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Anesth Analg 2000;90:954-957
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

A Comparison of Urapidil, Clonidine, Meperidine and Placebo in Preventing Postanesthetic Shivering

Swen N. Piper, MD, Wolfgang H. Maleck, Arzt, Joachim Boldt, MD, Stefan W. Suttner, MD, Christian C. Schmidt, MD, and Daniel G. P. Reich, MD

Department of Anesthesiology and Critical Care, Hospital of the City Ludwigshafen, Ludwigshafen, Germany

Address correspondence and reprint requests to Dr. Swen N. Piper, Department of Anesthesiology and Intensive Care, Hospital of the City Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
This placebo-controlled study was performed to evaluate the efficacy of urapidil compared with clonidine and meperidine in preventing postanesthetic shivering, which is common after anesthesia administration and may be very distressing. We studied 120 patients undergoing elective abdominal or orthopedic surgery under standardized general anesthesia. After surgery, patients were randomly assigned to one of four groups (each group n = 30) using a double-blinded protocol: Group A received 0.2 mg/kg urapidil; Group B, 3 µg/kg clonidine; Group C, 0.4 mg/kg meperidine; and Group D, saline 0.9% as placebo. Postanesthetic shivering was scored by using a five-point scale. Clonidine and meperidine significantly reduced the incidence and the severity of shivering in comparison with placebo, whereas there were no significant differences between the urapidil and placebo groups. Both clonidine and meperidine caused a significantly prolonged emergence time (13.4 ± 5.8 and 13.3 ± 5.0 min, respectively) compared with placebo (10.4 ± 5.3 min) and urapidil (11.4 ± 2.9 min). We confirmed that both clonidine and meperidine are effective in preventing postanesthetic shivering, whereas urapidil, in our setting and dosage, was not effective. Patients who received clonidine or meperidine had a prolonged emergence time. In the dosage used, urapidil seems to be unable to prevent postanesthetic shivering.

Implications: Shivering (irregular muscle activity) is common after surgery and anesthesia. This study compared urapidil (an antihypertensive drug) as a prophylaxis with two established antishivering drugs (meperidine and clonidine) and placebo. In the dosage used, we were unable to show a significant benefit of urapidil.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Postanesthetic shivering develops in up to 65% of patients recovering from general anesthesia (1,2). Many drugs are used to prevent and control postanesthetic shivering, including clonidine, nalbuphine, meperidine, tramadol, ketanserin, propofol, nefopam, physostigmine, fentanyl, alfentanil, sufentanil, doxapram, dexamethasone, and metamizol (1,3–14), but the ideal drug has still not been found. In several published studies, shivering was treated successfully by urapidil (15–17), an antihypertensive drug acting as an antagonist on {alpha}1-adrenergic receptors and as an agonist on 5-hydroxytryptamin-1a receptors (15). Ittner et al. (15) described that urapidil suppressed cold induced shivering in healthy volunteers, but only six men were included in this study. Urapidil completely stopped shivering in four volunteers. Two required a second application to obtain a complete suppression (15). Sia (16) reported on successful treatment of postepidural shivering. He found that 25 mg urapidil was effective in treating postepidural shivering, but that 30% of the patients in whom shivering was suppressed secondary to the urapidil application developed shivering again within 5 min (16). Fritz et al. (17) reported that postanesthetic shivering was completely suppressed in 7 of 10 patients given 25 mg urapidil and in 5 of 10 patients who had received 12.5 mg urapidil. No information on the weight of the patients was given in these two studies. In our study, 0.2 mg/kg urapidil was given IV at the end of surgery. We found no significant differences between the urapidil group and the untreated control group in prevention of postanesthetic shivering.

