Addition of adrenaline to pethidine for epidural analgesia after Caesarean section

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1 Addition of adrenaline to pethidine for epidural analgesia after Caesarean section W. D. Ngan Kee, M. L. Ma and K. S. Khaw Department of Anaesthesia and Intensive Care, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, People s Republic of China Summary We have investigated the addition of adrenaline to epidural pethidine for postoperative analgesia in 40 patients after Caesarean section. In a randomised, double-blind study, patients received pethidine 25 mg with adrenaline 50 mg (adrenaline group, n = 20) or pethidine 25 mg without adrenaline (plain group, n = 18) epidurally at the first request for postoperative analgesia. The median duration of analgesia was longer in the adrenaline group (196 min; IQR ) compared with the plain group (96 min; IQR ; p = 0.002) and plasma concentrations of pethidine in the first 30 min after injection were lower in the adrenaline group (p = 0.003). Visual analogue scale pain scores in the first 30 min after injection and onset of analgesia, defined by the time for pain scores to decrease by 50%, were similar between groups. Addition of adrenaline to epidural pethidine has advantages for analgesia after Caesarean section. Keywords Pain; postoperative. Anaesthetic techniques; epidural. Analgesics; pethidine, meperidine. Sympathetic nervous system; adrenaline, epinephrine.... Correspondence to: Dr W. D. Ngan Kee Accepted: 7 February 1997 Pethidine is effective for epidural analgesia after Caesarean section. It is superior to intravenous and intramuscular pethidine [1 3] and has advantages over epidural fentanyl [4, 5]. The addition of adrenaline to highly lipophilic epidural opioids such as fentanyl, sufentanil and diamorphine has been described previously [6 12], but little data are available about the addition of adrenaline to epidural pethidine, which has intermediate lipophilicity (octanol/ ph 7.4 buffer partition coefficient 38.8, compared with morphine sulphate 1.42, fentanyl 813 and sufentanil 1778) [13]. Therefore, we performed a randomised, doubleblind study of epidural pethidine 25 mg with or without adrenaline 50 mg given as a bolus after Caesarean section. Analgesia, side-effects and plasma concentrations of pethidine were compared. Method After obtaining approval from the local Clinical Research Ethics Committee, we studied 40 ASA physical status 1 and 2 Asian women undergoing elective Caesarean section. Using data from our previous investigations of epidural pethidine [14, 15], we calculated that a sample size of 19 would be sufficient to detect a 50% difference in duration of analgesia from a single dose of epidural pethidine 25 mg (levels of significance a = 0.05, b= 0.1). All patients gave written informed consent and were instructed in the use of a 100-mm visual analogue scale (VAS) and a patientcontrolled epidural analgesia (PCEA) device (Abbott Pain Management Provider, Abbott Laboratories, North Chicago, IL, USA). Patients received 150 mg ranitidine orally the night before and the morning of surgery and 0.3 M sodium citrate 30 ml on arrival in the operating theatre. After intravenous preload of 1000 ml lactated Ringer s solution, combined spinal epidural anaesthesia was administered using a needle-through-needle technique with the patient in the lateral position. The skin was infiltrated with lignocaine 1% and the epidural space was located with a 16-gauge Tuohy needle at the L2 3 or L3 4 vertebral interspace using a loss of resistance technique. An 11.9-cm 25-gauge Whitacre spinal needle was passed through the Tuohy needle and spinal anaesthesia was induced by intrathecal injection of ml 853

2 W. D. Ngan Kee et al. Addition of adrenaline to pethidine Anaesthesia, 1997, 52, pages hyperbaric bupivacaine 0.5%. The spinal needle was removed and an epidural catheter was inserted 3 4 cm into the epidural space. The patient was then turned supine with 15 left lateral tilt. Intravenous ephedrine was given for hypotension and intra-operative analgesia was provided if required with nitrous oxide via facemask or 10-mg intravenous increments of ketamine according to our standard practice. An epidural test dose was not given. In the recovery room, patients were randomly allocated by drawing of shuffled coded envelopes to receive epidural injection of preservative-free pethidine 25 mg with adrenaline 50 mg (adrenaline group) or without adrenaline (plain group) at the first request for analgesia. All doses were prepared by an anaesthetist or investigator who was not involved with subsequent patient assessments. Doses were diluted to a total volume of 5 ml with 0.9% sodium chloride and were injected through a 0.2-mm filter over 30 s. The epidural catheter and filter were then flushed with 1 ml 0.9% sodium chloride. VAS pain scores were measured immediately before the dose of pethidine and at 3, 6, 9, 12, 15, 20, 25 and 30 min after the dose. Onset of analgesia was defined by the time for the VAS pain score to fall to 50% of the initial score. Throughout the assessment period, patients were monitored by continuous pulse oximetry (Biox 3700e, Ohmeda, Louisville, CO, USA), noninvasive