The effects of physical treatment on induced fever in humans.

PURPOSE: Initial treatments for fever include the amelioration of underlying causes and administration of antipyretic medications. However, patients who fail these treatments are often actively cooled, which may be counterproductive because decreasing skin temperature increases the thermoregulatory core target temperature. Cooling may also provoke metabolic and autonomic stress and thermal discomfort. SUBJECTS AND METHODS: We studied 9 subjects, each on 3 days. Fever was induced each day with 100,000 IU/kg of interleukin-2 administered intravenously (elapsed time zero). Randomly assigned treatments were 1) control (a cotton blanket), 2) cooling (forced air at 15 degrees C), or 3) self-adjust (forced-air warming adjusted to comfort). Treatments were maintained for 3 to 8 elapsed hours. RESULTS: Peak core temperatures (mean +/- SD) were 38.4 +/- 0.5 degrees C on the control day, 38.1 +/- 0.5 degrees C on the cooling day, and 38.5 +/- 0.4 degrees C on the self-adjust day. Integrated core temperatures were 6.0 +/- 1.6 degrees C x h on the control day, 5.7 +/- 2.2 degrees C x h on the cooling day, and 6.4 +/- 1.2 degrees C x h on the self-adjust day. Neither peak nor integrated core temperatures differed significantly on the 3 days. Shivering was common on the cooling day but otherwise rare. Oxygen consumption was normal on the control and self-adjust days but increased 35% to 40% during cooling (P = 0.0001). Mean arterial pressure and plasma norepinephrine and epinephrine concentrations were significantly greater during cooling (P <0.05). On a self-reported thermal comfort scale, the subjects were miserable during cooling and significantly more comfortable on the self-adjust than control day (P <0.05). CONCLUSION: We conclude that active cooling should be avoided in unsedated patients with moderate fever, because it does not reduce core temperature but does increase metabolic rate, activate the autonomic nervous system, and provoke thermal discomfort.

Core cooling by central venous infusion of ice-cold (4 degrees C and 20 degrees C) fluid: isolation of core and peripheral thermal compartments.

BACKGROUND: Central venous infusion of cold fluid may be a useful method of inducing therapeutic hypothermia. The aim of this study was to quantify systemic heat balance and regional distribution of body heat during and after central infusion of cold fluid. METHODS: The authors studied nine volunteers, each on two separate days. Anesthesia was maintained with use of isoflurane, and on each day 40 ml/kg saline was infused centrally over 30 min. On one day, the fluid was 20 degrees C and on the other it was 4 degrees C. By use of a tympanic membrane probe core (trunk and head) temperature and heat content were evaluated. Peripheral compartment (arm and leg) temperature and heat content were estimated with use of fourth-order regressions and integration over volume from 18 intramuscular thermocouples, nine skin temperatures, and "deep" hand and foot temperature. Oxygen consumption and cutaneous heat flux estimated systemic heat balance. RESULTS: After 30-min infusion of 4 degrees C or 20 degrees C fluid, core temperature decreased 2.5 +/- 0.4 degrees C and 1.4 +/- 0.2 degrees C, respectively. This reduction in core temperature was 0.8 degrees C and 0.4 degrees C more than would be expected if the change in body heat content were distributed in proportion to body mass. Reduced core temperature resulted from three factors: (1) 10-20% because cutaneous heat loss exceeded metabolic heat production; (2) 50-55% from the systemic effects of the cold fluid per se; and (3) approximately 30% because the reduction in core heat content remained partially constrained to core tissues. The postinfusion period was associated with a rapid and spontaneous recovery of core temperature. This increase in core temperature was not associated with a peripheral-to-core redistribution of body heat because core temperature remained warmer than peripheral tissues even at the end of the infusion. Instead, it resulted from constraint of metabolic heat to the core thermal compartment. CONCLUSIONS: Central venous infusion of cold fluid decreases core temperature more than would be expected were the reduction in body heat content proportionately distributed. It thus appears to be an effective method of rapidly inducing therapeutic hypothermia. When the infusion is complete, there is a spontaneous partial recovery in core temperature that facilitates rewarming to normothermia.

Resistive heating is more effective than metallic-foil insulation in an experimental model of accidental hypothermia: A randomized controlled trial.

