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).     

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.     

Reduction in the Shivering Threshold Is Proportional to Spinal Block Height

Background: Hypothermia is nearly as common, and may be as severe, during spinal and epidural anesthesia as during general anesthesia. The authors have proposed that thermoregulatory failure results when regional anesthesia increases apparent leg skin temperature to a level far exceeding actual leg skin temperature. Extensive dermatomal blocks will alter thermal input to the hypothalamus from a greater skin-surface area more than less extensive ones and thus might be expected to impair central thermoregulatory control more. Accordingly, they tested the hypothesis that reduction in the shivering threshold is directly related to the number of dermatomes blocked during spinal anesthesia.

Methods: Eleven men, aged 62+/-6 yr (mean+/-SD), undergoing urologic surgery were studied. Ice-cold lactated Ringer's solution was administered intravenously before spinal blockade, and the shivering threshold (triggering core temperature) was established. Spinal anesthesia then was induced using a randomly assigned dose of 0.5% bupivacaine (2-4 ml). Again, sufficient cold lactated Ringer's solution was given to induce shivering. Tympanic membrane, ambient and skin temperatures were measured, and extent of block was defined by loss of temperature discrimination. Presence of shivering was evaluated by a blinded observer. Mean upper-body skin and ambient temperatures, cooling rates and intravenous fluid volumes at the two thresholds were compared using paired, two-tailed t tests (P < 0.05). Linear regression defined the relationship between reduction in shivering threshold and the number of dermatomes blocked.

Results: There were no significant differences between mean upper-body skin and ambient temperatures, cooling rates or intravenous fluid volumes at the control and spinal shivering thresholds. Spinal anesthesia reduced the shivering threshold in direct relation to the number of dermatomes blocked: Delta threshold = 0.74 - 0.06 (dermatomes blocked); r2 = 0.58, P < 0.006.     

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.     

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).     

Thermoregulatory Vasoconstriction Impairs Active Core Cooling

Background: Many clinicians now consider hypothermia indicated during neurosurgery. Active cooling often will be required to reach target temperatures < 34 degrees Celsius sufficiently rapidly and nearly always will be required if the target temperature is 32 degrees Celsius. However, the efficacy even of active cooling might be impaired by thermoregulatory vasoconstriction, which reduces cutaneous heat loss and constrains metabolic heat to the core thermal compartment. The authors therefore tested the hypothesis that the efficacy of active cooling is reduced by thermoregulatory vasoconstriction.

Methods: Patients undergoing neurosurgical procedures with hypothermia were anesthetized with either isoflurane/nitrous oxide (n = 13) or propofol/fentanyl (n = 13) anesthesia. All were cooled using a prototype forced-air cooling device until core temperature reached 32 degrees Celsius. Core temperature was measured in the distal esophagus. Vasoconstriction was evaluated using forearm minus fingertip skin-temperature gradients. The core temperature triggering a gradient of 0 degree Celsius identified the vasoconstriction threshold.

Results: In 6 of the 13 patients given isoflurane, vasoconstriction (skin-temperature gradient = 0 degree Celsius) occurred at a core temperature of 34.4 plus/minus 0.9 degree Celsius, 1.7 plus/minus 0.5 h after induction of anesthesia. Similarly, in 7 of the 13 patients given propofol, vasoconstriction occurred at a core temperature of 34.5 plus/minus 0.9 degree Celsius, 1.6 plus/minus 0.6 h after induction of anesthesia. In the remaining patients, vasodilation continued even at core temperatures of 32 degrees Celsius. Core cooling rates were comparable in each anesthetic group. However, patients in whom vasodilation was maintained cooled fastest. Patients in whom vasoconstriction occurred required nearly an hour longer to reach core temperatures of 33 degrees Celsius and 32 degrees Celsius than did those in whom vasodilation was maintained (P < 0.01).     

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.     

Relative Contribution of Skin and Core Temperatures to Vasoconstriction and Shivering Thresholds during Isoflurane Anesthesia

Background: Thermoregulatory control is based on both skin and core temperatures. Skin temperature contributes [approximate] 20% to control of vasoconstriction and shivering in unanesthetized humans. However, this value has been used to arithmetically compensate for the cutaneous contribution to thermoregulatory control during anesthesia-although there was little basis for assuming that the relation was unchanged by anesthesia. It even remains unknown whether the relation between skin and core temperatures remains linear during anesthesia. We therefore tested the hypothesis that mean skin temperature contributes [approximate] 20% to control of vasoconstriction and shivering, and that the contribution is linear during general anesthesia.

