The minimum effective doses of pethidine and doxapram in the treatment of post-anaesthetic shivering I. J. Wrench, P. Singh, A. R. Dennis, R. P. Mahajan and A. W. A. Crossley University Department of Anaesthesia, Queen s Medical Centre, Nottingham NG7 2UH, UK Summary This study was designed to find the minimum effective doses of doxapram and pethidine to stop post-anaesthetic shivering. Two hundred and twenty healthy patients who shivered following routine surgery were allocated randomly to receive one of 10 doses of doxapram (0.18, 0.23, 0.29, 0.35, 0.41, 0.47, 0.7, 0.93, 1.17 and 1.4 mg.kg ÿ1 ), one of five doses of pethidine (0.12, 0.18, 0.23, 0.29 and 0.35 mg.kg ÿ1 ) or saline. Probit analysis demonstrated that the number of patients who stopped shivering with doxapram was independent of the amount of drug given in this dose range. The lowest dose of doxapram (0.18 mg.kg ÿ1 ) was significantly more effective than placebo (p < 0.01). For pethidine there was a dose-dependent effect on shivering to a maximum of 95% of patients successfully treated with 0.35 mg.kg ÿ1. We conclude that 0.35 mg.kg ÿ1 of pethidine is the minimum dose required to treat post-anaesthetic shivering effectively. We also conclude that 0.18 mg.kg ÿ1 of doxapram is as effective as 1.4 mg.kg ÿ1 in the treatment of post-anaesthetic shivering. Further study is required to find the minimum effective dose of doxapram. Keywords Complications; shivering. Analgesics; pethidine. Analeptics; doxapram.... Correspondence to: Dr I. J. Wrench Accepted: 8 August 1996 The detrimental effects of post-anaesthetic shivering are well recognised and include increased oxygen consumption, hypoxaemia, difficulty in monitoring and distress to the patient [1]. Previous work has shown that 1.5 mg.kg ÿ1 of the cerebral stimulant doxapram and 0.33 mg.kg ÿ1 of pethidine are both effective in the treatment of this condition [2]. However, both of these agents are associated with side-effects [3, 4] which could be reduced by using the smallest effective dose. The purpose of this study, therefore, was to establish the minimum doses of pethidine and doxapram required to treat post-anaesthetic shivering effectively. Method The study was approved by the local hospital Ethics Committee. Two hundred and twenty patients who developed shivering in the recovery room were included. The patients were all ASA class I or II and had undergone routine general, orthopaedic, gynaecological or ENT surgery. As a consequence of the patients being selected as they recovered from anaesthesia, their consent was not considered valid and, as with previous studies [2] and with agreement from the hospital Ethics Committee, informed consent was not obtained. Patients with any contraindications to the use of doxapram or pethidine were not entered into the study. Routine care for patients in this hospital suffering from postoperative shivering consists of administering oxygen 4 l.min ÿ1 by Hudson mask and use of a heat-reflective blanket. In addition each study patient received an intravenous bolus dose of saline, pethidine or doxapram. This randomised double-blind placebo-controlled trial was conducted in two 110 patient phases with the guidance of a professional statistician. Randomisation was performed separately for each phase. In the first phase of the study there were five groups of 10 patients, each receiving the same dose of doxapram (0.47, 0.7, 0.93, 1.17 and 1.4 mg.kg ÿ1 ), five groups of 10 patients receiving the same dose of pethidine (0.12, 0.18, 0.23, 0.29 and 0.35 mg.kg ÿ1 ) and one group of 10 patients given 0.9% saline. In the second phase of the study a further five groups of 10 patients were given doxapram but in lower doses (0.18, 0.23, 0.29, 0.35, 0.41 mg.kg ÿ1 ), five groups 32