STUDY OBJECTIVE: We study a resistive-heating blanket in a volunteer model of severe accidental hypothermia to evaluate differences in rates of rewarming, core temperature afterdrop, and body heat content and distribution during active and passive rewarming. METHODS: Eight volunteers participated in a crossover design on 2 days. The volunteers were anesthetized and cooled to 33 degrees C (91.4 degrees F); anesthesia was subsequently discontinued, and shivering was prevented with meperidine. On one randomly assigned day, the volunteers were rewarmed passively with reflective foil (passive insulation), whereas on the other they were covered with a carbon fiber-resistive heating blanket set to 42 degrees C (107.6 degrees F; active rewarming). Trunk and head temperature and heat content were calculated from core (tympanic membrane) temperature. Peripheral (arm and leg) tissue temperature and heat content were estimated by using fourth-order regressions and integration over volume from 30 tissue and skin temperatures. RESULTS: Core heat content increased 73+/-14 kcal (mean+/-SD) during 3 hours of active warming, but only 31+/-24 kcal with passive insulation, a difference of 41+/-20 kcal (95% confidence interval [CI] 27 to 55 kcal; P <. 001). Peripheral tissue heat content increased linearly by 111+/-16 kcal during active warming but only by 38+/-31 kcal during passive warming, a difference of 74+/-34 kcal (95% CI 50 to 97; P <.001). Consequently, total body heat increased 183+/-22 kcal during active warming but only 68+/-54 kcal with passive insulation, a difference of 115+/-42 kcal (95% CI 86 to 144 kcal; P <.001). Core temperature increased from 32.9 degrees C+/-0.2 degrees C to 35.2 degrees C+/-0. 4 degrees C during 3 hours of active warming, a difference of 2.3 degrees C+/-0.4 degrees C. In contrast, core temperature with foil insulation only increased from 32.9 degrees C+/-0.2 degrees C to 33. 8 degrees C+/-0.5 degrees C, a difference of only 0.8 degrees C+/-0. 4 degrees C. The difference in the core temperature increase between the two treatments was thus 1.5 degrees C+/-0.4 degrees C (95% CI 1. 2 degrees C to 1.7 degrees C; P <.001 between treatments). Active warming was not associated with an afterdrop, whereas the afterdrop was 0.2 degrees C+/-0.2 degrees C and lasted a median of 45 minutes (interquartile range, 41 to 64 minutes) with passive insulation. CONCLUSION: Resistive heating more than doubles the rewarming rate compared with that produced by reflective metal foil and does so without producing an afterdrop. It is therefore likely to be useful in the prehospital setting.

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.

Opioids inhibit febrile responses in humans, whereas epidural analgesia does not: an explanation for hyperthermia during epidural analgesia.

BACKGROUND: Epidural analgesia is frequently associated with hyperthermia during labor and in the postoperative period. The conventional assumption is that hyperthermia is caused by the technique, although no convincing mechanism has been proposed. However, pain in the "control" patients is inevitably treated with opioids, which themselves attenuate fever. Fever associated with infection or tissue injury may then be suppressed by opioids in the "control" patients while being expressed normally in patients given epidural analgesia. The authors therefore tested the hypothesis that fever in humans is manifested normally during epidural analgesia, but is suppressed by low-dose intravenous opioid. METHODS: The authors studied eight volunteers, each on four study days. Fever was induced each day by 150 IU/g intravenous interleukin 2. Volunteers were randomly assigned to: (1) a control day when no opioid or epidural analgesia was given; (2) epidural analgesia using ropivacaine alone; (3) epidural analgesia using ropivacaine in combination with 2 microg/ml fentanyl; or (4) intravenous fentanyl at a target plasma concentration of 2.5 ng/ml. RESULTS: Fentanyl halved the febrile response to pyrogen, decreasing integrated core temperature from 7.0 +/- 3.2 degrees C. h on the control day, to 3.8 +/- 3.0 degrees C. h on the intravenous fentanyl day. In contrast, epidural ropivacaine and epidural ropivacaine-fentanyl did not inhibit fever. The fraction of core-temperature measurements that exceeded 38 degrees C was halved by intravenous fentanyl, and the fraction exceeding 38.5 degrees C was reduced more than fivefold. CONCLUSIONS: These data support the authors' proposed mechanism for hyperthermia during epidural analgesia. Fever during epidural analgesia should thus not be considered a complication of the anesthetic technique per se.

Tramadol reduces the sweating, vasoconstriction, and shivering thresholds.

UNLABELLED: The analgesic tramadol inhibits the neuronal reuptake of norepinephrine and 5-hydroxytryptamine, facilitates 5-hydroxytryptamine release, and activates mu-opioid receptors. Each of these actions is likely to influence thermoregulatory control. We therefore tested the hypothesis that tramadol inhibits thermoregulatory control. Eight volunteers were evaluated on four study days, on which they received no drugs, tramadol 125 mg, tramadol 250 mg, and tramadol 250 mg with naloxone, respectively. Skin and core temperatures were gradually increased until sweating was observed and then decreased until vasoconstriction and shivering were detected. The core temperature triggering each response defined its threshold. Tramadol decreased the sweating threshold by -1.03 +/- 0.67 degrees C microgram-1.mL (r2 = 0.90 +/- 0.12). Tramadol also decreased the vasoconstriction threshold by -3.0 +/- 4.0 degrees C microgram-1.mL (r2 = 0.94 +/- 0.98) and the shivering threshold by -4.2 +/- 4.0 degrees C microgram-1.mL(r2 = 0.98 +/- 0.98). The sweating to vasoconstriction interthreshold range nearly doubled from 0.3 +/- 0.4 degree C to 0.7 +/- 0.6 degree C during the administration of large-dose tramadol (P = 0.04). The addition of naloxone only partially reversed the thermoregulatory effects of tramadol. The thermoregulatory effects of tramadol thus most resemble those of midazolam, another drug that slightly decreases the thresholds triggering all three major autonomic thermoregulatory defenses. In this respect, both drugs reduce the "setpoint" rather than produce a generalized impairment of thermoregulatory control. Nonetheless, tramadol nearly doubled the interthreshold range at a concentration near 200 ng/mL. This indicates that tramadol slightly decreases the precision of thermoregulatory control in addition to reducing the setpoint. IMPLICATIONS: The authors evaluated the effects of the analgesic tramadol on the three major thermoregulatory responses: sweating, vasoconstriction, and shivering. Tramadol had only slight thermoregulatory effects. Its use is thus unlikely to provoke hypothermia or to facilitate fever.

