FENTANYL BY CONSTANT RATE I.V. INFUSION FOR POSTOPERATIVE ANALGESIA

Br. J. Anaesth. (1985), 5, 250-254 FENTANYL BY CONSTANT RATE I.V. INFUSION FOR POSTOPERATIVE ANALGESIA W. S. NIMMO AND J. G. TODD is a synthetic opioid analgesic 50 times more potent than morphine, with a more rapid onset and shorter duration of effect (Romagnoli, 193). The drug has been administered by i.v. infusion during anaesthesia and for short periods thereafter (McQuay et al., 199; Hengstmann, Stoeckel and Schuttler, 1980), but there is little information concerning attempts to prevent the onset of postoperative pain by infusing fentanyl i.v. for 24 h. Accurate infusion of drugs for 24 h usually requires a mechanical or electrical syringe driver or pump, and it is likely that this has reduced the popularity of this approach. We report a 24-h infusion study using a disposable infusion device requiring no external power source the Baxter Travenol Infusor. THE BAXTER TRAVENOL INFUSOR The infusor (fig. 1) (Ausman et al., 1982) consists of an elastomeric balloon which is distended by the operator filling it with 60 ml of the desired solution; the distension of the balloon provides the pressure for infusion. This pressure is in excess of 620 mm Hg and the infusion will continue even if the i.v. cannula is kinked or comes out of the vein and enters the tissues. The device is designed to run for 24 h, a flow restrictor within it regulating the rate of infusion to 2 ml h" 1. The 12 ml of infusion that remains within the device after this time is a reserve and should be discarded. The accuracy of the device depends on the viscosity of the solution and the manufacturers recommend that 5% dextrose is used as the diluent. Throughout our study, regular observations of the WALTER S. NIMMO*, M.D., M.R.C.P., F.F.A.R.C.S.; J. GORDON TODD, M.B., CH.B., F.F.A.R.C.S.; University Department of Anaesthesia, Western Infirmary, Glasgow Gil 6NT. *Present address: University Department of Anaesthesia, Medical School, Beech Hill Road, Sheffield S10 2RX. SUMMARY by continuous i. v. infusion (1.5 fig kg- 1 min or 0.5 \ig kg min ') was compared with placebo infusion as an analgesic regimen for 24 h after hysterectomy. The drugs were infused using a new disposable device which required no external power source. All patients were allowed morphine i.m. if they experienced pain. Patients in the higher dose fentanyl group demanded less i.m. morphine and had better pain relief after operation, without important respiratory depression. volume left in the infusor were made and no deviation from the predicted infusion rate was recorded. PATIENTS AND METHODS Twenty-four women undergoing elective hysterectomy through a transverse abdominal incision were studied on consecutive operating lists of one consultant gynaecologist. Informed consent and ethics committee approval were obtained. The patients were allocated randomly to three groups to receive one of three infusion regimens: (1) 1.5 jig kg" 1 h" 1 (nine patients) (2) 0.5 xg kg" 1 h" 1 (eight patients) (3) infusion of 5% dextrose (seven patients) The infusion was instituted 1-2 h before induction of anaesthesia. Premedication was with atropine 0.6 mg i.m. After induction of anaesthesia with thiopentone 3-5 mg kg"! and neuromuscular blockade, the trachea was intubated and the lungs were ventilated with 6% nitrous oxide and 1% halothane or enflurane in oxygen. A bolus dose of fentanyl 100 [xg was given i.v. At the end of anaesthesia, each patient was prescribed Cyclimorph (morphine 10 mg and cyclizine 50 mg) i.m., to be given on

I.V. FENTANYL INFUSION DEVICE 251 FIG. 1. The Baxter Travenol Infusor. The device is filled with the calculated amount of fentanyl diluted in 5% dextrose to a volume of 60 ml. It administers 2 ml h~' for 24 h. The reserve is then discarded. demand at the discretion of the recovery room nurse. All operations were carried, out by one surgeon, and anaesthesia was carried out by one of two anaesthetists. All assessments were carried out by an anaesthetist not otherwise involved in the care of the patient. The patient, surgeon, recovery room nurses and the assessor for the study were unaware of which infusion had been administered. The following assessments and observations were made by the assessor in the period after operation, at 4, 8, 12 and 24 h after the start of the infusion: (1) Pain scores. Pain was graded as none, mild, moderate or severe. (2) Conscious level. (3) Respiratory rate. (4) Heart rate. (5) Arterial pressure. (6) Peak respiratory flow using a Wright minipeak flow meter. The best of three attempts was expressed as a percentage of the value before operation. () Nausea or vomiting. (8) The number of doses of Cyclimorph administered. All observations were made with the patient semirecumbent in bed. Arterial blood-gas tensions were measured at 12 and 24 h. Plasma fentanyl concentrations were measured by radioimmunoassay at 12 and 24 h (Michiels, Hendriks and Heykants, 19). An overall assessment of pain was made by the patient and by the observer at 24 h. Statistical analysis was by analysis of variance, Mann-Whitney U test or Fisher's exact probability test. RESULTS Patient data are given in table I. There were no significant differences between the groups. Pain assessment Patients receiving the more concentrated infusion of fentanyl demanded significanfly fewer doses of Cyclimorph than those in the placebo group (P < 0.05) (table II). Compared with patients receiving placebo (18 of 28 observations of moderate to severe pain), both groups receiving fentanyl had a statistically significant reduction in the frequency of moderate to severe pain after surgery, the more concentrated infusion giving greater relief (fentanyl 1.5 (xg kg" 1 h~': of 5b observations were ot moderate to severe pain (P < 0.01 compared with placebo); fentanyl

