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Urapidil does not prevent postanesthetic shivering: a dose-ranging study

[L'urapidil n'empêche pas le frisson postanesthésique : une étude de dosage]

From the Department of Anesthesiology and Intensive Care Medicine, Klinikum Ludwigshafen, Ludwigshafen, Germany.

Address correspondence to: Dr. Swen N. Piper, Department of Anesthesiology and Intensive Care Medicine, Klinikum Ludwigshafen, Bremserstraße 79 D-67063, Ludwigshafen, Germany. Phone: 0049-621-503-3000; Fax: 0049-621-503-3024; E-mail: wolfgang_maleck{at}hotmail.com

	Abstract

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Purpose: To investigate the effect of 0.2 mg•kg^–1, 0.3 mg•kg^–1 and 0.4 mg•kg^–1 urapidil on the incidence and severity of postanesthetic shivering.

Methods: One hundred and fifty patients (ASA I–III) scheduled for elective abdominal, urologic or orthopedic surgery under standardized general anesthesia were randomly allocated to one of five groups (each group n=30) using a double-blind protocol: group A received 0.2 mg•kg^–1 urapidil, group B: 0.3 mg•kg^–1 urapidil, group C: 0.4 mg•kg^–1 urapidil, group D: 3 µg•kg^–1 clonidine (positive control group), and group E: saline 0.9% as placebo (negative control group). Postanesthetic shivering was scored using a five-point scale.

Results: Twelve patients of group A, 11 of group B, nine of group C, three of group D and 14 of group E showed signs of postanesthetic shivering. Postanesthetic shivering was significantly decreased in the clonidine group compared to the three urapidil groups and the placebo group. Significantly less patients treated with clonidine needed anti-shivering therapy. There were no significant differences between the urapidil and placebo groups. Therapeutic interventions for hemodynamic effects were not required in any group. Time to extubation, but not time to discharge, was prolonged in the clonidine group.

Conclusion: Urapidil showed no beneficial effect on shivering in any of the doses evaluated, whereas prophylactic administration of clonidine was effective in preventing postanesthetic shivering.

	Introduction

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POSTANESTHETIC shivering is a major cause of patient discomfort while recovering from general anesthesia.^1,2 The incidence of postanesthetic shivering was described to be as high as 65% .³ In addition to causing discomfort, it can trigger deleterious complications such as hypoxemia, raised oxygen consumption, lactic acidosis, increased intra-ocular pressure, and raised carbon dioxide production.^4,5 Thus, patients with cardiovascular or pulmonary diseases may be endangered by postanesthetic shivering. Shivering may also induce pain secondary to muscular contractions at the site of operation. Prophylaxis and therapy of postanesthetic shivering should be an important concern in the perioperative phase.

Several drugs are used for this purpose, but the ideal drug has still not been found. Urapidil, an antihypertensive medication was shown to be effective in the treatment of shivering.^6–8 The drug is an agonist of 5- hydroxytryptamin-1a receptors and an antagonist of ₁-adrenergic receptors.⁶ However, in a previous study 0.2 mg•kg^–1 urapidil did not show beneficial effects in preventing postanesthetic shivering.⁹ Because it has not been established whether higher doses of urapidil possess beneficial effects, the present study was designed to evaluate the efficacy of higher doses of urapidil (0.3 mg•kg^–1 and 0.4 mg•kg^–1) to prevent postanesthetic shivering compared to placebo (negative control group) or clonidine (positive control group).

	Methods

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After obtaining approval from the local Ethics Committee and written informed consent, we included 150 patients (ASA physical status I, II or III) scheduled for elective abdominal, urologic or orthopedic surgery. Exclusion criteria were: cardiac failure (NYHA III or IV), muscular disease, Parkinsons's disease, requirement for vasoconstrictors perioperatively, administration of ₂-adrenergic agonists for long-term treatment and fever (temperature >37.5°C). All patients were assigned to receive intravenously, in a random manner, 0.2 mg•kg^–1 urapidil, 0.3 mg•kg^–1 urapidil, 0.4 mg•kg^–1 urapidil, 3 µg•kg^–1 clonidine (positive control group) or 0.9% saline as placebo (negative control group). All drugs were given at the end of surgery in a blinded fashion. The drugs were diluted to 10 mL and administered slowly intravenously over two minutes. Premedication and general anesthesia were standardized as follows: midazolam po (7.5 mg) was given 45–60 min prior to induction of anesthesia. Anesthesia was induced by iv thiopentone (5 mg•kg^–1) and iv fentanyl (3 µg•kg^–1). Orotracheal intubation was facilitated with iv rocuronium (0.5 mg•kg^–1). Intraoperatively, a mixture of isoflurane (1.2 ± 0.6% end tidal), nitrous oxide (65%) and oxygen (35%) was given to maintain general anesthesia. Ventilation was controlled mechanically (Julian®, Dräger, Lübeck, Germany) to maintain end tidal carbon dioxide tension at 32–36 mmHg. Intraoperatively, no patient was warmed actively, but simply covered with sheets. All patients had complete recovery of neuromuscular blockade by a train-of-four monitoring at the end of surgery, so none received neuromuscular blocker reversal agents. After surgery, patients were transferred to the postanesthesia care unit (PACU).

