Shivering is often a complication in the postanesthesia recovery period (1). A number of drugs have been used for prevention and treatment of postanesthetic shivering partly without proper scientific background. The most frequently administered drugs for postanesthetic shivering are meperidine and clonidine (2). However, other central acting drugs—doxapram (3), ketanserin (2), nefopam (4,5), nalbuphin (6), and dexmedetomidine (7) —with different pharmacological profiles have also been found effective in preventing and treating postanesthetic shivering.
Urapidil—an antihypertensive drug with both cen-tral 5-hydroxytryptamine-1A-receptor (5-HT-1A)-agonist and peripheral α-adrenergic-antagonist properties—has recently been shown to suppress shivering in volunteers and patients (8–10). 1 Because of its central nervous system effects, we reasoned that urapidil may inhibit shivering by impairing central thermoregulatory control, which would most likely be manifested as a reduction in the vasoconstriction and shivering thresholds. We therefore used a previously described model (11) to investigate the effects of urapidil on thresholds for cutaneous vasoconstriction and shivering during cold-induced shivering in volunteers. We also investigated whether urapidil would affect oxygen consumption (𝑄̇O2) when used to treat cold-induced shivering.
The study was approved by the Ethics Committee of the Friedrich-Schiller-University Jena, and all volunteers gave written informed consent before participating. The volunteers fasted overnight, and the study began at eight the next morning. The men were minimally clothed during the entire procedure and reclined on a padded operating room table. Room temperature was kept at 25°C.
We used a cross-over design in which the volunteers were cooled by central venous infusion of a cold saline solution and pretreated with either urapidil or placebo on two study days separated by at least 48 h. This way, each volunteer received both treatments and served as his own control. On each of the two study days, the volunteers were cooled by central venous infusion of physiological saline at 4°C at a rate of 0.4 mL · kg−1 · min−1. Before cooling was started, volunteers were treated with either 25 mg of urapidil IV or placebo IV in a randomized double-blinded fashion. If shivering occurred, 25 mg of urapidil was administered IV. If shivering did not stop within 5 min, a second dose of 25 mg of urapidil was administered. The thermal comfort was evaluated during shivering immediately before and after administration of urapidil and at 5 and 10 min postinjection using a 100-mm visual analog scale. Zero mm was defined as the worst imaginable cold, 50 mm as thermally neutral, and 100 mm as insufferably hot (12).
Materials and Procedures.
After local anesthesia was administered, a central venous catheter was inserted through the left antecubital vein and positioned using an intravascular electrocardiogram tracing via the catheter’s guide wire. When an intraatrial P wave (P atrial) was observed, the catheter was withdrawn 2 cm back into the superior vena cava. Oxygen saturation, heart rate, and oscillometric mean arterial blood pressure were recorded every 5 min.
Core temperature was measured with a rectal thermocouple probe, and fingertip and forearm skin temperature was measured with thermocouple probes. As described by others, a 0°C gradient between the forearm and fingertip was considered to represent the onset of significant cutaneous vasoconstriction. The core temperature at which a 0°C cutaneous temperature gradient occurred was considered the thermoregulatory threshold for cutaneous vasoconstriction (13). Shivering was evaluated using 𝑄̇O2, as measured by a metabolic monitor (Deltatrac®, Datex, Helsinki, Finland). A sustained increase in 𝑄̇O2 of ≥30% identified shivering (14,15). 𝑄̇o2 was measured with a head canopy system. Measurements of 𝑄̇O2 were performed at 1-min intervals and averaged over 5-min periods before cooling at the thermoregulatory thresholds, during shivering, and after treatment with urapidil or placebo.
We used paired Student’s t- tests to compare thermoregulatory thresholds during the two treatment periods. An analysis of variance was performed to compare the 𝑄̇O2 and paired Student’s t-tests, or the Wilcoxon’s ranked sum test was used for intragroup comparison. All data are expressed as mean ± sd, and P < 0.05 was considered statistically significant.
We studied seven male volunteers age 30 ± 3 yr, weight 74 ± 6 kg, and height 180 ± 4 cm. Urapidil pretreatment led to a small but significant decrease in the mean arterial blood pressure (P < 0.05) and to increase in heart rate (P < 0.01) (Table 1).
The threshold for vasoconstriction was 36.8°C ± 0.2°C after placebo pretreatment and 36.4°C ± 0.2°C after urapidil pretreatment (mean difference 0.4°C ± 0.2°C;P < 0.001) (Table 2). The shivering threshold was 36.4°C ± 0.3°C after the placebo pretreatment and 35.9°C ± 0.4°C after the urapidil pretreatment (mean difference 0.5°C ± 0.3°C;P < 0.01).
Although normal saline was administered at a comparable rate during the two pretreatment periods, significant differences (P < 0.05) in the rate of core cooling between the placebo (0.29°C/h ± 0.04°C/h) and the urapidil pretreatment (0.47°C/h ± 0.21°C/h) were found. Whole-body 𝑄̇O2 did not differ between placebo and urapidil pretreatment during the entire experiment. However, 𝑄̇O2 increased significantly during shivering and returned to baseline levels after shivering ceased without any differences between the groups (Figure 1).
