EXTRADURAL CLONIDINE INFUSIONS FOR ANALGESIA AFTER TOTAL HIP REPLACEMENT

Transcription

1 British Journal of Anaesthesia 1992; 68: EXTRADURAL CLONIDINE INFUSIONS FOR ANALGESIA AFTER TOTAL HIP REPLACEMENT U. A. CARABINE, K. R. MILLIGAN, D. MULHOLLAND AND J. MOORE SUMMARY We have examined the effectiveness of extradural clonidine infusions for postoperative analgesia and the effect of clonidine on extradural morphine. In a double-blind, controlled study, patients, undergoing total hip replacement were allocated randomly to receive one of two doses of extradural clonidine (figh' 1 or 50ugh' 1 ), low dose extradural morphine or a combination of morphine and clonidine. Pain scores in the morphine group were significantly greater than in the clonidine groups (P < O.O1) and the combination group (P < 0.05) during the first 1 h after surgery. The requirements for systemic analgesia were least in the combination and larger dose clonidine group, and the duration of effect of the initial bolus dose was significantly longer compared with the morphine and low dose clonidine groups (P < 0.05). Arterial pressure was reduced in the clonidine groups, although the incidence of clinical hypotension was low. There were no significant differences between the groups in emetic symptoms or urinary retention. KEY WORDS Anaesthetic techniques: extradural. Analgesia: postoperative. Analgesics: morphine. Sympathetic nervous system: a adrenergic agonists, clonidine. As a result of the discovery of an adrenergic pain modulating system in the spinal cord [1], alpha 2 adrenergic agonists have been used in the management of postoperative pain. Although the analgesic properties of the alpha 2 adrenergic agonists have been well documented in both animal studies and clinical trials [2, 3], duration and efficacy are variable [4, 5]. Castro and co-workers assessed the physical properties, pharmacokinetics and dynamics of clonidine after i.v., extradural and intrathecal administration in sheep [6]. They concluded that extradural administration was the most appropriate route, and infusions were superior to bolus injections. The main side effects associated with the extradural use of clonidine are sedation, hypotension and a marked reduction in salivary flow. These properties are dose related [7-9], within therapeutic limits. is a complex drug [10]. Alpha, receptors at spinal cord level are thought to be responsible for the analgesic properties [11], and for the depressant effects on the cardiovascular system [12]. Although clonidine produces hypotension by a central effect, peripheral alpha j and alpha 2 receptors are thought to be responsible for some of the cardiovascular changes after extradural administration. Alpha a depressant effects predominate at smaller plasma concentrations, whereas alpha! pressor effects are found with greater doses. Previous studies on oral clonidine have demonstrated that anxiolysis could be achieved with minimal effects on the cardiovascular system [13]. Therefore, it may be possible to produce satisfactory analgesia without significant hypotension. In addition, synergism between alpha adrenergic and opioid systems has been suggested [14], although the precise mechanism is unclear. The benefit of such an interaction may lie in the potential to treat pain by precise manipulation of different receptors to achieve analgesia with a minimum of side effects. The aim of this study was to examine the analgesic efficacy of clonidine administered by extradural infusion. As synergism between opioids and alpha 2 adrenergic agonists has been suggested, clonidine was combined with a low dose of extradural morphine; a group which received extradural morphine only was included for comparison. PATIENTS AND METHODS After obtaining local Ethics Committee approval and informed patient consent, we studied patients (ASA grade I or II, aged yr, weights kg) undergoing total hip replacement under general anaesthesia. Patients were excluded if they were receiving any medication other than mild oral analgesics, or if there was any contraindication to extradural block. Patients were premedicated with oral temazepam 20 mg min before operation. On arrival of the patient in the anaesthetic room, an i.v. cannula was inserted and non-invasive arterial pressure, heart rate and tissue oxygen saturation monitoring U. A. CARABINE*, M.B., F.C.ANAES. ; K. R. MILLIGAN, M.D., F.C.ANAES.; D. MULHOLLAND, M.B., F.C.ANAES.; J. MOORE, PH.D., F.C.ANAES. ; Department of Anaesthetics, The Queen's University, and Musgrave Park Hospital, Belfast. Accepted for Publication: October 15, *Address for correspondence: Department of Clinical Anaesthesia, Royal Victoria Hospital, Grosvenor Road, Belfast.