I. J. Wrench et al. Post-anaesthetic shivering of 10 patients received pethidine as for phase 1 (0.12, 0.18, 0.23, 0.29 and 0.35 mg.kg ÿ1 ) and another group of 10 patients were given saline. Syringes containing the drug were prepared by recovery room staff following written instructions removed from a sealed envelope. The envelopes were inserted in a random order which was generated by computer using a shuffling technique. Solutions were presented as either 6 ml of saline or 15, 20, 25, 30, 35, 40, 60, 80, 100 or 120 mg of doxapram or 10, 15, 20, 25 or 30 mg of pethidine in identical unlabelled syringes given as a dose of 0.07 ml.kg ÿ1. The investigator giving the intravenous injection was unaware of the treatment received by the patient and assessed the shivering grade before treatment as described previously [2] (Table 1). The patients were observed for 5 min and the time taken to stop shivering was recorded. Tympanic membrane temperature was measured (First Temp Genius Thermometer) immediately prior to administering the treatment. Other data recorded consisted of duration of surgery, type of ventilation employed, patient s age, weight and gender. For statistical analysis SPSS for Windows version 6.1 was used, with a p value less than 0.05 taken to be significant. Shivering grade and gender were analysed using Kruskall-Wallis, Chi-squared and Fisher s exact test as appropriate. Analysis of variance (ANOVA) was used to assess differences in weight, age, duration of surgery and temperature between the groups. The dose response to both drugs in terms of the number of patients who stopped shivering within 5 min was subjected to Probit analysis as described by Finney [5]. Probit analysis assesses the effect of an independent variable (drug dose) on a dichotomous dependent variable (shivering or not shivering). Probit transformation replaces each of the observed proportions with the value of a standard normal curve below which the observed proportion of the area is found. The ratio of regression coefficient to its standard error is distributed as Student s t. In this case a value greater than 2.31 demonstrates that a dose-dependent effect is in evidence at the 5% significance level. Results Groups were similar in terms of gender, shivering grade at entry, weight, duration of surgery and temperature at time of treatment (Table 2). Groups were also similar with regard to age except that there was a significant difference in ages between groups in the doxapram arm of the study (p < 0.01) (Table 2). The control response rate was 25% (Figures 1 and 2). There was a dose-dependent increase in the proportion of patients who stopped shivering with pethidine (Fig. 1) (Probit analysis: regression coefficient ˆ 6.52, standard error ˆ 2.24, with 8 degrees of freedom, ratio ˆ 2.91). A dose of 0.18 mg.kg ÿ1 was calculated to be 50% effective (95% CI 0.035 0.23 mg.kg ÿ1 ). At the highest dose used (0.35 mg.kg ÿ1 ) 95% of patients stopped shivering. The highest four doses of pethidine were significantly better than placebo (p < 0.001 for 0.29 and 0.35 mg.kg ÿ1 and p < 0.01 for 0.18 and 0.23 mg.kg ÿ1 ), with the lowest dose not significantly different (0.12 mg.kg ÿ1 ). There was no relationship between the dose of doxapram given and the proportion of people who stopped shivering (Fig. 2) (Probit analysis: regression coefficient ˆ 0.09, standard error ˆ 0.40, with 8 degrees of freedom, ratio ˆ 0.23). The calculated response rate was Table 1 Classification of shivering. Grade Clinical signs 0 No shivering 1 One or more of: 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 entire body Figure 1 The proportion of patients who stop shivering with placebo A and different doses of pethidine B. Probit analysis of the dose response is represented by a solid line. 33
