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GENERAL ARTICLES

Lower-Body Warming Mimics the Normal Epidural-Induced Reduction in the Shivering Threshold

Anthony G. Doufas, MD, PhD^*, Nobutada Morioka, MD, Adel N. Maghoub, MD, Edward Mascha, PhD, and Daniel I. Sessler, MD

From the *Department of Anesthesia, Stanford University School of Medicine; Outcomes Research Group, Department of Anesthesia and Perioperative Care, University of California, San Francisco; Department of Quantitative Health Sciences, and Department of Outcomes Research, Cleveland Clinic, Cleveland, Ohio.

Address correspondence and reprint requests to Anthony G. Doufas, MD, PhD, Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Dr., H3590 – Stanford, CA 94305-5640. Address e-mail to agdoufas{at}stanford.edu.

	Abstract

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BACKGROUND: Neuraxial anesthesia reduces the shivering threshold 0.6°C. This effect might be mediated by an apparent (as opposed to actual) increase in lower body temperature. Accordingly, sufficient lower body warming should result in thermoregulatory inhibition comparable to that exerted by epidural anesthesia. We tested the hypothesis that increasing leg skin temperature to 38°C mimics the normal 0.6°C reduction in the shivering threshold during epidural anesthesia.

METHODS: Shivering threshold during internal body cooling was determined in nine female volunteers on two separate days: one unanesthetized control day, and one day with a T10-11 epidural block. On each study day, lower body skin temperature was maintained near 38°C and upper body skin temperature near 33°C. We assessed equivalency of the shivering thresholds on the control and epidural days using the two one-sided tests method.

RESULTS: The thresholds on the control (35.8°C ± 0.5°C; mean ± sd) and epidural (35.8°C ± 0.5°C) days were shown to be equivalent because the 95% CI for the difference in means, 0.0 (–0.4, 0.4), was within our prespecified limits of –0.6°C to +0.6°C (P < 0.025 for both one-sided equivalency tests).

CONCLUSIONS: Lower body warming mimics the normal epidural-induced reduction in the shivering threshold. Our results support a mechanism based on increased apparent lower body skin temperature during neuraxial anesthesia.

	Introduction

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Both spinal and epidural anesthesia reduce the shivering threshold (triggering core temperature) by 0.6°C.1 Although the mechanism remains unknown, in 1994, we proposed that the reduction might be mediated by an apparent (as opposed to actual) increase in lower body temperature.2

The basis for this theory is that skin temperature contributes 20% to activation of autonomic cold defenses including shivering.3 Neuraxial anesthesia blocks all thermal input. But because cold-receptor activity predominates at normal leg skin temperatures (i.e., 33°C),4 mostly cold signals are blocked. A possible consequence is that the autonomic thermoregulatory system will then interpret this loss of tonic cold signals as relative leg warming. The normal thermoregulatory response to leg warming, whether apparent or actual, is a reduction in the shivering threshold. Vasoconstriction and shivering thresholds, for example, are reduced about 0.5°C for each 5°C increase in leg skin temperature. A lower body skin temperature near 38°C, about 5°C above normal, should thus reduce the shivering threshold to the same extent that it is reduced by epidural anesthesia.2

This mechanism is supported by clinical evidence, which predicts that perception of warmth in the blocked area of the body should increase substantially during the onset of neuraxial anesthesia.5 However, a carefully controlled volunteer study failed to identify any epidural-induced increase in perception of warmth.6 One potential explanation is that autonomic and behavioral thermoregulatory consequences of epidural anesthesia differ. But it is also possible that our explanation for the reduced shivering threshold during epidural anesthesia is simply incorrect.

If the reduction in shivering threshold during neuraxial anesthesia results from an apparent increase in leg temperature, the shivering thresholds should be similar with or without epidural anesthesia when leg skin temperature is maintained at 38°C. We therefore tested the hypothesis that shivering thresholds are comparable when leg skin temperature is maintained at 38°C, with or without epidural anesthesia.

	METHODS

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With approval of the University of California, San Francisco Committee on Human Research, we evaluated nine healthy, nonobese, female volunteers during the first 10 days of their menstrual cycles. All volunteers gave written informed consent. Age was restricted to 18–45 yr. We excluded volunteers who took any medication (except oral contraceptives) or had a recent infection or fever, or diabetes. We similarly excluded those with a history of thyroid disease, dysautonomia, or Raynaud’s syndrome.

