominal or orthopedic surgery under standardized general anesthesia. After surgery, patients were randomly assigned to one of four groups (each group n = 30) using a double-blinded protocol: Group A received 0.2 mg/kg urapidil; Group B, 3 microg/kg clonidine; Group C, 0.4 mg/kg meperidine; and Group D, saline 0.9% as placebo. Postanesthetic shivering was scored by using a five-point scale. Clonidine and meperidine significantly reduced the incidence and the severity of shivering in comparison with placebo, whereas there were no significant differences between the urapidil and placebo groups. Both clonidine and meperidine caused a significantly prolonged emergence time (13.4 +/- 5.8 and 13. 3 +/- 5.0 min, respectively) compared with placebo (10.4 +/- 5.3 min) and urapidil (11.4 +/- 2.9 min). We confirmed that both clonidine and meperidine are effective in preventing postanesthetic shivering, whereas urapidil, in our setting and dosage, was not effective. Patients who received clonidine or meperidine had a prolonged emergence time. In the dosage used, urapidil seems to be unable to prevent postanesthetic shivering. IMPLICATIONS: Shivering (irregular muscle activity) is common after surgery and anesthesia. This study compared urapidil (an antihypertensive drug) as a prophylaxis with two established antishivering drugs (meperidine and clonidine) and placebo. In the dosage used, we were unable to show a significant benefit of urapidil.     

Amino acid-induced thermogenesis reduces hypothermia during anesthesia and shortens hospital stay

Amino acid infusion during general anesthesia induces thermogenesis and prevents postoperative hypothermia and shivering. We propose that amino acid prevention of hypothermia during anesthesia shortens the hospital stay. Core temperatures and pulmonary oxygen uptake were measured in 45 patients, receiving an IV amino acid mixture, 126 mL/h, before and/or during isoflurane anesthesia and 30 control patients receiving acetated Ringer's solution. At awakening, mean core temperature was 36.5 degrees+/-0.1 degrees C in the amino acid group and 35.7 degrees+/-0.1 degrees C (P < 0.001) in the controls. Energy expenditure increased by 54%+/-9% from baseline in amino acid patients in whom shivering was uncommon, but only by 5%+/-4% (P < 0.001) in control patients, of whom the majority developed postoperative shivering. The estimated difference in hospital stay between the two groups was 2.7 days (CI 95%: 1.3-4.0). Multiple regression analysis showed that the variables best predicting hospitalization were duration of surgery, amino acid treatment, and awakening temperatures. Duration of surgery was similar in the two groups and core temperatures at awakening were a result of amino acid infusion, which indicates that amino acid infusion during anesthesia and surgery was the most important factor for the shorter hospitalization. IMPLICATIONS: Amino acid infusion during general anesthesia induces thermogenesis and prevents postoperative hypothermia and shivering. Multiple regression analysis indicated that this resulted in a shorter hospital stay.     

Age-related thermoregulatory differences in a warm operating room environment (approximately 26 degrees C)

Inadvertent hypothermia occurs frequently at typical ambient operating room (OR) temperatures, especially in elderly patients receiving general anesthesia. The aims of the current study were to 1) determine the incidence and magnitude of core hypothermia in an unusually warm OR environment, and 2) to assess age-related differences in perioperative thermoregulatory responses under these circumstances. Forty patients receiving general anesthesia for orthopedic surgical procedures (20 younger patients, 20-40 yr old) and (20 older patients, 60-75 yr old) were enrolled. Mean ambient temperature in the ORs was 25.8 degrees +/- 0.2 degrees C. Core temperature, vasoconstriction, and shivering were compared in the younger and older age groups. Mean core temperature on admission to the postanesthesia care unit was not significantly different in the younger (36.7 degrees +/- 0.1 degrees C) and older (36.4 degrees +/- 0.1 degrees C) age groups. Only 10% of patients (n = 4, 1 younger, 3 older) were admitted with a core temperature <36.0 degrees C. Only 2% of patients (n = 1, older group) had a core temperature <35.5 degrees C. This very mild degree of hypothermia was associated with postoperative vasoconstriction in 80% of the younger and 55% of the older patients (P = 0.18). Postoperative shivering occurred in 40% of the younger patients and in 10% of the older patients (P = 0.06). In summary, an ambient OR temperature near 26 degrees C (79 degrees F) is effective in preventing core hypothermia during general anesthesia regardless of patient age. Even very mild postoperative hypothermia may initiate thermoregulatory responses. Implications: By increasing ambient temperature in the operating room to 26 degrees C (79 degrees F), the incidence of core hypothermia can be dramatically reduced in both younger and older patients.     

Rectal temperature reflects tympanic temperature during mild induced hypothermia in nonintubated subjects

INTRODUCTION: Mild induced hypothermia holds promise as an effective neuroprotective strategy following acute stroke and cardiac arrest. Dependable noninvasive measurements of brain temperature are imperative for the investigation and clinical application of therapeutic hypothermia. Although the tympanic membrane temperature correlates best with brain temperature, it is a cumbersome location to record from continuously in the clinical setting. Data are lacking regarding the relationship between rectal and tympanic temperatures in nonintubated humans undergoing induced hypothermia via surface cooling. METHODS: We induced mild hypothermia in healthy volunteers using a novel surface cooling method (Arctic Sun Temperature Management System, Medivance, Inc., Louisville, CO). Core temperatures were recorded at the tympanic membrane (Ttym) and rectum (Trec). The gradient was defined as (Ttym-Trec). Controlled hypothermia was maintained for up to 300 minutes with a target Ttym of 34 degrees C to 35 degrees C; subjects were then actively rewarmed to a target Ttym of 36 degrees C over 1.5 to 3 hours. RESULTS: Twenty-two volunteers (10 males and 12 females) 31 +/- 8 years of age were studied. Subjects showed a triphasic temperature response: induction, maintenance, and rewarming. The mean gradient at baseline was -0.1 +/- 0.3 degrees C and the maximum gradient increased to -0.6 +/- 0.4 degrees C at 105 minutes. During maintenance of hypothermia (from 150 to 300 minutes), the mean gradient was -0.3 +/- 0.5 degrees C (95% confidence limits, -1.2 degrees C to 0.6 degrees C). CONCLUSIONS:: Our data suggest that Ttym and Trec are not related during the induction of hypothermia via surface cooling but correlate during the maintenance phase, with a -0.3 degrees C gradient. These findings support the use of rectal temperature as a measure of tympanic and, therefore, brain temperature during maintenance of induced hypothermia in nonintubated humans.     

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.     

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.