J. J. Wrench et al. Post-anaesthetic shivering Anaesthesia, 1997, 52, pages 32 36 Entry shivering Duration of Age (years) Weight (kg) grade Temp ( C) surgery (min) M/F mean (range) mean (SD) median (range) mean (SD) mean (SD) Saline 7/13 32.6 (21 55) 72.3 (8.72) 3 (2 4) 36.4 (0.6) 60.8 (38.6) Doxapram (mg.kg ÿ1 ) 0.18 3/7 26.9 (18 33) 72.1 (9.6) 3 (2 4) 36.7 (0.2) 50 (27.2) 0.23 3/6 35.6 (20 45) 73 (12) 4 (2 4) 36.7 (0.4) 41 (12.2) 0.29 8/2 37.8 (21 54) 65.6 (9.8) 4 (3 4) 36.2 (0.6) 84.5 (37.6) 0.35 2/8 33.6 (21 46) 69.6 (6.2) 4 (2 4) 36.7 (1) 68.5 (31.5) 0.41 3/7 26.3 (18 44) 69.8 (8.5) 3 (2 4) 36.9 (0.4) 70 (43) 0.47 6/4 35.5 (19 59) 65.6 (6.8) 3 (2 3) 36.6 (0.8) 59.5 (29.1) 0.7 3/6 32.2 (18 47) 64.4 (7.5) 3 (2 4) 36.6 (0.9) 54.3 (28.9) 0.93 4/6 28.9 (18 45) 70.6 (10.4) 3 (2 4) 37 (0.6) 71 (55.7) 1.17 6/4 23.7 (18 41) 68.7 (13.5) 4 (3 4) 36.3 (0.5) 59.5 (26.8) 1.4 5/5 42.3 (18 64) 77.1 (17.7) 3 (2 4) 36.6 (0.4) 63.3 (39.7) Table 2 Demographic data for patients receiving doxapram (n ˆ 10 for all groups except 0.23 and 0.7 mg.kg ÿ1 (n ˆ 9)), pethidine (n ˆ 20 for all groups) and saline (n ˆ 20). The groups were similar except that there was a significant difference in ages between the groups in the doxapram arm of the study (p < 0.01, ANOVA). Pethidine (mg.kg ÿ1 ) 0.12 8/12 28 (18 44) 68.4 (10) 4 (2 4) 36.6 (0.7) 67.8 (44.5) 0.18 14/6 32.8 (18 50) 73.5 (13.8) 3 (2 4) 36.7 (0.7) 70 (43.9) 0.23 11/9 32 (18 55) 68.6 (11.1) 4 (2 4) 36.5 (0.8) 89.5 (95) 0.29 7/13 28 (18 55) 70.2 (10.2) 4 (2 4) 36.5 (0.8) 61 (34) 0.35 11/9 31.8 (19 53) 69.6 (9.3) 4 (2 4) 36.4 (0.64) 65.7 (29.4) approximately 70% across the dose range studied. Significantly more patients stopped shivering with the lowest dose of doxapram used (0.18 mg.kg ÿ1 ) compared with placebo (p < 0.01). There was no significant difference between the number of patients who stopped shivering with 0.18 mg.kg ÿ1 compared with 1.4 mg.kg ÿ1 of doxapram. Discussion Figure 2 The proportion of patients who stop shivering with placebo A and different doses of doxapram B. Probit analysis of the dose response is represented by a solid line. This study was performed in two phases. The data from the first 110 patients recruited indicated that there was a dose-dependent increase in the proportion of patients who stopped shivering with pethidine. However, the doses of doxapram used (0.47 1.4 mg.kg ÿ1 ) were as effective in the treatment of post-anaesthetic shivering. It was therefore decided to extend the study to include lower doses of doxapram (0.18 0.41 mg.kg ÿ1 ). In the second phase of the study a further five groups of 10 patients were recruited to receive these new doses of doxapram along with five groups of 10 patients for pethidine and one group of 10 patients for saline as in phase 1. The pethidine dose response was included in the second phase of the study in order to maintain the same conditions for randomisation as for phase 1, thus avoiding observer bias. The aim of the study was to find the minimum effective doses of pethidine and doxapram, so that shivering could be treated adequately with the fewest side-effects. The side-effects of both agents have been well described [3, 4] and are dose dependent. We did not feel that it was 34
I. J. Wrench et al. Post-anaesthetic shivering necessary to look specifically for side-effects in the study as the incidence was likely to be low, thus requiring large numbers to find any differences between groups. Indeed during the course of the study no detrimental effects of either drug on any patient were noted during routine postoperative monitoring. Previous studies with pethidine for the treatment of post-anaesthetic shivering were not performed on a mg.kg ÿ1 basis [6, 7]. We have shown that there is a dose-dependent increase in the percentage of patients who stop shivering with pethidine from 55% with 0.12 mg.kg ÿ1 to 95% with 0.35 mg.kg ÿ1. We suggest that a bolus of 0.35 mg.kg ÿ1 of