measurement of arterial pressure (Dinamap, Critikon Inc., Tampa, FL, USA) and observation of level of consciousness. An intravenous cannula for blood sampling was inserted into a forearm vein on the side opposite to the intravenous infusion. Blood samples for subsequent measurement of plasma concentration of pethidine were taken immediately before injection of the dose and at 10, 20 and 30 min after the dose. Samples were immediately centrifuged and the plasma was stored at 70 C before assay using a modified gas chromatography method [16]. The calibration curves for the assay were linear over the range ng.ml 1 with coefficients of variation for within-day variation of 7.98% and 4.08% at 50 and 500 ng.ml 1, and coefficients of variation for between-day variation of 11.56% and 9.18% at 50 and 500 ng.ml 1. The lower limit of detection was 20 ng.ml 1. After 30 min, patients were asked to grade nausea and dizziness using the visual analogue scale. PCEA was then made available using pethidine 5 mg.ml 1 (dose 25 mg, lockout interval 15 min, 4-h maximum 150 mg). After confirming that patients were haemodynamically stable and ensuring that movement of the legs was returning, patients were transferred to the postnatal ward where they were observed according to our standard protocol for PCEA, which includes hourly measurement of respiratory rate and level of consciousness. Duration of analgesia, defined by the time from injection of the study dose of pethidine to the first PCEA demand, and total pethidine consumption over 24 h were obtained subsequently from the electronic memory of the PCEA device. Patient characteristics, onset and duration of analgesia, 24-h pethidine consumption and side-effect scores were compared using the Mann Whitney U-test. Frequency data were compared using Fisher s exact test. VAS pain scores and plasma concentrations of pethidine were analysed by plotting measurements against time and calculating the area under the curve using the trapezium rule; results were then compared using the Mann Whitney U-test. A value of p < 0.05 was considered statistically significant. Results Data were analysed from 38 patients. Technical problems with anaesthesia occurred in four patients: one in whom accidental dural puncture with the Tuohy needle occurred and three in whom dural puncture with the spinal needle was unsuccessful. These patients were rejected from the study before randomisation and four patients were recruited as replacements. Two patients in the plain group were rejected from the study because of postoperative obstetric complications. Patient characteristics were similar between groups (Table 1). Three patients in the adrenaline group and two patients in the plain group required intra-operative analgesia with nitrous oxide; of these, one patient in the adrenaline group also received ketamine 10 mg. Blood samples could not be obtained for technical reasons from three patients in the adrenaline group and two patients in the plain group. Onset of analgesia, VAS pain scores and 24-h consumption of pethidine were similar between groups (Table 2, Fig. 1). Duration of analgesia was longer in the adrenaline group than in the plain group (Table 2). Plasma concentrations of pethidine were lower in the adrenaline group compared with the plain group (Fig. 2). Only three patients had nausea or dizziness at 30 min (two in the adrenaline group and one in the plain group); in all cases this was mild and did not require treatment. Table 1 Patient characteristics. Median (interquartile range). Adrenaline group Plain group (n ¼ 20) (n ¼ 18) Age; years 31.5 ( ) 33 (30 36) Weight; kg 64 ( ) 67.5 (62 74) Height; cm ( ) ( ) Intra-operative analgesia required; n

3 W. D. Ngan Kee et al. Addition of adrenaline to pethidine Table 2 Pain relief after epidural injection of pethidine 25 mg with or without adrenaline 50 mg. Median (interquartile range). Adrenaline group Plain group (n ¼ 20) (n ¼ 18) p Time for VAS pain score to decrease by 50%; min 9 (6 17.5) 10.5 (6 15) 0.99 Duration of analgesia; min 196 ( ) 96 (43 113) h consumption of pethidine; mg 250 ( ) 263 ( ) 0.45 VAS = visual analogue scale. No patient needed treatment for arterial oxygen desaturation, hypotension or sedation during the assessment period. Discussion Disadvantages of lipophilic epidural opioids include a short duration of action and high vascular uptake which may result in plasma concentrations equivalent to those found with systemic administration [17 21]. The addition of adrenaline in doses of mg (concentrations of mg.ml 1 ) has generally been shown to increase the duration of analgesia and decrease the vascular uptake of epidural opioids, and some studies have shown a reduction in sedation, perhaps as a result of the reduction in plasma opioid concentrations [9, 12]. Minimal side-effects have been reported except for an increase in pruritus with epidural fentanyl [6, 9] and an increase in nausea and vomiting with diamorphine [12]. In common with studies Figure 1 Visual analogue scale (VAS) pain scores (median and interquartile range) after epidural injection of pethidine 25 mg with adrenaline 50 mg (X), or without adrenaline (W). The area under the curve was similar