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 mu- and kappa-agonist) treats shivering better than equianalgesic doses of pure mu-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 mu-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 microg/ml; and (3) a target plasma alfentanil concentration of 0.2 microg/ml. Skin temperatures were maintained near 31 degrees C, 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. Conclusions The authors could not confirm the hypothesis that meperidine reduces the gain or maximum intensity of shivering more than alfentanil does. These results suggest that meperidine's special antishivering effect is primarily mediated by a disproportionate reduction in the shivering threshold.

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Epidural Anesthesia Reduces the Gain and Maximum Intensity of Shivering

Anesthesiology ◽

10.1097/00000542-199804000-00002 ◽

1998 ◽

Vol 88 (4) ◽

pp. 851-857 ◽

Cited By ~ 24

Author(s):

Jin-Soo Kim ◽

Takehiko Ikeda ◽

Daniel I. Sessler ◽

Minang Turakhia ◽

Renee Jeffrey

Keyword(s):

Oxygen Consumption ◽

Regional Anesthesia ◽

Core Temperature ◽

Epidural Anesthesia ◽

Maximum Intensity ◽

Upper Body ◽

Sensory Level ◽

Intensity Increase ◽

Lower Body ◽

Thermoregulatory System

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 degrees C, 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 approximately 0.4 degrees C, from 36.7 +/- 0.6 to 36.3 +/- 0.5 degrees C (means +/- SD; P < 0.05). Systemic gain, as determined by oxygen consumption, was reduced from -581 +/- 186 to -215 +/- 154 ml x min(-1) x degrees C(-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/degrees C (P < 0.01). However, upper-body gain had no compensatory increase: -1.3 +/- 1.1 units/degrees C control versus 2.0 +/- 2.1 units/degrees C epidural. Maximum oxygen consumption was decreased by one third during epidural anesthesia: 607 +/- 82 versus 412 +/- 50 ml/min (P < 0.05). Conclusions These results confirm that regional anesthesia reduces the shivering threshold. Epidural anesthesia reduced the gain of shivering by 63% because upper-body muscles failed to compensate for lower-body paralysis. The thermoregulatory system thus fails to recognize that regional anesthesia reduces metabolic heat production, instead responding as if lower-body muscular activity remained intact.

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Isoflurane Alters Shivering Patterns and Reduces Maximum Shivering Intensity

Anesthesiology ◽

10.1097/00000542-199804000-00004 ◽

1998 ◽

Vol 88 (4) ◽

pp. 866-873 ◽

Cited By ~ 33

Author(s):

Takehiko Ikeda ◽

Jin-Soo Kim ◽

Daniel I. Sessler ◽

Chiharu Negishi ◽

Minang Turakhia ◽

...

Keyword(s):

Oxygen Consumption ◽

Core Temperature ◽

Muscular Activity ◽

Linear Increase ◽

Maximum Intensity ◽

Initial Increase ◽

Intensity Increase ◽

Isoflurane Anesthesia ◽

The Core ◽

End Tidal

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 degrees C. 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 degrees C. 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 x min(-1) x degrees C(-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. Conclusions These data indicate that isoflurane anesthesia markedly changes the overall pattern of shivering during progressive hypothermia from a linear increase to an unusual saw-tooth pattern. They further suggest that clonic muscular activity combines with shivering to increase the initial gain of shivering during isoflurane anesthesia, but that isoflurane peripherally inhibits the maximum expression of shivering.

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Suppression of Shivering during Hypothermia Using a Novel Drug Combination in Healthy Volunteers

Anesthesiology ◽

10.1097/aln.0b013e3181a979a3 ◽

2009 ◽

Vol 111 (1) ◽

pp. 110-115 ◽

Cited By ~ 29

Author(s):

Rainer Lenhardt ◽

Mukadder Orhan-Sungur ◽

Ryu Komatsu ◽

Raghavendra Govinda ◽

Yusuke Kasuya ◽

...

Keyword(s):