pethidine (equivalent to 24.5 mg for a 70 kg patient) would treat post-anaesthetic shivering effectively with minimal side-effects. Comparative studies have shown that pethidine, a m- agonist which also binds to k-receptors [8], is superior to the relatively specific m-agonists fentanyl and morphine [8] in the treatment of post-anaesthetic shivering [7]. The k- agonist/antagonist butorphanol has also been shown to decrease shivering effectively [9]. Other workers have found that the antishivering action of pethidine is inhibited by high-dose naloxone which blocks m- and k- receptors but not low-dose naloxone which blocks only m-receptors [10]. These observations suggests that the treatment of post-anaesthetic shivering by pethidine may be mediated, at least in part, by k-receptor stimulation. Our results suggest that 70% of patients will stop shivering with doxapram in the dose range that we studied. This is similar to the findings of other workers who have shown that 75% of patients given doxapram stopped shivering within 5 min [2, 11]. We suggest that the lowest dose of doxapram (0.18 mg.kg ÿ1 ) should be used since it is as effective as higher doses but with less likelihood of causing side-effects. There was a significant difference in ages between groups in the doxapram arm of the study. However, although the incidence of post-anaesthetic shivering varies with age [1], there is no evidence that age influences the effectiveness of antishivering treatment. We did not believe, therefore, that this difference would have influenced our results. In previous studies demonstrating the efficacy of doxapram in the treatment of post-anaesthetic shivering the dose was chosen empirically [2, 11]. We have found that 80% of patients were successfully treated with 0.18 mg.kg ÿ1 of doxapram compared with 90% who stopped shivering with 1.4 mg.kg ÿ1. In order to establish whether this 10% difference between the highest and lowest doses of doxapram is significant, 196 patients would have been required in each group (assuming a power of 0.8 at a significance level of p < 0.05). Although our group sizes are relatively small we felt that this difference was not important clinically so that further recruitment of patients was unnecessary. The mechanism of action of doxapram in the treatment of post-anaesthetic shivering is unknown. It has been suggested that shivering occurs as a result of differential recovery after discontinuing anaesthesia, with spinal recovery occurring before higher inhibitory centres [12]. Thus it is possible that a cerebral stimulant such as doxapram may enhance recovery of the brain from anaesthesia and establish normal control over reflex spinal activity. Alternatively, recent in vitro work has shown that doxapram displaces [ 3 H]diprenorphine (an opioid ligand) from opioid receptors [13]. This group stated that a 1.5 mg.kg ÿ1 bolus of doxapram resulted in plasma concentrations sufficient to displace 20% of this opiate ligand. Thus doxapram may inhibit post-anaesthetic shivering via opiate receptors. However, our study indicates that doxapram is equally effective at relatively low doses, which would be less likely to result in significant opioid receptor binding. In conclusion, we have shown that 0.35 mg.kg ÿ1 of pethidine treats post-anaesthetic shivering more effectively than lower doses. We have also demonstrated that a 10-fold reduction in the dose of doxapram does not impair its ability to treat shivering. Further study is required to find the minimum effective dose of doxapram. Acknowledgment We gratefully acknowledge the assistance of P. Riley (statistician at the Cripps Computer Centre, University of Nottingham) with the statistical analysis of this paper. References 1 Crossley AWA. Peri-operative shivering. 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