The effect of pyrogen administration on sweating and vasoconstriction thresholds during desflurane anesthesia.

BACKGROUND: General anesthetics increase the sweating-to-vasoconstriction interthreshold range (temperatures not triggering thermoregulatory defenses), whereas fever is believed to only increase the setpoint (target core temperature). However, no data characterize thresholds (temperatures triggering thermoregulatory defenses) during combined anesthesia and fever. Most likely, the combination produces an expanded interthreshold range around an elevated setpoint. The authors therefore tested the hypothesis that thermoregulatory response thresholds during the combination of fever and anesthesia are simply the linear combination of the thresholds resulting from each intervention alone. METHODS: The authors studied eight healthy male volunteers. Fever was induced on the appropriate days by intravenous injection of 30 IU/g human recombinant interleukin 2 (IL-2), followed 2 h later by an additional 70 IU/g. General anesthesia consisted of desflurane 0.6 minimum alveolar concentration (MAC). The volunteers were randomly assigned to the following groups: (1) control (no desflurane, no IL-2); (2) IL-2 alone; (3) desflurane alone; and (4) desflurane plus IL-2. During the fever plateau, volunteers were warmed until sweating was observed and then cooled to vasoconstriction. Sweating was evaluated from a ventilated capsule and vasoconstriction was quantified by volume plethysmography. The tympanic membrane temperatures triggering significant sweating and vasoconstriction identified the respective response thresholds. Data are presented as the mean +/- SD; P < 0.05 was considered significant. RESULTS: The interthreshold range was near 0.40 degrees C on both the control day and during IL-2 administration alone. On the IL-2 alone day, however, the interthreshold range was shifted to higher temperatures. The interthreshold range increased significantly during desflurane anesthesia to 1.9+/-0.6 degrees C. The interthreshold range during the combination of desflurane and IL-2 was 1.2+/-0.6 degrees C, which was significantly greater than on the control and IL-2 alone days. However, it was also significantly less than during desflurane alone. CONCLUSION: The combination of desflurane and IL-2 caused less thermoregulatory inhibition than would be expected based on the effects of either treatment alone. Fever-induced activation of the sympathetic nervous system may contribute by compensating for a fraction of the anesthetic-induced thermoregulatory impairment.

Alfentanil reduces the febrile response to interleukin-2 in humans.

OBJECTIVE: Manifestation of intraoperative fever is impaired by volatile anesthetics and muscle relaxants. Opioids are common anesthetic adjuvants and remain the dominant treatment for postoperative surgical pain and sedation of critically ill patients. The effect of opioids on normal thermoregulatory control is well established. However, the extent to which these drugs might inhibit fever remains unknown. Accordingly, we tested the hypothesis that relatively low plasma concentrations of the mu-receptor agonist alfentanil reduce fever magnitude. DESIGN: Prospective, randomized, crossover study. SETTING: Outcomes Research Laboratory, at the Department of Anesthesia and Perioperative Care, University of California, San Francisco. PATIENTS: Eight healthy male volunteers, aged 25-31 yrs, each studied on three separate days. INTERVENTION: Each volunteer was given an intravenous injection of 30 IU/g interleukin (IL)-2, followed 2 hrs later by 70 IU/g. One hour after the second dose, the volunteers were randomly assigned to three doses of alfentanil: a) none (control); b) a target plasma concentration of 100 ng/mL; and c) a target concentration of 200 ng/mL. Opioid administration continued for 5 hrs. METHODS AND MAIN RESULTS: Alfentanil significantly reduced the febrile response to pyrogen, decreasing integrated tympanic membrane temperatures from 7.5+/-2.2 degrees C x hr on the control day, to 4.9+/-1.5 degrees C x hr with 100 ng/mL alfentanil, and to 5.1+/-1.7 degrees C x hr with 200 ng/mL alfentanil (p = .011). Peak temperatures were also significantly reduced from 38.5+/-0.4 degrees C on the control day, to 38.0+/-0.4 degrees C on the 100 ng/mL-alfentanil day and 38.0+/-0.6 degrees C on the 200-ng/mL day (p = .019). Plasma cytokine concentrations increased after IL-2 administration, roughly in proportion to the elevation in core temperature. However, cytokine concentrations did not differ significantly among the treatment groups. CONCLUSION: Alfentanil significantly reduced the febrile response to IL-2 administration. However, the reduction was comparable at plasma concentrations near 100 and 200 ng/mL. These data indicate that concentrations of opioids commonly observed in critical care patients significantly inhibit the manifestation of fever.