2 EXTRADURAL CLONIDINE 339 commenced using the Hewlett Packard 78554A monitor, with a continuous printout. Before induction of anaesthesia, an extradural catheter was sited at Ll-2 or L2-3, using a standard 16-gauge Portex minipack. To test for accidental intrathecal insertion of the catheter, 1.5 % plain lignocaine 3 ml was administered and sensation tested with ice to exclude subarachnoid block. A standardized general anaesthetic was administered, using thiopentone 4mgkg~ 1 and fentanyl l.sugkg" 1 for induction; neuromuscular block was provided by vecuronium O.lmgkg" 1, and anaesthesia was maintained with 1-1.5% isoflurane, with 65% nitrous oxide in oxygen, with intermittent positive pressure ventilation to normocapnia. During insertion of the femoral component of the hip prosthesis (approximately 30 min before the end of surgery), patients were allocated randomly to receive one of four treatments via the extradural catheter: (1) clonidine 150 ug (lml) diluted to 10 ml in 0.9% saline, followed by an extradural infusion of clonidine ig ml" 1 ; (2) clonidine 150 ug (lml) diluted to 10 ml in 0.9% saline, followed by an extradural infusion of clonidine 50 ug ml" 1 ; (3) morphine 1 mg diluted to 10 ml in 0.9% saline, followed by an infusion of extradural morphine 0.1 mgml" 1 ; (4) clonidine 150 ug (1 ml) plus morphine 1 mg diluted to 10 ml with 0.9% saline followed by an extradural infusion of morphine 0.1 mg ml" 1. In all groups, the rate of infusion was set at 1 ml h" 1, and was commenced immediately after the bolus injection and continued for 24 h after surgery. The injections and infusions were prepared and administered by an operator who had no further part in the study. At the end of the procedure, residual neuromuscular block was antagonized and the patient allowed to wake up quietly. During the initial 1 h after operation, patients recovered in a theatre recovery ward and for the remainder of the 24-h study period, they were nursed in a high dependency unit. Arterial pressure and heart rate were recorded at 10-min intervals for the first 1 h, and thereafter at 1-h intervals for 12 h. Systolic pressure less than 85 mm Hg was treated initially with ephedrine 5 mg i.v., repeated if required. Mean arterial pressure was calculated from the formula: diastolic pressure plus one-third (systolic diastolic pressure). A heart rate of < 45 beat min" 1 was treated with atropine 0.3 mg i.v. All assessments of sedation and pain were made by the first author, who was unaware of the nature of the extradural injection or infusion. In the recovery ward, patients were assessed on a three-point scale (awake, drowsy or asleep) at 30 and 60 min. Pain was assessed at 30 and 60 min after surgery by the observer, on a four-point scale (no pain, mild, moderate or severe pain). After objective assessment at 30 and 60 min, patients completed a 100-mm VAS for pain (no pain at one extreme and worst possible pain at the other). In all patients, a separate i.v. cannula was inserted in the non-infused arm for use with a patient controlled analgesia system (PCAS), set to provide boluses of morphine 1 mg with an initial lockout time of 20 min and no fixed dose limit. The lockout time was adjusted as required to ensure that analgesia was adequate. Effectiveness of analgesia was assessed by the total requirements from the PCAS during the first 24 h after surgery. In addition, the time from extradural administration of the test drug during operation until the time of the first use of PCAS after operation was recorded. Postoperative blood loss was measured by weighing swabs and recording suction loss and replaced promptly with colloid and packed cells. Haemoglobin oxygen saturation was monitored continuously and ventilatory frequency was noted at 15-min intervals during the 24-h study. The incidence of nausea or vomiting, urinary retention requiring catheterization and any spontaneously volunteered side effects were recorded. Results are presented as mean (SD) for parametric data, and median and range for non-parametric data. Statistical analysis was by repeated measures analysis of variance (ANOVA), Mann-Whitney U test and chi square. Statistical significance was assumed at P < RESULTS The four groups were comparable in age, weight and height (table I). The male to female ratio was not distributed evenly among the groups, with the clonidine ug (P < 0.05) and combination (P < 0.05) groups having a larger number of female patients compared with the two other groups. There were no significant differences between the groups with respect to the MAP values immediately before extradural injection (fig. 1). With between-group analysis, MAP was significantly less in the combination group compared with the other groups from 5 min after extradural injection until 20 min after injection (P < 0.05). During the period from 30 min to 2 h after operation, arterial pressure was significantly greater in the morphine group compared with the three other groups (P < 0.01). At 18 and 24 h after surgery, arterial pressure was significantly less in both the clonidine groups than in the morphine and combination groups (P < 0.05). On within-group analysis, MAP was significandy less in both the clonidine groups compared with preinduction values from 15 min after extradural injection to the end of the study (P < 0.05). In the morphine group, the values for MAP were significandy smaller than baseline from 10 to 30 min after injection (P < 0.05). The MAP values in the combination group were significandy smaller than the preinduction value for the period from 5 to 30 min after injection (P < 0.05). During the first min after extradural injection, three, one and two patients in the clonidine ug, morphine and combination groups, respectively, required vasoconstrictor therapy to correct systolic pressure less than 85 mm Hg. In all cases,

