Effect of amino acid infusion on central thermoregulatory control in humans

BACKGROUND: Administration of protein or amino acids enhances thermogenesis, presumably by stimulating oxidative metabolism. However, hyperthermia results even when thermoregulatory responses are intact, suggesting that amino acids also alter central thermoregulatory control. Therefore, the authors tested the hypothesis that amino acid infusion increases the thermoregulatory set point. METHODS: Nine male volunteers each participated on 4 study days in randomized order: (1) intravenous amino acids infused at 4 kJ x kg(-1) x h(-1) for 2.5 h combined with skin-surface warming, (2) amino acid infusion combined with cutaneous cooling, (3) saline infusion combined with skin-surface warming, and (4) saline infusion combined with cutaneous cooling. RESULTS: Amino acid infusion increased resting core temperature by 0.3 +/- 0.1 degrees C (mean +/- SD) and oxygen consumption by 18 +/- 12%. Furthermore, amino acid infusion increased the calculated core temperature threshold (triggering core temperature at a designated mean skin temperature of 34 degrees C) for active cutaneous vasodilation by 0.3 +/- 0.3 degrees C, for sweating by 0.2 +/- 0.2 degrees C, for thermoregulatory vasoconstriction by 0.3 +/- 0.3 degrees C, and for thermogenesis by 0.4 +/- 0.5 degrees C. Amino acid infusion did not alter the incremental response intensity (i.e., gain) of thermoregulatory defenses. CONCLUSIONS: Amino acid infusion increased the metabolic rate and the resting core temperature. However, amino acids also produced a synchronous increase in all major autonomic thermoregulatory defense thresholds; the increase in core temperature was identical to the set point increase, even in a cold environment with amble potential to dissipate heat. In subjects with intact thermoregulatory defenses, amino acid-induced hyperthermia seems to result from an increased set point rather than increased metabolic rate per se.     

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.     

Effect of Amino Acid Infusion on Central Thermoregulatory Control in Humans

Background: Administration of protein or amino acids enhances thermogenesis, presumably by stimulating oxidative metabolism. However, hyperthermia results even when thermoregulatory responses are intact, suggesting that amino acids also alter central thermoregulatory control. Therefore, the authors tested the hypothesis that amino acid infusion increases the thermoregulatory set point.

Methods: Nine male volunteers each participated on 4 study days in randomized order: (1) intravenous amino acids infused at 4 kJ [middle dot] kg-1 [middle dot] h-1 for 2.5 h combined with skin-surface warming, (2) amino acid infusion combined with cutaneous cooling, (3) saline infusion combined with skin-surface warming, and (4) saline infusion combined with cutaneous cooling.

Results: Amino acid infusion increased resting core temperature by 0.3 +/- 0.1[degrees]C (mean +/- SD) and oxygen consumption by 18 +/- 12%. Furthermore, amino acid infusion increased the calculated core temperature threshold (triggering core temperature at a designated mean skin temperature of 34[degrees]C) for active cutaneous vasodilation by 0.3 +/- 0.3[degrees]C, for sweating by 0.2 +/- 0.2[degrees]C, for thermoregulatory vasoconstriction by 0.3 +/- 0.3[degrees]C, and for thermogenesis by 0.4 +/- 0.5[degrees]C. Amino acid infusion did not alter the incremental response intensity (i.e., gain) of thermoregulatory defenses.     

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.     

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).     

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.     

Sweating threshold during isoflurane anesthesia in humans

Isoflurane anesthesia in humans markedly decreases the threshold temperature triggering peripheral thermoregulatory vasoconstriction (i.e., central temperature triggering vasoconstriction). However, it is not known whether the sweating threshold remains unchanged (e.g., near 37 degrees C), decreases along with the vasoconstriction threshold, or increases during anesthetic administration. Accordingly, the hypothesis that isoflurane anesthesia increases the thermoregulatory threshold for sweating was tested. Forehead sweating was evaluated in five healthy patients given isoflurane anesthesia. The sweating threshold was prospectively defined as the distal esophageal temperature at which significant sweating was first observed. Sweating was observed in each patient at a mean central temperature of 38.3 +/- 0.3 degrees C and an end-tidal isoflurane concentration of 1.1% +/- 0.2%. The interthreshold range (difference between vasoconstriction and sweating thresholds) without anesthesia is approximately 0.5 degrees C; isoflurane anesthesia increases this range to approximately 4 degrees C.     