All volunteers reported feeling warm immediately after a single administration of 25 mg of urapidil (Figure 2). This warm feeling was quantified as a significant increase of the thermal comfort (P < 0.01). Only one volunteer needed a repeated dose of urapidil to stop shivering completely.
In this study we demonstrate that urapidil pretreatment leads to a decrease in important thermoregulatory thresholds during infusion of cooled saline in volunteers. Furthermore, we demonstrate the efficacy of urapidil in the treatment and prevention of cold-induced shivering in humans (8,9).
Urapidil has both central and peripheral effects; both may have contributed to the findings of our study. Although it is clear that urapidil has central agonistic effects at the 5-HT-1A-receptors, the exact relationship between these receptors and thermoregulation is not clear. Our observation that urapidil administration during shivering immediately caused a pronounced feeling of warmth in all volunteers suggests a direct action on central thermoregulation. One may postulate that urapidil may have caused a decrease in the set-point adjustment of temperature below the normal neutral zone (36.7°C–37.1°C) (16). Additionally, urapidil may be involved in the motor response of shivering (17). Licata et al. (18) have shown that 5-HT is able to modulate the motor glutamatergic input to the red nucleus, which plays a major role in motor control (19). Consistent with these findings, the 5-HT-1A-receptors, primarily located on presynaptic nerve terminals, serve to inhibit neuronal cell firing (20). Thus, a number of central mechanisms may be involved in the urapidil-induced inhibition of shivering.
Urapidil has profound effects of peripheral vasomotor tone. Urapidil is a known peripheral postsynaptic α-1-adrenoceptor antagonist (21). Furthermore, peripheral 5-HT-1-receptors located on arterioles mediate vasodilation and lead to reductions in arterial pressure in several animal species (22). These vascular effects of urapidil induce a peripheral vasodilation that may contribute to the decrease of threshold for cutaneous vasoconstriction. An alteration of the peripheral component of shivering by vasodilation with ketanserin, a 5-HT-2 antagonist, supports this interpretation (2).
During cooling, metabolic heat production increases dramatically (16). Urapidil pretreatment did not affect 𝑄̇O2 during the experiment. In contrast, preventive clonidine administration reduced the 𝑄̇O2 in comparison with the placebo. It appears that clonidine may not only decrease the thermoregulatory threshold for shivering, but also decrease its magnitude, once triggered (11).
Despite administration of comparable rates of cold saline, pretreatment with urapidil led to a significantly faster core cooling as compared with pretreatment with placebo. The peripheral vasodilating effects of urapidil can explain this phenomenon, which leads to a redistribution of heat from central to peripheral compartments and to a faster heat loss from the body surface. Despite differences in the rate of cooling, it was surprising that 𝑄̇O2 (as a measure of metabolic heat production) did not differ between the two pretreatment groups. This further points towards a decrease in the central temperature regulation and a possible decreasing of the set point below the neutral zone during urapidil treatment.
We used a single-bolus application of urapidil to describe its influence on thermoregulation at a clinically relevant dosage and application mode. Furthermore, this study was a follow-up of our previous observation where we had used a single-bolus application (8,9). A limitation of our study is that we did not measure urapidil plasma concentrations. But, urapidil plasma concentrations do not closely correlate to vasoconstriction response at cold stimulation (23).
In this study, core temperature was measured with a rectal thermocouple probe. A limitation of using rectal temperatures is that they can overestimate the core temperature during measurements of the thermoregulatory thresholds. The limitations of this method will become especially important during rewarming (24). Furthermore, a recent study suggests the rectal temperature monitoring is a valid method of measuring core temperature (25).
An additional limitation of our study was that we did not measure mean skin temperature. Skin temperature can contribute up to 20% to thermoregulatory control of vasoconstriction and shivering. However, as described for other antishivering drugs, this contribution can vary among individuals, and individual concentration-response curves will be inaccurate (15). Because we studied a rather small number of volunteers, we restricted our measurements to forearm and fingertip temperatures and to core temperature.
In summary, urapidil decreased normal thermoregulatory responses in conscious volunteers during a mild hypothermic state. Thus, shivering, but not hypothermia, was treated. One important application of this information is that whenever urapidil is used in the postoperative period, the patient’s body temperature should be monitored especially closely. External warming methods might be needed to replace the metabolic heat production and prevent further cooling.
Cold-induced shivering can be effectively stopped with urapidil. In accordance with our previously published data (8,9), urapidil can be well considered as an alternative to other antishivering drugs in anesthesia because of the absence of respiratory depression and sedation. However, further studies are necessary that address the optimal dose of urapidil to treat postanesthestic shivering.
The authors acknowledge the advice of Don Bredle on the preparation of the manuscript. We would like to thank the staff of the Institut fuer Medizinische Statistik, Informatik, und Dokumentation for help with the statistical analysis.
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