The postoperative evaluation of patients and their shivering score was assessed by an anesthesiologist in the PACU, who was unaware of patient grouping. All patients were continuously monitored for signs of shivering by an investigator until T3 (see below for definitions of T3 and T4). From T3 to T4, the PACU nurse in charge of the patient monitored the patient; at T4, an investigator reviewed the PACU chart and, additionally, asked both nurse and patient for shivering in this time interval. The severity of postanesthetic shivering was assessed according to a five point scale similar to that validated by Wrench et al.:¹⁰ 0=no shivering; 1=one or more of the following: piloerection, peripheral vasoconstriction, peripheral cyanosis without other cause, but without visible muscular activity; 2=visible muscular activity confined to one muscle group; 3=visible muscular activity in more than one muscle group; 4=gross muscular activity involving the entire body. If a score of two or more was reached, 10 mg nefopam, an established drug in treating postanesthetic shivering,^11–13 was given iv. Mean arterial blood pressure (MAP) and heart rate (HR) were measured at the following times: after induction of anesthesia, but before surgery began (T0), five minutes (T1), 15 min (T2), 30 min (T3) and 60 min (T4) after extubation. During surgery, rectal temperature was measured continuously and the lowest temperature was documented. In addition, the temperature was measured (also rectally) at T0, and postoperatively at T2 and T4. The time from end of administration of isoflurane and nitrous oxide until extubation (extubation time) was documented. Postanesthetic recovery was scored using the Aldrete score¹⁴ on arrival in the PACU and on discharge. Patients in all groups were allowed to receive the opioid piritramide to treat pain by giving iv bolus-doses (increments of 3.75 mg).

Demographic data, duration of surgery and anesthesia, recovery time between end of anesthesia and extubation and the effects of treatment on all studied parameters (rectal temperature, MAP, HR) were analyzed with a Student's t test. The incidence of shivering was analyzed with Fishers' exact test. The ranked sum test of Raatz¹⁵ was used to analyze the shivering and Aldrete scores, and postoperative consumption of piritramide and nefopam. The Raatz test is a modified rank order test to be used for values that fall into classes (e.g., school notes or scores). It was used for piritramide and nefopam consumption as these variables are, theoretically, continuous but, in reality, in discrete classes as the medications are administered in increments of 0.5 mL. Before the study, the number of patients required in each group was determined after a power calculation based on data from a previous investigation in our institution on the incidence of postanesthetic shivering secondary to abdominal and orthopedic surgery.⁹ We expected an incidence of shivering in the placebo group of at least 50% and a reduction of the incidence to about 15% with an effective medication such as clonidine. Consequently, to detect a reduction in incidence from 50% to 15% with an -error of 0.05 (two-sided) and a ß-error of 0.2,¹⁶ a minimum of 27 patients per group was required. All values are expressed as mean (SD) or as median (range). P values <0.05 were considered significant.

	Results

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All groups were similar with regard to demographics, duration of anesthesia and surgery (Table I), and postoperative piritramide consumption (Table III). Rectal temperatures were not statistically different at any time (Table II).

Clonidine-treated patients had a significantly longer extubation time than patients who had been given placebo or urapidil (Table I). Postanesthetic recovery assessed by the Aldrete score showed significantly lower values in clonidine-treated patients on arrival in the recovery room compared to untreated patients and all urapidil groups. At discharge all scores were similar (Table III).

Severity and incidence of shivering is presented in Figure 1. Analyzing the shivering score (using the Raatz test) we found that clonidine reduced the score significantly compared to the four other groups (Figure). Using Fisher's exact test we found a significant reduction of postanesthetic shivering in the clonidine group compared to the placebo-treated patients (P <0.007). There were no significant differences between all urapidil groups and the placebo group.