Heart Rate ◽

Oxygen Consumption ◽

Maximum Intensity ◽

Healthy Men ◽

Ringer’S Solution ◽

Tympanic Membrane Temperature ◽

Target Plasma ◽

Target Plasma Concentration ◽

Lactated Ringer's Solution ◽

Novel Drug

Background Hypothermia may be beneficial in stroke victims; however, it provokes vigorous shivering. Buspirone and dexmedetomidine each linearly reduce the shivering threshold with minimal sedation and no respiratory depression. This study tested the hypotheses that the combination of buspirone and dexmedetomidine would (1) synergistically reduce the shivering threshold, (2) synergistically reduce the gain and maximum intensity of shivering, and (3) produce sufficient inhibition to permit cooling to 34 degrees C without excessive hypotension or sedation. Methods Eight healthy men were randomly assigned on 4 days to (1) no drug, (2) buspirone (60 mg orally), (3) dexmedetomidine (intravenous infusion to target plasma concentration of 0.6 ng/ml), or (4) combination of buspirone and dexmedetomidine at same doses. Lactated Ringer's solution (approximately 3 degrees C) was infused intravenously to decrease tympanic membrane temperature by 1.5 degrees C/h. Shivering threshold was defined as an increase in oxygen consumption greater than 20%. Sedation was evaluated using the Observer's Assessment of Sedation/Alertness scale. Results Mean arterial pressure and heart rate were slightly lower on dexmedetomidine and combination days. Likewise, the level of sedation was statistically different on these 2 days but clinically unimportant. Buspirone reduced the shivering threshold from 36.6 degrees C +/- 0.4 degrees C to 35.9 degrees C +/- 0.4 degrees C, dexmedetomidine reduced it to 34.7 degrees C +/- 0.5 degrees C, and the combination to 34.1 +/- 0.4 degrees C. The interaction effect of 0.04 degrees C was not significant. The gain of shivering and maximum shivering intensity were similar on each day. Conclusions The combination of buspirone and dexmedetomidine additively reduced the shivering threshold. Thus, supplementing dexmedetomidine with buspirone blocks shivering and causes only minimal sedation.

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

Anesthesiology ◽

10.1097/00000542-199505000-00011 ◽

1995 ◽

Vol 82 (5) ◽

pp. 1160-1168 ◽

Cited By ~ 156

Author(s):

Christi Cheng ◽

Takashi Matsukawa ◽

Daniel I. Sessler ◽

Ozaki Makoto ◽

Andrea Kurz ◽

...

Keyword(s):

Skin Temperature ◽

Core Temperature ◽

Central Venous ◽

Men And Women ◽

Ringer’S Solution ◽

The Core ◽

Temperature Thresholds ◽

Venous Infusion ◽

Lactated Ringer's Solution ◽

Skin Temperatures

Background The contribution of mean skin temperature to the thresholds for sweating and active precapillary vasodilation has been evaluated in numerous human studies. In contrast, the contribution of skin temperature to the control of cold responses such as arteriovenous shunt vasoconstriction and shivering is less well established. Accordingly, the authors tested the hypothesis that mean skin and core temperatures are linearly related at the vasoconstriction and shivering thresholds in men. Because the relation between skin and core temperatures might vary by gender, the cutaneous contribution to thermoregulatory control also was determined in women. Methods In the first portion of the study, six men participated on 5 randomly ordered days, during which mean skin temperatures were maintained near 31, 34, 35, 36, and 37 degrees C. Core hypothermia was induced by central venous infusion of cold lactated Ringer's solution sufficient to induce peripheral vasoconstriction and shivering. The core-temperature thresholds were then plotted against skin temperature and a linear regression fit to the values. The relative skin and core contributions to the control of each response were calculated from the slopes of the regression equations. In the second portion of the study, six women participated on three randomly ordered days, during which mean skin temperatures were maintained near 31, 35, and 37 degrees C. At each designated skin temperature, core hypothermia sufficient to induce peripheral vasoconstriction and/or shivering was again induced by central venous infusion of cold lactated Ringer's solution. The cutaneous contributions to control of each response were then calculated from the skin- and core-temperature pairs at the vasoconstriction and shivering thresholds. Results There was a linear relation between mean skin and core temperatures at the response thresholds in the men: r = 0.90 +/- 0.06 for vasoconstriction and r = 0.94 +/- 0.07 for shivering. Skin temperature contributed 20 +/- 6% to vasoconstriction and 19 +/- 8% to shivering. Skin temperature in the women contributed to 18 +/- 4% to vasoconstriction and 18 +/- 7% to shivering, values not differing significantly from those in men. There was no apparent correlation between the cutaneous contributions to vasoconstriction and shivering in individual volunteers. Conclusions These data indicate that skin and core temperatures contribute linearly to the control of vasoconstriction and shivering in men and that the cutaneous contributions average approximately 20% in both men and women. The same coefficients thus can be used to compensate for experimental skin temperature manipulations in men and women. However, the cutaneous contributions to each response vary among volunteers; furthermore, the contributions to the two responses vary within volunteers.

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Nefopam and Alfentanil Additively Reduce the Shivering Threshold in Humans whereas Nefopam and Clonidine Do Not

Anesthesiology ◽

10.1097/aln.0b013e3181a979c1 ◽

2009 ◽

Vol 111 (1) ◽

pp. 102-109 ◽

Cited By ~ 16

Author(s):

Pascal Alfonsi ◽

Andrea Passard ◽

Valérie Gaude–Joindreau ◽

Bruno Guignard ◽

Daniel I. Sessler ◽

...