Our aim was to evaluate the efficacy of urapidil in preventing postanesthetic shivering in patients undergoing elective surgery in comparison with clonidine and meperidine, which are commonly used to treat and prevent shivering (1,2,8,10,11,14). This is the first report investigating the effect of urapidil in the prevention of postanesthetic shivering.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining approval from the local ethics committee and informed consent, we studied 120 patients (ASA physical status I or II) scheduled for elective abdominal or orthopedic surgery. The patients were randomly assigned to one of four groups (n = 30 each group): Group U received 0.2 mg/kg urapidil; Group C, 3 µg/kg clonidine; Group M, 0.4 mg/kg meperidine; and Group P, saline 0.9% as placebo. Patients needing vasoconstrictors during surgery, having received {alpha}2-adrenergic agonists for long-term treatment, patients with fever (temperature > 37.5°C), disease of the muscles, or Parkinson’s disease were excluded.

Oral lorazepam (0.02 mg/kg) was given 30–45 min before the induction of anesthesia, which was induced by using thiopental (5 mg/kg), and fentanyl (3 µg/kg). Atracurium (0.4 mg/kg) was given to facilitate orotracheal intubation, and general anesthesia was maintained with 60% nitrous oxygen in oxygen and isoflurane (1.2% ± 0.5% end tidal). Ventilation was controlled to maintain an end tidal carbon dioxide tension of 30–35 mm Hg. The fresh gas flow was 2 L/min. The patients were covered with sheets during anesthesia but were not actively warmed.

All test drugs were given IV at the end of surgery by using a double-blinded protocol. The prophylactic effect on shivering was assessed by one of the investigators in charge of the postanesthesia care unit, who was not aware of the administered drug. Postanesthetic shivering was graded by using a scale similar to that validated by Wrench et al. (18) (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). Before surgery (T0), 5 min (T1), 15 min (T2), 30 min (T3), and 1 h (T4) after extubation, mean arterial blood pressure (MAP), heart rate (HR), and rectal temperature were measured. During surgery, rectal temperature was measured continuously, and the lowest temperature was documented. Emergence time (from end of application of isoflurane until extubation) was noted. Furthermore, postanesthesia recovery was scored according to the Aldrete scoring system (19) on arrival at the recovery room and on discharge. Postoperative pain was treated on patient demand by giving IV bolus doses piritramide (increments of 7.5 mg).

A study population of 30 patients for each group was determined to have 90% power at {alpha} = 0.05 (two-tailed) to detect a difference of 25% in the incidence compared with the placebo group in response to urapidil, clonidine, and meperidine treatment for postanesthetic shivering. The incidence of prophylaxis of shivering was tested statistically by using the {chi}2 test and the severity of shivering was compared statistically by the ranked sum test of Raatz. Differences in the Aldrete scores were also tested statistically by using the Raatz-test. Differences in demographic data, length of surgery and anesthesia, piritramide doses, and the effects of treatment on all studied variables were tested by analysis of variance and subsequently by unpaired t-test with Bonferroni correction for multiple comparisons. Data were presented as mean ± SD. P values < 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The groups did not differ significantly with regard to demographics, duration of surgery and anesthesia, and perioperative use of analgesics (Table 1). There were no significant differences concerning rectal temperature at all data points (Table 2). MAP was significantly lower in the urapidil patients at all postoperative data points compared with the meperidine and the placebo groups (Table 2). Clonidine-treated patients showed a significant decrease of MAP at T1 and T2 in comparison with the placebo and the meperidine group (Table 2). HR decreased significantly in the clonidine and in the meperidine group compared with both other groups postoperatively (Table 2). However, in no group did hemodynamic effects require therapeutic interventions.


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  		Table 1. Demographic Characteristics, Perioperative Data, and Incidence of Postanesthetic Shivering
 

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  		Table 2. Mean Arterial Blood Pressure, Heart Rate, and Rectal Temperature
 
The emergence time was significantly longer in the clonidine- (13.4 ± 5.8 min) and in the meperidine- (13.3 ± 5.0 min) treated patients compared with the patients who received placebo (10.4 ± 5.3 min), whereas urapidil-treated patients (11.4 ± 2.9 min) were similar to the control group (Table 1). Aldrete scores on arrival at the recovery room were significantly lower in patients who received meperidine (median [med]: 7.0, range [ran]: 6–9) than in untreated patients (med: 8.0, ran: 7–10). There were no significant differences between the placebo group and clonidine (med: 7.5, ran: 6–9) and urapidil groups (med: 8.0, ran: 7–9), concerning Aldrete scores on arrival at the recovery room. At discharge there were no differences among the groups.

