1 OUTCOMES RESEARCHTM Institute and 2 Department of Anesthesiology and Perioperative Medicine, University of Louisville, Louisville, KY, USA
* Corresponding author. E-mail: agdoufas{at}louisville.edu
Accepted for publication January 21, 2005.
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Abstract |
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Methods. We studied nine healthy male volunteers (1840 yr) on two randomly assigned treatment days: (1) control and (2) magnesium (80 mg kg1 followed by infusion at 2 g h1). Lactated Ringer's solution (4°C) was infused via a central venous catheter over a period of approximately 2 h to decrease tympanic membrane temperature by 1.5°C h1. A significant and persistent increase in oxygen consumption identified the threshold. The gain of shivering was determined by the slope of oxygen consumption vs core temperature regression. Sedation was evaluated using a verbal rating score (VRS) from 0 to 10 and bispectral index (BIS) of the EEG. Peripheral muscle strength was evaluated using dynamometry and spirometry. Data were analysed using repeated measures ANOVA; P<0.05 was statistically significant.
Results. Magnesium reduced the shivering threshold (36.3 [SD 0.4] °C vs 36.6 [0.3] °C, P = 0.040). It did not affect the gain of shivering (control, 437 [289] ml min1 °C1; magnesium, 573 [370] ml min1 °C1; P=0.344). The magnesium bolus did not produce significant sedation or appreciably reduce muscle strength.
Conclusions. Magnesium significantly reduced the shivering threshold. However, in view of the modest absolute reduction, this finding is considered to be clinically unimportant for induction of therapeutic hypothermia.
Keywords: brain, protection ; complications, hypothermia ; complications, shivering ; heart, cardiac protection ; ions, magnesium ; monitoring, temperature ; thermoregulation
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Introduction |
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Effective thermoregulatory defences prevent the induction of mild to moderate hypothermia7 8 in unanaesthetized patients.9 Drugs known to markedly impair thermoregulation are either anaesthetics10 or major sedatives,11 and they produce unacceptable amounts of respiratory depression. Thus the search continues for drugs which sufficiently improve thermoregulatory tolerance without simultaneously producing excessive sedation or respiratory depression. In practice, this constitutes a search for drugs which reduce the shivering threshold (triggering core temperature) to a value approximating the target therapeutic core temperature.12 13
Intravenous magnesium has been shown to suppress postoperative shivering,14 suggesting that this agent reduces the shivering threshold. Recently, the addition of intravenous magnesium sulphate to a pharmacological anti-shivering regimen increased the cooling rate in unanaesthetized volunteers.13 The drug not only exerts a central effect,15 but is also a mild muscle relaxant16 and thus may simultaneously reduce the gain of shivering (incremental shivering intensity with progressing hypothermia). Magnesium also confers substantial neurological and cardiac protection in several animal models.1719
Thus magnesium is an especially attractive candidate for inducing thermoregulatory tolerance since it may simultaneously protect against tissue ischaemia. Therefore we tested the hypothesis that magnesium sulphate administration reduces the threshold and gain of shivering sufficiently to permit the induction of hypothermia without causing clinically significant sedation or muscle weakness.
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Methods |
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Protocol
Volunteers participated on two study days, and they fasted for at least 8 h before each study day. A minimum of 24 h elapsed between the study days. On both days, the volunteers were minimally clothed and rested supine on a standard operating room table. Ambient temperature was maintained near 21°C. On the first study day, each volunteer was randomly assigned in a double-blind manner to receive either normal saline (control) or magnesium. The volunteers were given the alternative treatment on the subsequent study day. On the magnesium day, volunteers were given an i.v. bolus of magnesium sulphate 80 mg kg1 administered by a syringe pump over a 30-min period. This was followed by an infusion of 2 g h1. On the control day, the volunteers received an equal volume of saline. An investigator who was not otherwise involved in the study prepared syringes containing saline or magnesium; thus the study was fully double-blinded.
A catheter was introduced into the superior vena cava via an antecubital vein. This catheter was used for cold-fluid infusion and blood sampling. A venous catheter was inserted in the other arm for drug administration. A circulating-water blanket (Cincinnati Sub-Zero, Cincinnati, OH) and a forced-air blanket (Augustine Medical Inc., Eden Prairie, MN) were placed under and on top of the volunteers, respectively, to maintain mean skin temperature at 31°C throughout the study. Furthermore, the back, upper body, and lower body were individually maintained at the designated value.