Each volunteer participated on two separate days, separated by at least 72 h. On the first study day, volunteers were randomly assigned to an unanesthetized control day or to epidural anesthesia. They were then given the alternative treatment on the second study day.

Protocol
Volunteers fasted at least 8 h before each study day. They were minimally clothed (i.e., swimming suit) during the study and reclined on a padded table. Ambient temperature was maintained at 21°C–22°C. A 16-gauge, 20-cm-long catheter was inserted into a vein at the antecubital fossa. A Foley bladder catheter was inserted to prevent pain associated with bladder distention. The volunteers were prewarmed for 1 h with forced-air and circulating water to minimize redistribution hypothermia.

On the appropriate study day, epidural anesthesia was started after a 1-h prewarming period and IV administration of 500 mL warmed lactated Ringer’s solution. After infiltration of the skin with a local anesthetic, the ligamentum flavum was punctured with an 18-gauge Tuohy needle at the L3-4 interspace and an epidural catheter was introduced in the epidural space. The epidural catheter was injected with 3 mL 2% lidocaine with epinephrine 1:100,000. This test dose was followed in 5 min by slow administration of 15–20 mL 2% 2-chloroprocaine (Chloroprocaine HCl, Abbott Laboratories, North Chicago, IL) without epinephrine.

The initial volume of 2-chloroprocaine was chosen based on each volunteer’s height and calculated to produce a dermatomal level of sensory blockade near T10-11, as determined by loss of cutaneous cold sensation and response to pinprick. Subsequently, a continuous infusion of 2% 2-chloroprocaine was administered at a rate of 16–20 mL/h to maintain a T10-11 sensory blockade level. The volunteers were observed for at least 30 min after the local anesthetic injection to confirm continued peripheral vasodilation and a stable arterial blood pressure. The sensory blockade was tested at regular intervals during the trial and adjustments were made, if necessary, to maintain the block at the designated target.

Independent forced-air and circulating water systems were adjusted to maintain lower body skin temperature near 38°C and upper body skin temperature near 33°C. Core hypothermia was induced by IV infusion of lactated Ringer’s solution cooled to 4°C. Core cooling rates were restricted to <3°C/h because such rates are unlikely to trigger dynamic thermoregulatory responses.7 The infusion was continued until the shivering threshold was identified (see below).

Measurements
Heart rate was measured continuously using an electrocardiogram. Arterial blood pressure was determined oscillometrically at 5-min intervals. Oxygen saturation was measured with a pulse oximeter. Core temperature was recorded from the tympanic membrane using Mon-a-therm thermocouples (Mallinckrodt Anesthesiology Products, Inc., St. Louis, MO). The aural probe was inserted by the volunteers themselves until they felt the thermocouple touch the tympanic membrane. Appropriate placement was confirmed when volunteers easily detected gentle rubbing of the attached wire. The aural canal was occluded with cotton, the probe securely taped in place, and a gauze bandage positioned over the external ear. Mean upper and lower body skin surface temperatures were determined from 15 area-weighted sites.8

All temperatures were recorded using Mon-a-therm thermocouples. These probes are well insulated and unaffected by surface heating or cooling devices. Temperatures were recorded from thermocouples connected to calibrated Iso-Thermex 16-channel electronic thermometers having an accuracy of 0.1°C and a precision near 0.01°C (Columbus Instruments International, Corp., Columbus, OH).

Oxygen consumption (VO₂), as measured by a DeltaTrac (SensorMedics Corp., Yorba Linda, CA) metabolic monitor, quantified shivering, as in several prior studies from our group. The DeltaTrac uses a mixing chamber to collect expired gases. It analyzes these gases using a paramagnetic oxygen sensor for Fio₂ and FeO₂, and calculates the difference between Fio₂ and FeO₂. The monitor also measures the CO₂ concentration of inspired and expired gases using an infrared sensor. A constant flow generator is incorporated to produce a known total (constant) flow. VO₂, as well as CO₂ production (VCO₂), is estimated. Respiratory quotient is calculated as the VCO₂ to VO₂ ratio. The system was used in "canopy-mode".9 Measurements were averaged over 1-min intervals and recorded every minute. Volunteers were not administered supplemental O₂ during the trial. End-tidal Pco₂ was measured from nasal prongs with an Ohmeda monitor (Rascal II, OHMEDA, Salt Lake City, UT). Exhaust gas from this monitor was returned to the metabolic monitor.