252 BRITISH JOURNAL OF ANAESTHESIA TABLE I. Patient data (mean ± SD) l.sugkg" 1 h" 1 0.5ngkg"' h" 1 n 9 8 Age (yr) 36 ± 3 ± 10 48 ± 15 Weight (kg) 5.6± 5.5 59.4 ±10.2 5.6 ± 5.5 Duration of surgery (min) 6 ± 19 69 ±20. 6 ± T; 0.5 ug kg 'h ': 12 of 20 observations were of moderate to severe pain (P < 0.05)). Independent patient and observer assessments of the overall pain experienced in the 24 h were in complete agreement, and are shown in table II. Both fentanyl groups experienced significantly less pain than the placebo group, but relief was statistically greater with fentanyl 1.5 ug kg" 1 h" 1 (P < 0.01) than with 0.5 ug kg" 1 h" 1 (P < 0.05). Respiratory effects There was no evidence of important respiratory depression in any of the groups (table III). In four patients the respiratory rate decreased to less than 12 b. p. m. once in the 24 h, but it was never less than 8 b.p.m. These patients were all in the high-dose fentanyl group, and the group as a whole had respiratory rates at 12 and 24 h which were significantly less than those of patients in the placebo group. In only two patients (one in the placebo group and one in the high-dose fentanyl group) did arterial carbon dioxide tension reach a value greater than 5.8 kpa (44 mm Hg) (6.2 kpa (4 mm Hg) in each). There were no statistically significant differences between the groups in the arterial blood-gas tensions of oxygen or carbon dioxide at 12 and 24 h (table III). There was a significant difference between the groups in the number of observations of greater than 50% of the preoperative peak expiratory flow (table III), compatible with the improved analgesia in the group receiving fentanyl 1.5 ug kg" 1 h~". The mean peak expiratory flow at 12 h was 62%, 61% and 46% of the _preoperative value in the fentanyl 1.5 ug kg" 1 h" 1, fentanyl 0.5 ug kg" 1 h" 1 and placebo groups, respectively. Other observations Throughout the study, there were no important changes in heart rate, arterial pressure or level of consciousness. In particular, all patients remained conscious and orientated throughout. There was a high incidence of vomiting in all three groups, but no significant difference between them: six patients in the fentanyl 1.5 ug kg"' h~', four in the fentanyl 0.5 ug kg" 1 h" 1 and three in the placebo groups, respectively, vomited. Plasma fentanyl concentrations The mean plasma fentanyl concentrations are shown in table IV. There were no statistically significant within-group differences between the concentrations at 12 and 24 h in the two groups who received fentanyl. Assuming the concentration at 24 h represented a steady state concentration, the mean fentanyl clearance was 1.0 ± 5.6 ml kg" 1 min" 1 (± SD) in the fentanyl 0.5 ug kg" 1 h" 1 infusion and 1.0 ± 9.2 ml kg" 1 min" 1 in the fentanyl 1.5 ug kg" 1 h" 1 infusion. TABLE II. Pain assessment. Compared with placebo: *P<0.05; **P<0.0I l.sugkg-'h- 1 O.Sugkg-'h- 1 Doses of Cyclimorph (mean ± SD) 2.0 ±0.* 2.6 ±1.6 3.6 ±0.8 Pain: no. None-mild 29 20 10 observations Moderate-severe ** 12* 18 24-h assessment of pain None-mild Moderate-severe 8 1** 4 4* 0