Keyword(s):

Oxygen Consumption ◽

Therapeutic Hypothermia ◽

Core Temperature ◽

Individual Effect ◽

Mean Skin Temperature ◽

Ringer’S Solution ◽

The Core ◽

Individual Effects ◽

Lactated Ringer's Solution ◽

The Individual

Background Induction of therapeutic hypothermia is often complicated by shivering. Nefopam reduces the shivering threshold with minimal side effects. Consequently, nefopam is an attractive component for induction of therapeutic hypothermia. However, nefopam alone is insufficient; it will thus need to be combined with another drug. Clonidine and alfentanil each reduce the shivering threshold. This study, therefore, tested the hypothesis that nefopam, combined either with clonidine or alfentanil, synergistically reduces the shivering threshold. Methods For each combination, ten volunteers were studied on 4 days. Combination 1: (1) control (no drug); (2) nefopam (100 ng/ml); (3) clonidine (2.5 microg/kg); and (4) nefopam plus clonidine (100 ng/ml and 2.5 microg/kg, respectively). Combination 2: (1) control (no drug); (2) nefopam (100 ng/ml); (3) alfentanil (150 ng/ml); and (4) nefopam plus alfentanil (100 ng/ml and 150 ng/ml, respectively). Lactated Ringer's solution (approximately 4 degrees C) was infused to decrease core temperature. Mean skin temperature was maintained at 31 degrees C. The core temperature that increased oxygen consumption to more than 25% of baseline identified the shivering threshold. Results With nefopam and clonidine, the shivering thresholds were significantly lower than on the control day. The shivering threshold decreased significantly less than would be expected on the basis of the individual effects of each drug (P = 0.034). In contrast, the interaction between nefopam and alfentanil on shivering was additive, meaning that the combination reduced the shivering threshold as much as would be expected by the individual effect of each drug. Conclusions Nefopam and alfentanil additively reduce the shivering threshold, but nefopam and clonidine do not.

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Effects of infection on oxygen consumption and core temperature in experimental thermal injury

Plastic & Reconstructive Surgery ◽

10.1097/00006534-198704000-00081 ◽

1987 ◽

Vol 79 (4) ◽

pp. 678

Author(s):

Errikos Constant ◽

L. H. Aulick

Keyword(s):

Oxygen Consumption ◽

Core Temperature ◽

Thermal Injury

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Effects of Infection on Oxygen Consumption and Core Temperature in Experimental Thermal Injury

Journal of Burn Care & Rehabilitation ◽

10.1097/00004630-198811000-00032 ◽

1988 ◽

Vol 9 (6) ◽

pp. 679

Author(s):

Louis H. Aulick ◽

Albert T. McManus ◽

Arthur D. Mason ◽

Basil A. Pruitt

Keyword(s):

Oxygen Consumption ◽

Core Temperature ◽

Thermal Injury

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Reduced stress- and cold-induced increase in energy expenditure in interleukin-6-deficient mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00514.2005 ◽

2006 ◽

Vol 291 (3) ◽

pp. R551-R557 ◽

Cited By ~ 56

Author(s):

Ingrid Wernstedt ◽

Amanda Edgley ◽

Anna Berndtsson ◽

Jenny Fäldt ◽

Göran Bergström ◽

...

Keyword(s):

Heart Rate ◽

Oxygen Consumption ◽

Energy Expenditure ◽

Core Temperature ◽

Cold Exposure ◽

Interleukin 6 ◽

Utilization Rate ◽

Sympathetic Outflow ◽

Wild Type ◽

Deficient Mice

Interleukin-6 (IL-6) deficient (-/-) mice develop mature onset obesity. Pharmacological studies have shown that IL-6 has direct lipolytic effects and when administered centrally increases sympathetic outflow. However, the metabolic functions of endogenous IL-6 are not fully elucidated. We aimed to investigate the effect of IL-6 deficiency with respect to cold exposure and cage-switch stress, that is, situations that normally increase sympathetic outflow. Energy metabolism, core temperature, heart rate, and activity were investigated in young preobese IL-6−/− mice by indirect calorimetry together with telemetry. Baseline measurements and the effect of cage-switch stress were investigated at thermoneutrality (30°C) and at room temperature (20°C). The effect of cold exposure was investigated at 4°C. At 30°C, the basal core temperature was 0.6 ± 0.24°C lower in IL-6−/− compared with wild-type mice, whereas the oxygen consumption did not differ significantly. The respiratory exchange ratio at 20°C was significantly higher and the calculated fat utilization rate was lower in IL-6−/− mice. In response to cage-switch stress, the increase in oxygen consumption at both 30 and 20°C was lower in IL-6−/− than in wild-type mice. The increase in heart rate was lower in IL-6−/− mice at 30°C. At 4°C, both the oxygen consumption and core temperature were lower in IL-6−/− compared with wild-type mice, suggesting a lower cold-induced thermogenesis in IL-6−/− mice. The present results indicate that endogenous IL-6 is of importance for stress- and cold-induced energy expenditure in mice.

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