Alertness of the volunteers was evaluated using the responsiveness component of Observer’s Assessment of Alertness/Sedation Score (OAA/S, Table 1).10 A score was obtained at 0.2°C intervals throughout cooling by an investigator who was blinded to the treatment and core temperature.

Data Analysis
A sustained increase in VO₂ of 20% identified the shivering threshold. The shivering threshold was determined post hoc by an investigator blinded to the treatment and core temperature. All hemodynamic, respiratory, metabolic, and temperature data were tested for normality using the Kolmogorov–Smirnov test with the [alpha] level set at 0.05 and visual data checks. Normally distributed data are presented as means (sd) and compared between the epidural and control treatments using paired t-test. Otherwise, data are presented as medians (quartiles) and compared using the Wilcoxon signed rank test. Results are reported as means of individually obtained differences between treatments (95% confidence intervals), or as P values.

For the primary outcome of shivering threshold (triggering core temperature), the primary analysis was to formally assess equivalency. We assessed equivalency of the shivering thresholds on control and epidural days using the two one-sided tests equivalency method,11 with an equivalency region of –0.6°C to 0.6°C. Our null hypothesis was that the mean temperature difference between control and epidural days was outside of these limits. We thus tested the alternative of whether the mean difference was both more than –0.6°C and less than +0.6°C with two one-sided t-tests. Equivalency would be concluded if both tests were significant at P < 0.025 (or 0.05/2), which would correspond to a 95% CI for the mean difference occurring within the a priori specified equivalency interval. Results are expressed as means ± standard deviations and confidence intervals. A significance level of 0.05 was used for each hypothesis.

With n = 9 patients, we had 90% power to show equivalency between the two methods at the 0.05 significance level assuming a sd of 0.5°C for the within-subject differences and an equivalency buffer of 0.6°C. The equivalency buffer was chosen based on the smallest difference that would be clinically important.

	RESULTS

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All nine volunteers completed the study. They were 31 ± 6 yr old, weighed 63 ± 8 kg, and were 161 ± 8 cm tall.

Hemodynamic and respiratory responses, ambient temperature, and relative humidity at the shivering threshold did not differ significantly on the two study days. The total amount of lactated Ringer’s solution infused and the rate of decrease of the core body temperature were also similar on the control and epidural days. Epidural anesthesia was associated with a lower systemic VO₂ at baseline, compared with the control treatment (Table 2, Fig. 1). On each study day, the Fio₂ was 0.21 and the FiCO₂ was effectively zero. The respiratory quotient remained between 0.75 and 1.08 throughout and was similar with each treatment at the shivering threshold (Table 2). All volunteers remained fully awake (OAA/S = 5) throughout the trial on both treatments.

View larger version (19K): [in this window] [in a new window]   Figure 1. Upper graphs show 1-min averages (sd, across volunteers) of the systemic O2 consumption (VO2) during a 20-min baseline, before initiation of the cold infusion, and at the shivering threshold (ST) on the control and epidural (after establishment of the block) treatment days. Lower graphs present individual VO2 values at baseline and at the shivering threshold for the two treatments. Medians (interquartile ranges) are also presented. Baseline VO2 was significantly lower in the epidural compared with control treatment (P = 0.016, Table 2).

The shivering thresholds on the control and the epidural day did not differ significantly (Table 2, Fig. 2). The mean difference in the shivering threshold was 0.03°C ± 0.47°C, which with its 95% CI of –0.4°C and +0.4°C was within our a priori equivalence interval (–0.6°C, +0.6°C). Correspondingly, both one-sided tests were significant at the 0.025 level (P = 0.013 and P = 0.019 for the lower and upper bounds, respectively). We therefore conclude equivalence of the two treatments in terms of their effect on the shivering threshold.