I.V. FENTANYL INFUSION DEVICE 253 l.sngkg-'h- 1 o.sngkg-'h- 1 TABLE III. Respiration (mean + SD). Compared with placebo: * <0.0S; **P<0.01 Resp. rate (b.p.m.) 12h 24 h 14 ±3* 19 ±2 21±1 15 ±4* 18 ± 2 19± 1 12h 10.8 ±1.3 10.4 ±0.8 11.5 PO 2 (kpa) 24 h 10.3 9.6 ±1.5 11.1 12h 5.5 5.2 4.8 ±0.6 PC0 2 (ki 24 h 5.3 5.2 ±0.4 4.9 ±0.6 Peak expiratory flow: no. of observations <50%normal >50% normal 12 24** 13 19* 20 8 DISCUSSION Infusion of fentanyl 1.5 ug kg" 1 h" 1 for 24 h produced satisfactory postoperative analgesia without important respiratory depression. Patients receiving this regimen had less pain, better peak expiratory flow measurements and demanded less additional prescribed opioids. An infusion regimen of 0.5 ug kg" 1 h" 1 did not differ markedly from placebo, although the pain relief was significantly better. The regimen was designed so that fentanyl infusion began 1-2 h before surgery and a bolus dose of 100 ug was given during anaesthesia in the hope that plasma concentrations would approximate to the "analgesic" steady state concentrations when the patients recovered from anaesthesia. Other studies, in which opioid infusions have been established after surgery, have experienced early failure of analgesia or have included a bolus dose of opioid in the recovery room (Stapleton, Austin and Mather, 199; Rutter, Murphy and Dudley, 1980). However, patients in the group receiving fentanyl 1.5,ug kg" 1 h" 1 received a larger combined total dose of opioid agents than the placebo group, in spite of the fact that the latter group demanded more doses of Cyclimorph. This smaller dosage in our placebo group is compatible with previous studies that have suggested that patients prescribed i.m. pulsed doses of opioid analgesia "on demand" receive too little drug in the period after operation (Hug, 1980; Hull and Sibbald, 1981). TABLE IV. Plasma fentanyl concentrations (ng mt') (mean ± SD) 12 h 24 h l.sug 1.62 ±0.2 1.9 ±0.6 0.61 ±0.32 0.56 + 0.25 The clearance of fentanyl described in this study (1 ml kg^min" 1 ) is not very different from that reported after a single i.v. dose in volunteers (13.3 ml kg^min" 1 ) (McClain and Hug, 1980). The use of disposable infusors might make this type of provision of analgesia easier for patients and nursing staff. The device itself is quite expensive and requires that some drug is discarded after 24 h. The high pressure within the balloon means that the infusion will not stop if the catheter leaves the vein and enters the tissues. Little is known of prolonged infusion of fentanyl to the tissues. However, this method of delivering analgesia seems worthy of study in other types of postoperative pain. It improves pain relief and avoids the high capital investment and maintenance costs of conventional electrical infusion pumps. ACKNOWLEDGEMENTS We are grateful to Travenol Laboratories Ltd for supplies of the infusor and to Dr Susanne Bower for analysis of plasma fentanyl concentrations. REFERENCES Ausman, R. K., Caballero, G. A., Quebbeman, E., and Ausman, D. C. (1982). Long term ambulatory, continuous intravenous infusion of 5-fluorouracil for the treatment of metastatic adenocarcinoma in the liver. Wis. Med.J., 81, 25. Hengstmann, J. G., Stoeckel, H., and Schuttler, J. (1980). Infusion model for fentanyl based on pharmacokinetic analysis. Br. J.Anaesth., 52, 1021. Hug, C. C. (1980). Improving analgesic therapy. Aneslhesiology, 53,441. Hull, C. J., and Sibbald, A. (1981). Control of postoperative pain by interactive demand analgesia. Br. J. Anaesth., 53, 385. McClain, D. A., and Hug, C. C. (1980). Intravenous fentanyl kinetics. Clin. Pharmacol. Ther., 28, 106. McQuay, H. J., Moore, R. A., Paterson, G. M. C, and Adams, A. P. (199). Plasma fentanyl concentrations and clinical observations during and after operation. Br. J. Anaesth., 51, 543. Michiels, M., Hendriks, R., and Heykants, J. (19). A sensitive radioimmunoassay for fentanyl plasma level in dogs and man. Eur.J. Clin. Pharmacol., 12, 153.

254 BRITISH JOURNAL OF ANAESTHESIA Romagnoli,A.(193). Duration of action of fentanyl. Anesthesiology, 39, 568. Rutter, P. C, Murphy, F., and Dudley, H. A. F. (1980). Morphine: controlled trial of different methods of administration for postoperative pain relief. Br. Med.J., 1, 12. Stapleton, J. V., Austin, K. L., and Mather, L. E. (199). A pharmacokinetic approach to postoperative pain: continuous infusion of pethidine. Anaesth. Intens. Care,, 25.