Methods: Eight healthy male volunteers each participated on 3 separate days. On each day, they were anesthetized with 0.6 minimum alveolar concentrations of isoflurane. They then were assigned in random order to a mean skin temperature of 29, 31.5, or 34 [degree sign]C. Their cores were subsequently cooled by central-venous administration of fluid at [almost equal to] 3 [degree sign]C until vasoconstriction and shivering were detected. The relation between skin and core temperatures at the threshold for each response in each volunteer was determined by linear regression. The proportionality constant was then determined from the slope of this regression. These values were compared with those reported previously in similar but unanesthetized subjects.

Results: There was a linear relation between mean skin and core temperatures at the vasoconstriction and shivering thresholds in each volunteer: r2 = 0.98 +/- 0.02 for vasoconstriction, and 0.96 +/- 0.04 for shivering. The cutaneous contribution to thermoregulatory control, however, differed among the volunteers and was not necessarily the same for vasoconstriction and shivering in individual subjects. Overall, skin temperature contributed 21 +/- 8% to vasoconstriction, and 18 +/- 10% to shivering. These values did not differ significantly from those identified previously in unanesthetized volunteers: 20 +/- 6% and 19 +/- 8%, respectively.     

Relative contribution of skin and core temperatures to vasoconstriction and shivering thresholds during isoflurane anesthesia.

BACKGROUND: Thermoregulatory control is based on both skin and core temperatures. Skin temperature contributes approximately 20% to control of vasoconstriction and shivering in unanesthetized humans. However, this value has been used to arithmetically compensate for the cutaneous contribution to thermoregulatory control during anesthesia--although there was little basis for assuming that the relation was unchanged by anesthesia. It even remains unknown whether the relation between skin and core temperatures remains linear during anesthesia. We therefore tested the hypothesis that mean skin temperature contributes approximately 20% to control of vasoconstriction and shivering, and that the contribution is linear during general anesthesia. METHODS: Eight healthy male volunteers each participated on 3 separate days. On each day, they were anesthetized with 0.6 minimum alveolar concentrations of isoflurane. They then were assigned in random order to a mean skin temperature of 29, 31.5, or 34 degrees C. Their cores were subsequently cooled by central-venous administration of fluid at approximately 3 degrees C until vasoconstriction and shivering were detected. The relation between skin and core temperatures at the threshold for each response in each volunteer was determined by linear regression. The proportionality constant was then determined from the slope of this regression. These values were compared with those reported previously in similar but unanesthetized subjects. RESULTS: There was a linear relation between mean skin and core temperatures at the vasoconstriction and shivering thresholds in each volunteer: r2 = 0.98+/-0.02 for vasoconstriction, and 0.96+/-0.04 for shivering. The cutaneous contribution to thermoregulatory control, however, differed among the volunteers and was not necessarily the same for vasoconstriction and shivering in individual subjects. Overall, skin temperature contributed 21+/-8% to vasoconstriction, and 18+/-10% to shivering. These values did not differ significantly from those identified previously in unanesthetized volunteers: 20+/-6% and 19+/-8%, respectively. CONCLUSIONS: The results in anesthetized volunteers were virtually identical to those reported previously in unanesthetized subjects. In both cases, the cutaneous contribution to control of vasoconstriction and shivering was linear and near 20%. These data indicate that a proportionality constant of approximately 20% can be used to compensate for experimentally induced skin-temperature manipulations in anesthetized as well as unanesthetized subjects.     

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.     

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.     

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.     

Lack of Nonshivering Thermogenesis in Infants Anesthetized with Fentanyl and Propofol

Background: Sweating, vasoconstriction, and shivering have been observed during general anesthesia. Among these, vasoconstriction is especially important because-once triggered-it minimizes further hypothermia. Surprisingly, the core-temperature plateau associated with vasoconstriction appears to preserve core temperature better in infants and children than adults. This observation suggests that vasoconstriction in anesthetized infants may be accompanied by hypermetabolism. Consistent with this theory, unanesthetized infants rely on nonshivering thermogenesis to double heat production when vasoconstriction alone is insufficient. Accordingly, the authors tested the hypothesis that intraoperative core hypothermia triggers nonshivering thermogenesis in infants.