After a 30-min i.v. bolus, drug infusion was initiated in order to maintain stable magnesium plasma levels (Fig. 1). Sedation, thermal comfort, and muscle strength were evaluated in the peribolus period. Ten minutes after the beginning of drug infusion, lactated Ringer's solution, cooled to 4°C, was infused at rates sufficient to decrease the tympanic membrane temperature by
1.5°C h1 (cooling phase). Fluid was infused until further reduction in core temperature no longer increased oxygen consumption (see section on data analysis) or a total of 70 ml kg1 had been given. This is a standard and effective way of reducing core temperature as demonstrated in previous studies. Blood samples were obtained at the end of the drug bolus (post-bolus), 10 min after the initiation of the drug infusion (precooling) and at the shivering threshold (Fig. 1). The volunteers were asked again about their thermal comfort level when the shivering threshold was detected.
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All body temperatures were measured using Mon-a-therm thermocouples (Tyco-Mallinckrodt Anesthesiology Products Inc., St Louis, MO). Core temperature was recorded from the tympanic membrane. Volunteers inserted the aural probe 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 was securely taped in place and a gauze bandage was positioned over the external ear. Mean skin surface temperature was determined from 15 area-weighted sites.20 Temperatures were recorded from thermocouples connected to calibrated Iso-Thermex 16-channel electronic thermometers which had an accuracy of 0.1°C and a precision of 0.01°C (Columbus Instruments International Corporation, Columbus, OH). Individual and mean skin temperatures were computed by a data acquisition system, displayed at 1-s intervals and recorded at 1-min intervals.
Arteriovenous shunt vasomotor tone was evaluated from forearmfingertip and calftoe skin temperature gradients. There is an excellent correlation between skin temperature gradients and volume plethysmography.21 Vasoconstriction was defined by a forearm skin temperature gradient >0°C.
As in previous studies,12 2227 we used oxygen consumption, as measured by a DeltaTracTM (SensorMedics Corporation, Yorba Linda, CA) metabolic monitor, to quantify shivering; the system was used in canopy mode. Measurements were averaged over 1-min intervals and recorded every minute. Oxygen consumption () measurement started immediately after the end of the bolus infusion and lasted throughout the trial. A substantial and sustained increase in
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25% above the baseline, identified the shivering threshold. Exhaust gases from the
monitor were returned to the oxygen consumption monitor.
To ascertain that the stability of the magnesium concentrations was within an acceptable clinical level throughout the trial, we obtained blood samples 10 min after the bolus (magnesium or saline) administration, just before the start of active cooling and at the shivering threshold.
Sedation was evaluated using a verbal rating score (VRS) for sleepiness (0=wide awake to 10=asleep) and the bispectral index (BIS) of the electroencephalogram. BIS data were collected using four sensors arranged in a frontotemporal montage after mild abrasion of the skin. Impedance of the sensors was evaluated at 15-min intervals and kept <5 k. BIS values were transmitted to a data acquisition system every 5 s, and the smoothing window was set at 30 s. Volunteers were advised to keep their eyes closed, especially during the recording period.
Thermal comfort was also evaluated using a VRS (0=worst imaginable cold, 5=adequate thermal comfort, 10=worst imaginable heat). On each study day, sedation level was evaluated before (by VRS), during (VRS and BIS) and after (VRS) bolus administration of magnesium or saline. Thermal comfort (VRS) was evaluated at 3-min intervals during bolus administration and at the shivering threshold.
During bolus administration, cardiorespiratory physiology values (HR, MAP, , RR,
), mean skin temperatures and core temperature were also evaluated every 3 min. At the same times, laser Doppler flowmetry28 was used to detect changes in the skin blood flow associated with vasodilation. A laser detector was placed on the chest and an increase in values from the baseline of laser Doppler flowmetry indicated increasing blood flow.
Muscle strength was evaluated in the right upper and left lower extremities using a hand-held dynamometer (MICROFET2, Hoggan Health Industries Inc., Drapper, UT). This is a simple hand-held device with a small internal load cell capable of measuring muscular force. It is applied to the subject's limb and the subject generates force in an attempt to move the hand-held dynamometer that is held firmly in place by the test administrator.29 The peak force generated after each test is recorded and digitally displayed in pounds (lb). The average of three measurements taken before and after bolus administration was used for further analysis. At the same time as an additional index of peripheral muscle strength, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured using a hand-held spirometer (MicroPlus, Micro Medical Ltd, Rochester, UK).
Data analysis
Threshold differences <0.5°C are of questionable clinical importance. Previous similar studies in volunteers indicate that the standard deviation of shivering threshold measurements is 0.4°C. Thus nine volunteers were required to provide a 90% power to detect a difference of 0.5°C in the shivering threshold with a cross-over design using a paired t-test with an level of 0.05. KolmogorovSmirnov and ShapiroWilk tests were used to test shivering threshold data for normality.