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 threshold and gain of thermoregulatory vasoconstriction differs during anesthesia in the dependent and upper arms in the lateral position

Increased intraluminal pressure may help maintain vasodilation in a dependent arm even after hypothermia triggers centrally mediated thermoregulatory vasoconstriction. We therefore tested the hypotheses that the threshold (triggering core temperature) and gain (increase in vasoconstriction per degree centigrade) of cold-induced vasoconstriction is reduced in the dependent arm during anesthesia. Anesthesia was maintained with 0.4 minimum alveolar anesthetic concentration of desflurane in 10 volunteers in the left-lateral position. Mean skin temperature was reduced to 31 degrees C to decrease core body temperature. Fingertip blood flow in both arms was measured, as was core body temperature.The vasoconstriction threshold was slightly, but significantly, less in the dependent arm (36.2 degrees C +/- 0.3 degrees C, mean +/- SD) than in the upper arm (36.5 degrees C +/- 0.3 degrees C). However, the gain of vasoconstriction in the dependent arm was 2.3-fold greater than in the upper arm. Consequently, intense vasoconstriction (i.e., a fingertip blood flow of 0.15 mL/min) occurred at similar core temperatures. In the lateral position, the vasoconstriction threshold was reduced in the dependent arm; however, gain was also increased in the dependent arm. The thermoregulatory system may thus recognize that hydrostatic forces reduce the vasoconstriction threshold and may compensate by sufficiently augmenting gain. IMPLICATIONS: The threshold for cold-induced vasoconstriction is reduced in the dependent arm, but the gain of vasoconstriction is increased. Consequently, the core temperature triggering intense vasoconstriction was similar in each arm, suggesting that the thermoregulatory system compensates for the hydrostatic effects of the lateral position.     

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.     

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.     

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.     

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.     

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).     

Shivering and shivering-like tremor during labor with and without epidural analgesia.

BACKGROUND: Effective treatment and prevention of hyperthermia and shivering-like tremor during labor is hindered by a poor understanding of their causes. The authors sought to identify the incidence of nonthermoregulatory shivering-like tremor and the factors associated with this activity. METHODS: The authors studied women in spontaneous full-term labor who chose epidural analgesia (n = 21) or opioid sedation (n = 31). Shivering-like tremor and sweating were evaluated by observation. Core temperature was recorded in the external auditory canal using a compensated infrared thermometer. Arteriovenous shunt tone was evaluated with forearm minus fingertip skin temperature gradients; gradients less than 0 were considered evidence of vasodilation. Tremor was considered nonthermoregulatory when core temperature exceeded 37 degrees C and the arms were vasodilated. Pain was evaluated using a visual analog scale. RESULTS: Shivering-like tremor was observed in 18% of 290, 30-min data-acquisition epochs before delivery. The patients were both normothermic and vasodilated during 15% of these epochs. Shivering was observed in 16% of 116 postdelivery epochs and was nonthermoregulatory in 28%. Sweating was observed in 30% of predelivery epochs, and the patients were both hypothermic and vasoconstricted during 12%. The mean core temperature in patients given epidural analgesia was approximately 0.2 degrees C greater than in those given sedation. Hyperthermia was observed during 10 epochs (38.4+/-0.3 degrees C) during epidural analgesia and during 10 epochs (38.4+/-0.3 degrees C) with sedation. The patients were vasoconstricted in more than 50% of these epochs in each group. Multivariate mixed-effects modeling identified high pain scores and vasoconstriction as significant predictors of shivering. There were no predictors for shivering epochs in patients who were simultaneously normothermic and vasodilated. Significant predictors of sweating were time before delivery, high pain scores, hypothermia with vasoconstriction, high thermal comfort, and low mean skin temperature. There were no predictors for sweating epochs in patients who were simultaneously hypothermic and vasoconstricted. CONCLUSIONS: This study confirms the clinical impression that some peripartum shivering-like tremor is nonthermoregulatory. The authors also identified nonthermoregulatory sweating. These data indicate that shivering-like tremor and sweating in the peripartum period is multifactorial.     

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.     

Effect of halothane on the peripheral cutaneous vasoconstriction and shivering induced by internal body cooling in rabbits]

Although suppression of thermoregulatory mechanisms by anesthetics is generally assumed, the extent to which thermoregulatory responses are active during general anesthesia is not known. To evaluate the effect of anesthetics on thermoregulation, we investigated the threshold body core temperatures to induce peripheral cutaneous vasoconstriction and shivering in spontaneously breathing rabbits. Rabbits are anesthetized with halothane at 0.05, 0.2 and 0.4 MAC (minimum alveolar concentration). Internal whole body cooling was performed by perfusing the cool water through an intestinal U-shaped thermode placed in the colon. Core (esophagus) and peripheral (ear) temperatures were measured with thermistors. The esophageal temperatures at the beginning of peripheral cutaneous vasoconstriction and shivering induced by internal whole body cooling were determined. Peripheral cutaneous vasoconstriction was not significantly affected by halothane. However, the incidence of shivering was significantly decreased by halothane dose-dependently. Threshold of shivering (37.3 +/- 0.8 degrees C) was significantly lower than that of peripheral cutaneous vasoconstriction (38.9 +/- 1.1 degrees C). We conclude that the halothane can exert an influence on shivering.     