Methods: With Ethics Committee approval and written parental consent, the authors studied six infants undergoing abdominal surgery. All were aged 1 day to 9 months and weighed 2.4-9 kg. Anesthesia was maintained with propofol and fentanyl. The infants were mechanically ventilated and allowed to cool passively until core (distal esophageal) temperatures reached 34-34.5 degrees Celsius. Oxygen consumption-the authors' index of metabolic rate- was recorded throughout cooling. Because nonshivering thermogenesis triples circulating norepinephrine concentrations, arterial blood was analyzed for plasma catecholamines at [nearly equal] 0.5 degrees Celsius intervals. Thermoregulatory vasoconstriction was evaluated using forearm - fingertip, skin-surface gradients, with gradients exceeding 4 degrees Celsius, indicating intense vasoconstriction. The patients were subsequently rapidly rewarmed to 37 degrees Celsius. Regression analysis was used to correlate changes in oxygen consumption and plasma catecholamine concentrations with core temperature.

Results: All patients were vasoconstricted by the time core temperature reached 36 degrees Celsius. Further reduction in core temperature to 34-34.5 degrees Celsius did not increase oxygen consumption. Instead, oxygen consumption decreased linearly. Hypothermia also failed to increase plasma catecholamine concentrations.     

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.     

Changes in epicardial and core temperatures during resuscitation of hemorrhagic shock

The hypothermic effect of resuscitation solution temperature on epicardial and core temperatures in 15 dogs during hemorrhagic shock was studied. Hemorrhagic shock was induced and dogs were then resuscitated with either body-temperature lactated Ringer's, room-temperature lactated Ringer's, 4 degrees C blood, warmed blood, or cold blood mixed with 50 degrees C lactated Ringer's. There was a significant decrease (p = 0.001) from baseline temperature recordings with the use of room-temperature lactated Ringer's, cold blood, and cold blood mixed with 50 degrees C lactated Ringer's. Baseline temperatures were not significantly changed with the use of warmed blood or body-temperature lactated Ringer's. The results of this study support the use of warmed blood or body-temperature lactated Ringer's during resuscitation from hemorrhagic shock.     

Influence of Thermoregulatory Vasomotion and Ambient Temperature Variation on the Accuracy of Core-temperature Estimates by Cutaneous Liquid-crystal Thermometers

Background: Recently, liquid crystal skin-surface thermometers have become popular for intraoperative temperature monitoring. Three situations during which cutaneous liquid-crystal thermometry may poorly estimate core temperature were monitored: (1) anesthetic induction with consequent core-to-peripheral redistribution of body heat, (2) thermoregulatory vasomotion associated with sweating (precapillary dilation) and shivering (minimal capillary flow), and (3) ambient temperature variation over the clinical range from 18-26 degrees Celsius.

Methods: The core-to-forehead and core-to-neck temperature difference was measured using liquid-crystal thermometers having an [nearly equal] 2 degrees Celsius offset. Differences exceeding 0.5 degrees Celsius (a 1 degree Celsius temperature range) were a priori deemed potentially clinically important. Seven volunteers participated in each protocol. First, core-to-peripheral redistribution of body heat was produced by inducing propofol/desflurane anesthesia; anesthesia was then maintained for 1 h with desflurane. Second, vasodilation was produced by warming unanesthetized volunteers sufficiently to produce sweating; intense vasoconstriction was similarly produced by cooling the volunteers sufficiently to produce shivering. Third, a canopy was positioned to enclose the head, neck, and upper chest of unanesthetized volunteers. Air within the canopy was randomly set to 18, 20, 22, 24, and 26 degrees Celsius.