The incidence of postanesthetic shivering was significantly less frequent in the clonidine- (20%) and in the meperidine- (16.6%) treated patients than in the placebo group (53.3%). We found no significant differences between the urapidil (40%) and the placebo group. The degree of postanesthetic shivering was significantly less frequent in the clonidine and in the meperidine groups in comparison with the patients who received placebo (Figure 1). Also, the shivering score of the clonidine and meperidine groups was significantly lower compared with the placebo group, whereas no significant differences between urapidil and placebo-treated patients were found (Figure 1).



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  		Figure 1. Severity of shivering, by using a scale similar to that validated by Wrench et al (18). Shivering grade 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. *P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Postanesthetic shivering is very common after general anesthesia. In our study, 16 of 30 patients (53.3%) in the placebo group shivered postoperatively. This is in accordance with various studies (1,2,20). Clonidine and meperidine reduced the incidence and the severity of shivering significantly compared with the placebo group. This is not surprising, because both drugs are effective in treatment and in prophylaxis of postanesthetic shivering (1–3,8,10,11,14,20). Urapidil, however, was unable to suppress postanesthetic shivering significantly in the dosage used.

Limitations of the study include a lack of a formal dose-response study for urapidil to establish whether larger doses could suppress shivering without major adverse effects. Furthermore, although the study was sufficiently powered to confirm the anti-shivering effects of clonidine and meperidine, it failed to show a significant difference of urapidil to either placebo or the effective drugs. Consequently, a shivering-preventing effect of urapidil in the dosage used can neither be proven nor excluded, but is likely to be smaller than the effects of meperidine or clonidine.

µ receptor opioids reduce postanesthetic shivering (8). Meperidine is a more effective treatment for shivering than equianalgesic doses of other µ-opioid agonists (3,10,11). This special antishivering activity may be based on its {kappa}-receptor activity (3,11). However, the effectiveness of opioids in the treatment and prevention of shivering is limited by the risks of respiratory depression and sedation, especially when repeated doses are necessary (5). We found a significantly longer emergence time and a lower Aldrete score on arrival at the recovery room in the meperidine group compared with placebo, but no patient required therapeutic intervention secondary to a respiratory depression. Also, the time in the recovery room was not prolonged when using any study drug compared with placebo.

Urapidil, clonidine, and meperidine showed some hemodynamic effects. MAP decreased significantly in the urapidil and in the clonidine groups. This is not surprising, because both drugs have well known hypotensive effects and are used in the therapy of hypertension. HR decreased significantly in the clonidine and meperidine groups. Various studies have shown similar results (5,8,20). However, in neither group did hemodynamic effects require treatment.