View larger version (14K): [in this window] [in a new window]   Figure 2. Hemodynamic responses and shivering thresholds (triggering core temperature) with and without epidural anesthesia. Circles show the individual responses; squares and vertical whiskers indicate medians (interquartile range) for the hemodynamic responses, or means (95% confidence intervals) for the shivering thresholds. Lower body skin temperature was maintained near 38°C in each treatment. Equivalency for the two treatments was shown using the two one-sided tests procedure (P < 0.025); the 95% CI was within prespecified equivalency interval of –0.6°C to +0.6°C.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
A corollary of our working theory is that sufficient leg warming should reduce the amount of tonic cold input from the legs to near zero levels. Subsequent induction of neuraxial anesthesia would then have little or no effect on thermal signals reaching the brain. Our data confirm this predication: core temperature at shivering was virtually identical with and without epidural anesthesia. We caution, though, that while consistent with our theory, our result in no way proves the theory. Although skin warming reduces the shivering threshold without neuraxial anesthesia and neuraxial anesthesia reduces the shivering threshold, our demonstration that the thresholds are comparable with leg warming and epidural anesthesia does not necessarily indicate that there is any mechanistic link between these phenomena.

Although epidural anesthesia halves the anesthetic requirement of sevoflurane for immobility,12 it produces only mild sedation (OAA/S = 4–5) when administered as a sole anesthetic in healthy volunteers.13 We have previously shown that a reduction in the shivering threshold of about 0.6°C, which equals that produced by epidural anesthesia, corresponds to a midazolam effect of moderate sedation (OAA/S = 3).14 In the present study, our volunteers were fully awake on the epidural day throughout the trial. Thus, a mechanism other than sedation seems predominantly responsible for the thermoregulatory effect of epidural anesthesia.

There are certainly other potential mechanisms that might explain how neuraxial anesthesia reduces the shivering threshold. For example, systemic absorption of epidurally administered local anesthetic might well have central effects, including impairment of thermoregulatory control. Plasma lidocaine concentrations, for example, are substantial during epidural anesthesia15 and lidocaine exerts a significant clinical effect16 including sedation.17,18 However, systemic absorption of local anesthetic does not appear to reduce shivering threshold, since the reduction is similar with epidural and spinal anesthesia, although there cannot possibly be meaningful systemic absorption of the small doses given for subarachnoid blocks. Furthermore, the shivering threshold is reduced as usual when chloroprocaine is used for epidural anesthesia,1 although the drug is rapidly degraded in plasma.19,20 We nonetheless chose chloroprocaine for the current study to eliminate systemic absorption as a possible confounding factor.

We did not reconfirm that epidural anesthesia reduces the shivering threshold 0.6°C at typical perioperative lower body skin temperatures. However, the thermoregulatory consequences of neuraxial anesthesia have been demonstrated numerous times with consistent results.1,2,21 In addition, the lower VO₂ at baseline in the epidural, compared with the control day, is an effect of neuraxial anesthesia22 and it does not seem to confound our major finding. Our group has used indirect calorimetry (DeltaTract metabolic monitor in a canopy mode) numerous times to quantify the shivering threshold. Although certain limitations may apply to this methodology, we stress the fact that, in general, thermoregulatory studies are focused on the abrupt increase in the VO₂, which defines the shivering threshold, rather than on the estimation of its absolute value. This is especially the case with our crossover design, which automatically cancels out any systematic error.

Could the participation of only female volunteers in our study be characterized as a limitation? Women have a setpoint that is about 0.3°C higher than men during the follicular phase of their menstrual cycles. However, the precision of thermoregulatory control is comparable and there is no evidence that the effects of regional anesthesia differ in men and women.

In summary, several competing theories explain how neuraxial anesthesia might impair thermoregulatory cold defenses. One theory, proposed in 1994, includes the testable prediction that sufficient lower body warming mimics the normal epidural-induced reduction in the shivering threshold. Our results confirm the theory’s predication, thus offering support for a mechanism based on increased apparent (as opposed to actual) lower body skin temperature during neuraxial anesthesia.

	Footnotes

 
Accepted for publication August 21, 2007.

Supported by NIH Grant GM 061655 (Bethesda, MD) and the Joseph Drown Foundation (Los Angeles, CA). The study sponsors were not involved in the design of the study; the collection, analysis, or interpretation of the data; or the preparation of the manuscript. The thermocouples used in this study were generously donated by Mallinckrodt Anesthesiology Products, Inc. (St. Louis, MO). None of the authors has a personal financial interest in this research. Nancy Alsip, PhD, edited the manuscript (Outcomes Research Institute, University of Louisville).

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