Results: Redistribution of body heat accompanying induction of anesthesia had little effect on the core-to-forehead skin temperature difference. However, the core-to-neck skin temperature gradient decreased [nearly equal] 0.6 degrees Celsius in the hour after induction of anesthesia. Vasomotion associated with shivering and mild sweating altered the core-to-skin temperature difference only a few tenths of a degree centigrade. The absolute value of the core-to-forehead temperature difference exceeded 0.5 degrees Celsius during [nearly equal] 35% of the measurements, but the difference rarely exceeded 1 degree Celsius. The core-to-neck temperature difference typically exceeded 0.5 degrees Celsius and frequently exceeded 1 degree Celsius. Each 1 degree Celsius increase in ambient temperature decreased the core-to-forehead and core-to-neck skin temperature differences by less than 0.2 degree Celsius.     

Heat Flow and Distribution during Induction of General Anesthesia

Background: Core hypothermia after induction of general anesthesia results from an internal core-to-peripheral redistribution of body heat and a net loss of heat to the environment. However, the relative contributions of each mechanism remain unknown. The authors evaluated regional body heat content and the extent to which core hypothermia after induction of anesthesia resulted from altered heat balance and internal heat redistribution.

Methods: Six minimally clothed male volunteers in an [nearly equal] 22 degrees Celsius environment were evaluated for 2.5 control hours before induction of general anesthesia and for 3 subsequent hours. Overall heat balance was determined from the difference between cutaneous heat loss (thermal flux transducers) and metabolic heat production (oxygen consumption). Arm and leg tissue heat contents were determined from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. To separate the effects of redistribution and net heat loss, we multiplied the change in overall heat balance by body weight and the specific heat of humans. The resulting change in mean body temperature was subtracted from the change in distal esophageal (core) temperature, leaving the core hypothermia specifically resulting from redistribution.

Results: Core temperature was nearly constant during the control period but decreased 1.6 plus/minus 0.3 degrees Celsius in the first hour of anesthesia. Redistribution contributed 81% to this initial decrease and required transfer of 46 kcal from the trunk to the extremities. During the subsequent 2 h of anesthesia, core temperature decreased an additional 1.1 plus/minus 0.3 degrees Celsius, with redistribution contributing only 43%. Thus, only 17 kcal was redistributed during the second and third hours of anesthesia. Redistribution therefore contributed 65% to the entire 2.8 plus/minus 0.5 degrees Celsius decrease in core temperature during the 3 h of anesthesia. Proximal extremity heat content decreased slightly after induction of anesthesia, but distal heat content increased markedly. The distal extremities thus contributed most to core cooling. Although the arms constituted only a fifth of extremity mass, redistribution increased arm heat content nearly as much as leg heat content. Distal extremity heat content increased [nearly equal] 40 kcal during the first hour of anesthesia and remained elevated for the duration of the study.     

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.     

Do Standard Monitoring Sites Reflect True Brain Temperature When Profound Hypothermia Is Rapidly Induced and Reversed?

Background: Brain temperature is closely approximated by most body temperature measurements under normal anesthetic conditions. However, when thermal autoregulation is overridden, large temperature gradients may prevail. This study sought to determine which of the standard temperature monitoring sites best approximates brain temperature when deep hypothermia is rapidly induced and reversed during cardiopulmonary bypass.

Methods: Twenty-seven patients underwent cardiopulmonary bypass and deep hypothermic circulatory arrest in order for each to have a giant cerebral aneurysm surgically clipped. Brain temperatures were measured directly with a thermocouple embedded in the cerebral cortex. Eight other body temperatures were monitored simultaneously with less invasive sensors at standard sites.

Results: Brain temperature decreased from 32.6 + 1.4 degrees Celsius (mean plus/minus SD) to 16.7 plus/minus 1.7 degrees Celsius in 28 plus/minus 7 min, for an average cerebral cooling rate of 0.59 + 0.15 degree Celsius/min. Circulatory arrest lasted 24 plus/minus 15 min and was followed by 63 + 17 min of rewarming at 0.31 plus/minus 0.09 degree Celsius/min. None of the monitored sites tracked cerebral temperature well throughout the entire hypothermic period. During rapid temperature change, nasopharyngeal, esophageal, and pulmonary artery temperatures corresponded to brain temperature with smaller mean differences than did those of the tympanic membrane, bladder, rectum, axilla, and sole of the foot. At circulatory arrest, nasopharyngeal, esophageal, and pulmonary artery mean temperatures were within 1 degree Celsius of brain temperature, even though individual patients frequently exhibited disparate values at those sites.     

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).