In conclusion, the IV administration of both clonidine (3 µg/kg) and meperidine (0.4 mg/kg) was effective in the prevention of postanesthetic shivering in our setting. However, the sedative effects of both drugs prolonged the initial emergence time in comparison with untreated patients by about two minutes. Urapidil (0.2 mg/kg) showed no significant differences from placebo for prophylaxis of shivering. It seems that urapidil in the dosage used is not as effective as clonidine or meperidine for prevention of postanesthetic shivering.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Horn EP, Werner C, Sessler DI, et al. Late intraoperative clonidine administration prevents postanesthetic shivering after total intravenous or volatile anesthesia. Anesth Analg 1997;84:613–7.[Abstract]
  2. Buggy D, Higgins P, Moran C, et al. Clonidine at induction reduces shivering after general anaesthesia. Can J Anaesth 1997;44:263–7.[Web of Science][Medline]
  3. Wang JJ, Ho ST, Lee SC, Liu YC. A comparison among nalbuphine, meperidine, and placebo for treating postanesthetic shivering. Anesth Analg 1999;88:686–9.[Abstract/Free Full Text]
  4. De Witte J, Kim JS, Sessler DI, et al. Tramadol reduces the sweating, vasoconstriction, and shivering thresholds. Anesth Analg 1998;87:173–9.[Abstract/Free Full Text]
  5. Joris J, Banache M, Bonnet F, et al. Clonidine and Ketanserin both are effective treatment for postanesthetic shivering. Anesthesiology 1993;79:532–9.[Web of Science][Medline]
  6. Cheong KF, Low TC. Propofol and postanaesthetic shivering. Anaesthesia 1995;50:550–2.[Web of Science][Medline]
  7. Piper SN, Schmidt CC, Suttner SW, et al. Nefopam administration protects from post-anaesthetic shivering. Intensivmed Notfallmed Schmerzther 1998;33:786–9.
  8. Horn EP, Standl T, Sessler DI, et al. Physostigmine prevents postanesthetic shivering as does meperidine or clonidine. Anesthesiology 1998;88:108–13.[Web of Science][Medline]
  9. Wheelahan JM, Leslie K, Silbert BS. Epidural fentanyl reduces the shivering threshold during epidural lidocaine anesthesia. Anesth Analg 1998;87:587–90.[Abstract/Free Full Text]
  10. Ikeda T, Sessler DI, Tayefeh F, et al. Meperidine and alfentanil do not reduce the gain or maximum intensity of shivering. Anesthesiology 1998;88:858–65.[Web of Science][Medline]
  11. Alfonsi P, Sessler DI, Du Manoir B, et al. The effect of meperidine and sufentanil on the shivering threshold in postoperative patients. Anesthesiology 1998;89:43–8.[Web of Science][Medline]
  12. Sarma V, Fry ENS. Doxapram after general anaesthesia: its role in stopping shivering during recovery. Anaesthesia 1991;46:460–1.[Web of Science][Medline]
  13. Yared JP, Starr NJ, Hoffmann-Hogg L, et al. Dexamethasone decreases the incidence of shivering after cardiac surgery: a randomized, double-blinded, placebo-controlled study. Anesth Analg 1998;87:795–9.[Abstract/Free Full Text]
  14. Monso A, Riudeubas J, Barbal F, et al. A randomized, double-blind, placebo-controlled trial comparing pethidine to metamizol for treatment of post-anaesthetic shivering. Br J Pharmacol 1996;42:307–11.
  15. Ittner KP, Bucher M, Riebel K, et al. Urapidil, an {alpha} 1-adrenergic-antagonist/5-HT1A-agonist, suppresses cold induced shivering in humans [abstract]. Anesthesiology 1996;85:A170.
  16. Sia S. Urapidil for the treatment of postepidural shivering: a preliminary study [abstract]. Br J Anaesth 1998;80 (Suppl):A415.
  17. Fritz H, Schwarzkopf K, Hoff H, et al. Effect of urapidil on post-anaesthetic shivering: a double-blind study [abstract]. Br J Anaesth 1999;82 (Suppl 1):122.
  18. Wrench IJ, Cavill G, Ward JEH, et al. Comparison between alfentanil, pethidine and placebo in the treatment of post-anaesthetic shivering. Br J Anaesth 1997;79:541–2.[Abstract/Free Full Text]
  19. Aldrete JA, Kroulik D. A postanesthetic recovery score. Anesth Analg 1970;49:924–33.[Free Full Text]
  20. Piper SN, Suttner SW, Schmidt CC, et al. Nefopam and clonidine in the prevention of postanaesthetic shivering. Anaesthesia 1999;54:695–9.[Web of Science][Medline]
Accepted for publication December 1, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press