A substantial and sustained increase in oxygen consumption identified the shivering threshold. The baseline for this analysis was the steady-state value after the bolus administration but before core cooling had started. Maximum intensity of shivering was identified by oxygen consumption which failed to increase further despite continued reduction in core temperature. The gain of shivering was determined by the slope of oxygen consumption vs core temperature regression. Data from the threshold until the maximum intensity of shivering were used for gain calculation. The paired t-test was used to compare values between the two treatments.
On each study day haemodynamic and respiratory responses, as well as ambient temperature and relative humidity, were averaged within each volunteer; these values were then averaged across volunteers. The 30-min bolus administration and cooling periods were treated separately.
Interaction between the time (baseline, post-bolus) and the drug (magnesium, saline) administered was evaluated using two-factor analysis of variance (ANOVA). Results of repeated measures during the bolus administration on the two study days were compared using repeated measures ANOVA. To confirm magnesium concentrations were stable, plasma concentrations at the different time-points were compared between the two treatments (magnesium, saline) using two-factor ANOVA (interaction of time with treatment). Results are expressed as mean (SD); P<0.05 was considered statistically significant.
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Results |
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Two-factor ANOVA showed that magnesium serum concentration on both study days was maintained essentially stable over time, from the post-bolus time-point until the shivering threshold (P=0.619) (Table 1).
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Discussion |
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Currently, there is little evidence that hypothermia protects against ischaemia in humans, although the evidence is overwhelming in animals. There is certainly little basis for recommending a specific target temperature for therapeutic hypothermia. Nonetheless, target temperatures from 33 to 34°C are being used clinically by some physicians and in ongoing clinical trials. Because magnesium reduces the shivering threshold only about a tenth of the amount necessary, it seems unlikely that magnesium has the potential to facilitate induction of therapeutic hypothermia, at least as a lone agent.
Magnesium seemed likely to induce thermoregulation tolerance because it is an effective treatment for postoperative shivering.14 That raises the question of how magnesium can be an effective treatment for postoperative shivering, and yet reduce the shivering threshold by only a few tenths of a degree Celsius. The answer is that many postoperative patients have core temperatures only slightly below the normal shivering threshold. This may be the case even when core temperature is relatively low because residual anaesthetics impair thermoregulatory control. Consequently, treatments that reduce the shivering threshold by a few tenths of a degree Celsius may be sufficient to attenuate postoperative shivering.40 However, such treatments will be inadequate for induction of therapeutic hypothermia.
Recently, the addition of magnesium sulphate to a meperidine-based pharmacological anti-shivering regimen increased the cooling rate in unaesthetized volunteers.13 This effect was attributed to the observed vasodilation in the majority of the volunteers and associated with increased thermal comfort. In our study, increased thermal comfort during magnesium bolus was not related to peripheral vasodilation in our subjects, as determined by extremity temperature gradients. It seems that, despite the modest effect of magnesium on the shivering threshold, this agent could potentially play a contributory role in the induction of therapeutic hypothermia.
Magnesium sulphate, as used clinically, increases cerebrospinal fluid (CSF) magnesium concentrations by only about 2025%, with a peak concentration reached after 24 h depending on the concentration gradient between plasma and CSF.41 We used an intravenous infusion of magnesium as proposed by Sibai and colleagues42 for seizure prophylaxis in pre-eclamptic women. Relatively high plasma concentrations were achieved immediately after the bolus administration; these were maintained until the shivering threshold was reached about 2 h after magnesium bolus initiation, thus ensuring adequate CSF levels. Because of this, we were unable to determine whether the observed thermoregulatory action of magnesium was of central15 or peripheral origin.16
Despite the known central15 and peripheral muscle relaxation16 effects of magnesium, we were unable to demonstrate any significant changes in the sedation level or muscle strength during the bolus administration. It is likely that larger doses of magnesium sulphate would produce both greater thermoregulatory effects and a greater risk of complications. Nonetheless, previous studies indicate that the thermoregulatory response to most intravenous drugs is a linear function of plasma concentration.43 44 Thus an even larger, potentially hazardous, dose of magnesium seems unlikely to produce a useful reduction in the shivering threshold.
A limitation of our study is that it was conducted in healthy volunteers. Most results from volunteer studies can be extrapolated to patients; however, patients with underlying disease and those who are critically ill may respond differently. Thus it remains possible that magnesium will prove more effective at inducing thermoregulatory tolerance in patients with stroke or other serious neurological problems.
In summary, magnesium in doses sufficient to increase plasma concentrations more than 2-fold reduced the shivering threshold marginally and did not significantly alter the gain of shivering in healthy volunteers. Thus magnesium exerts a clinically unimportant effect as a sole agent; however, it remains to be studied as a potentially useful adjunct for induction of therapeutic hypothermia in patients with stroke or myocardial ischaemia.
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Acknowledgments |
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Footnotes |
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References |
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