Effects of dantrolene on rat diaphragm muscle during postnatal maturation

BACKGROUND: Dantrolene is the only known effective treatment for malignant hyperthermia. However, its effects on diaphragm muscle during postnatal maturation remain unknown. METHODS: The effects of dantrolene (10(-8) to 10(-4) M) were investigated in vitro on diaphragm muscle strips in adult rats and in postnatal rats aged 3, 10, and 17 days, and compared with those of ryanodine (10(-8) to 10(-6) M). The authors studied contraction and relaxation under isotonic and isometric conditions (29 degrees C, Krebs-Henseleit solution, tetanic stimulation at 50 Hz). Data are mean +/- SD. RESULTS: During postnatal maturation, the authors observed a progressive increase in active force developed per cross-sectional area (from 34 +/- 25 to 69 +/- 32 mN/mm2; P < 0.05) and maximum shortening velocity (from 2.9 +/- 0.5 to 4.9 +/- 1.4 Lmax/s; P < 0.05). Dantrolene induced a negative inotropic effect in diaphragm muscles in isotonic and isometric conditions in all groups, but this effect was significantly less marked in the 3-day-old rats compared with older rats. Dantrolene did not induce significant lusitropic effects during postnatal maturation. Developmental changes in the pharmacologic response to dantrolene were more rapid than those of ryanodine. CONCLUSION: Dantrolene induced less pronounced negative inotropic effects on the diaphragm in neonatal rats as compared with adult rats. Our study suggests that developmental changes in the pharmacologic response to dantrolene are more rapid than those of ryanodine.     

Chronic treatment with antipsychotics enhances intraoperative core hypothermia

Antipsychotics can induce hypothermia, but intraoperative temperature regulation in schizophrenic patients taking antipsychotics remains unclear. We investigated intraoperative temperature regulation and postoperative shivering in chronic schizophrenic patients receiving antipsychotics. We studied 30 schizophrenic patients and 30 control patients who underwent orthopedic surgery. Tympanic membrane temperatures (35.7 degrees C +/- 0.5 degrees C, 35.6 degrees C +/- 0.5 degrees C, 35.6 degrees C +/- 0.4 degrees C, 35.5 degrees C +/- 0.4 degrees C, 35.4 degrees C +/- 0.5 degrees C, and 35.4 degrees C +/- 0.3 degrees C) 15, 30, 45, 60, 75, and 90 min, respectively, after induction in schizophrenic patients were significantly (P < 0.001) lower than those (36.5 degrees C +/- 0.5 degrees C, 36.4 degrees C +/- 0.5 degrees C, 36.3 degrees C +/- 0.4 degrees C, 36.2 degrees C +/- 0.5 degrees C, 36.2 degrees C +/- 0.4 degrees C, and 36.1 degrees C +/- 0.4 degrees C) in control patients. Mean skin temperatures (31.1 degrees C +/- 0.4 degrees C [P = 0.008], 31.1 degrees C +/- 0.3 degrees C [P = 0.007], and 31.1 degrees C +/- 0.2 degrees C [P = 0.006]) 60, 75, and 90 min, respectively, after induction in schizophrenic patients were significantly lower than those (31.5 degrees C +/- 0.3 degrees C, 31.5 degrees C +/- 0.3 degrees C, and 31.5 degrees C +/- 0.3 degrees C) in control patients. Four of 30 schizophrenic patients and 7 of 30 control patients developed postanesthesia shivering. There were no significant differences within 1 h after tracheal extubation in tympanic membrane temperatures between patients who shivered and those who did not shiver. In conclusion, chronic schizophrenic patients were more hypothermic during anesthesia. The incidence of postanesthesia shivering was not significantly increased. IMPLICATIONS: Antipsychotics inhibit autonomic thermoregulation. This is caused by decreased heat production, increased heat loss, and impaired central action at the hypothalamus. Thus, schizophrenic patients receiving antipsychotics may have impaired intraoperative temperature regulation.     

The effects of dantrolene on the contraction, relaxation, and energetics of the diaphragm muscle.

Dantrolene is used in patients with muscle spasticity and is the only known effective treatment for malignant hyperthermia. However, its effects on muscle relaxation and energetics are unknown and may have important consequences in diaphragmatic function. We studied the effects of dantrolene (10(-8) to 10(-4) M) on diaphragm muscle strips (n = 12) in the hamster in vitro (Krebs-Henseleit solution, 29 degrees C, 95% oxygen/5% carbon dioxide) in response to tetanic stimulation (50 Hz). We studied contraction and relaxation under isotonic and isometric conditions, as well as energetics. Data are mean +/- SD. Dantrolene induced a negative inotropic effect in the hamster diaphragm (active force at 10(-4) M: 34% +/- 7% of baseline; P < 0.05) but did not significantly modify the curvature of the force-velocity relationship. Dantrolene did not significantly modify isotonic relaxation. Dantrolene, up to 10(-5) M, did not significantly impair isometric relaxation. In conclusion, dantrolene induced a marked negative inotropic effect on diaphragm muscle without affecting myothermal efficiency and relaxation. Implications: Dantrolene induced a significant and concentration-dependent negative inotropic effect on diaphragm muscle but did not modify isotonic relaxation, which suggests no alteration of the calcium reuptake by the sarcoplasmic reticulum; up to 10(-5) M dantrolene did not alter isometric relaxation, i.e., myofilament calcium sensitivity. Dantrolene did not modify the energetics of diaphragm muscle.