View larger version (28K): [in this window] [in a new window]   FIGURE Severity of shivering, using the scale of Wrench et al.18 White bars: no. shivering; Striped bars: one or more of the following: piloerection, peripheral vasoconstriction, peripheral cyanosis without other cause, but without visible muscular activity; Gray bars: visible muscular activity confined to one muscle group; Hatched bars: visible muscular activity in more than one muscle group; Black bars: gross muscular activity involving the entire body. *P<0.05 different vs all other groups.

	Discussion

TOP Abstract Introduction Methods Results Discussion References

 
In the present double-blind study we showed that 3 µg•kg^–1 clonidine were effective to prevent postanesthetic shivering, but 0.2 mg•kg^–1, 0.3 mg•kg^–1 and 0.4 mg•kg^–1 urapidil had no prophylactic effect. Thirteen patients of the placebo group developed postanesthetic shivering with signs of muscular activity (43.3%) and one patient (3.3%) showed signs of piloerection, peripheral vasoconstriction, or peripheral cyanosis. This high incidence of shivering is well known and has been described often.^3,9,17 The major predisposing factor for shivering is perioperative hypothermia and vasoconstriction,^1,18 but normothermia at the end of surgery does not necessarily prevent shivering,^1,3 because shivering at normal body temperature is a complex and poorly understood response requiring polysynaptic neural transmission. Also, clonidine which influences alpha-2 receptors in various areas of the central nervous system, may have complex mechanisms of suppression of shivering.¹⁹ In our study, the rectal temperature could have been influenced more during abdominal and urological surgery, than it would have been during orthopedic surgery. However, there were no significant differences between the groups with regard to the type of operation and rectal temperatures were not statistically different at any time. Several other factors may have an influence on the incidence of postanesthetic shivering: volatile anesthetics,²⁰ thiopentone,²¹ length of surgery and anesthesia,²² uninhibited spinal reflexes^2,3 perioperative pain and blood loss.²⁴ In the present study, we found that clonidine was effective in preventing shivering compared to placebo. This is in accordance with most other studies that had shown that clonidine reduced both shivering and vasoconstriction, and that it was effective in the treatment of established shivering^1,17,25,26 and for its prophylaxis.^9,11,17,27 Moreover we have demonstrated that clonidine is superior to all urapidil doses (0.2 to 0.4 mg•kg^–1) for the prophylaxis of shivering. Three groups had reported on the successful treatment of shivering by urapidil.^6–8 Schwarzkopf et al. showed some efficacy in treating shivering, but urapidil was less effective compared to meperidine and clonidine.⁷ The limitations of both other placebo controlled reports were the lack of comparison of a group with an established drug in the treatment of shivering.^6,8 In addition, these studies have only been published as abstracts.^6,8 In a recently published investigation, we demonstrated that low-dose urapidil (0.2 mg•kg^–1) was less effective than clonidine or meperidine to suppress postanesthetic shivering.⁹ As shown by the present data, higher doses of urapidil also have no benefit in the prophylaxis of postanesthetic shivering. Increasing the dose of urapidil may not be appropriate since patients who received 0.4 mg•kg^–1 developed a significant decrease of MAP.

Clonidine has well-known sedative effects.²⁸ In our study, we found a prolonged extubation time and a lower Aldrete score on arrival in the recovery room in the clonidine group, compared to placebo and all urapidil groups. The clinical and economic relevance of these findings is, however, questionable. The time in the recovery room, however, was not prolonged and, on discharge, there were no differences between groups. Authors have reported that clonidine either has no influence,^28,29 or that it prolongs recovery.¹¹ The timing of administration of clonidine may be of importance. In investigations showing no influence on the recovery time, the drug was administered before the end of surgery while, in studies reporting a prolonged recovery, clonidine was given at the end of surgery. The dose of clonidine (3 µg•kg^–1) was administered in accordance with various other studies.^9,11,28 However, others showed that lower doses were also effective in reducing shivering.^17,19,26 Maybe the dose of 3 µg•kg^–1 clonidine would be expected to show a higher incidence of sedation. However, no therapeutic intervention secondary to a clonidine-induced sedation was required in our study.

In conclusion we have shown that the administration of 0.2 mg•kg^–1, 0.3 mg•kg^–1 and 0.4 mg•kg^–1 urapidil does not prevent postanesthetic shivering in comparison to placebo. Urapidil is significantly less effective than clonidine in preventing postanesthetic shivering.

Revision received May 2, 2001. Accepted for publication March 15, 2001.

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