between groups; p = Figure 2 Plasma concentrations of pethidine (median interquartile range) after epidural injection of pethidine 25 mg with adrenaline 50 mg (X), or without adrenaline (W). The area under the curve was greater in the plain group (median 2771 (interquartile range ) min.ng.ml 1 ) compared with the adrenaline group (1286 ( ) min.ng.ml 1 ); p = of other opioids, we have found that addition of adrenaline 50 mg to epidural pethidine 25 mg was also of benefit, doubling the duration of analgesia and significantly reducing systemic absorption compared with injection of pethidine alone. This is in contrast to a previous investigation of the addition of adrenaline to epidural pethidine given for analgesia in labour [22]. In that study, the addition of adrenaline 50 mg to pethidine 50 mg improved the quality but did not increase the duration of analgesia compared with pethidine alone. However, that study was not blinded and used historical controls. We chose to give a dose of epidural pethidine 25 mg diluted to a total volume of 5 ml with saline based on our previous experience with epidural pethidine after Caesarean section. In these studies, we found that epidural pethidine 25 mg gave analgesia of faster onset and longer duration compared with a dose of 12.5 mg, but increasing the dose to 50 mg, 75 mg or 100 mg had no advantages and was associated with higher plasma concentrations of pethidine and a higher incidence of side-effects [14]. Dilution of epidural pethidine 25 mg to 5 ml with normal saline improved quality and onset of analgesia compared with the same dose injected in a volume of 2 ml, but there was no advantage to increasing the diluent volume to 10 ml [15]. In comparison, the current study suggests that addition of adrenaline to epidural pethidine 25 mg in 5 ml saline is a more effective method of improving analgesia than increasing dose size or volume. The mechanism by which adrenaline prolongs the duration of action of epidural opioids is thought to be reduction of vascular uptake secondary to vasoconstriction. Reduced removal of drug from the epidural space would maintain the concentration gradient for diffusion across the dura and enhance analgesia by increasing the 855

4 W. D. Ngan Kee et al. Addition of adrenaline to pethidine Anaesthesia, 1997, 52, pages amount of drug reaching the site of action in the spinal cord [11, 23]. Reduced vascular absorption of opioids is reflected in the lower plasma concentrations of pethidine in the adrenaline group compared with the plain group. An additional mechanism is a direct analgesic action by stimulation of a 2 -adrenoceptors in the spinal cord [24] which has been demonstrated both in animals [25] and in humans [26]. We chose to use a combined spinal epidural (CSE) technique for anaesthesia. This had the advantages of a rapid and profound surgical block from the spinal component and the use of an epidural catheter for postoperative analgesia. We did not use adrenaline-containing intrathecal solutions and avoided injection of epidural or intrathecal opioids, both of which may have affected our subsequent pain assessments. The problems we encountered with CSE have been described previously [27]. We did not give a formal test dose after insertion of the epidural catheter. All catheters were carefully observed for blood or cerebrospinal fluid after insertion and no patients received local anaesthetic through the catheter. Although it was not possible completely to exclude accidental intrathecal or intravenous placement, because only 25-mg boluses of pethidine were given through the catheter, accidental intravenous placement would have had few clinical consequences. Pethidine has local anaesthetic activity [28] and intrathecal pethidine 1 mg.kg 1 has been used as the sole agent for Caesarean section [29]. Therefore, it is likely that, had our study dose of pethidine 25 mg been given intrathecally, it would have produced signs of spinal block. Thus, the dose itself effectively served as a test dose for detection of accidental intrathecal placement of the catheter. We checked all patients for regression of motor block before discharging them to the postnatal ward with PCEA. Our study showed advantages when adrenaline was added to a single dose of epidural pethidine. When adrenaline 3.33 mg.ml 1 was added to a continuous epidural infusion of fentanyl after thoracotomy, patients required less drug and had lower plasma concentrations of fentanyl compared with patients receiving fentanyl without adrenaline [8]. Similarly, when adrenaline 2.5 mg.ml 1 was added to sufentanil given by PCEA, patients made fewer PCEA demands and used less drug compared with patients receiving sufentanil without adrenaline [30]. Further work is required to determine whether adding adrenaline to epidural pethidine given by infusion or PCEA has advantages. Acknowledgment We thank Ms Perpetua Tan for her assistance with drug assays. References 1 Brownridge P, Frewin DB. A comparative study of techniques of postoperative analgesia following caesarean section and lower abdominal surgery. Anaesthesia and Intensive Care 1985; 13: Perriss BW, Latham BV, Wilson IH. 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