3 340 BRITISH JOURNAL OF ANAESTHESIA TABLE I. Patient characteristics (mean (SD or range)). * P < 0.05 compared with clonidine 50 fig and morphine groups mg 50 ug Morphine n Age(yr) Weight (kg) Height (cm) Sex(M:F) 61 (43-75) 67 (10) 158(5) 5:15* 64 (45-75) 72(12) 160(6) 9:11 67 (38-75) 70 (14) 162 (4) 10:10 63 (41-75) 68(11) 159 (7) 2:18* CD I E E a. < Time (min) Time (h) FIG. 1. Changes in mean arterial pressure (MAP) during the study period (mean, SD). 30 = Pre-induction value; 0 = administration of extradural test drug. *P<0.05 compared with other groups. O = clonidine ug; D = clonidine 50 ug; # = morphine; = combination c 'E _ Operation Recovery Time (min) Time (h) FIG. 2. Changes in heart rate (HR) during the study period (mean, SD). 30 = Pre-induction value; 0 = administration of the cxtradural test drug. * P < 0.05 compared with morphine group. O = clonidine ug; = clonidine 50 ug; = morphine; = combination. one dose of ephedrine 5 mg was suflbcient to correct the hypotension and no further treatment was required. There were no significant differences in heart rate between the groups in the period immediately before injection. The values for heart rate were significantly smaller in both the clonidine groups compared with the morphine group at 15 and 20 min after injection, and from 6 to 24 h after operation (P < 0.05) (fig. 2). On within-group analysis, the heart rate values during the first 1 h after surgery in the clonidine \ig group were significantly smaller than baseline

4 EXTRADURAL CLONIDINE 341 TABLE II. Sedation scores. *P < 0.05 compared with morphine group Ug 50 ng Morphine 30 min 60 min 30min 60 min 30 min 60 min 30 min 60 min Awake (No.) Drowsy (No.) Asleep (No.) 10* 8* * TABLE III. Analgesia (mean (SD or range)). P < 0.05: * compared with morphine group; t compared with clonidine fig and morphine groups Mg 50 (ig Morphine PCAS morphine (mg) Time to first use PCAS (min) No PCAS needed (No. patients) VAS at 30 min VAS at 60 min 14.5(7) 144(99) 0 23 (0-75)* 24 (0-65)* 10.5 (6)* 286(112)t 2 8(0-^10)* 18 (0-65)* 15.9(11) 109(99) 1 49 (0-90) 45(0-89) 9.3(6)t 283 (120)t 3 24 (0-80)* (0-65)* Nausea/vomiting (No.) Urinary retention (No.) TABLE IV. Side effects ng 50 jig Morphine 7/1 1/0 5/ /0 5 (P < 0.05). There were no significant differences from baseline in the other groups. No patients required treatment for bradycardia. At 30 min, but not 60 min, after surgery, significantly more patients in the morphine group were either drowsy or asleep, compared with the clonidine ug and combination groups (P < 0.05) (table II). At 30 min, significantly more patients in the morphine group (seven) had moderate pain compared with the clonidine ug (three) and clonidine 50 ug (zero) groups. Four patients in the combination group had moderate pain, but this was not significant compared with the other three groups. By 60 min, the morphine group had a significantly greater number of patients with moderate pain (10) compared with the other three groups (one, two and one patients in the clonidine ug, clonidine 50 ug and combination groups, respectively). Subjective assessment of pain was similar. At both 30 and 60 min after operation, all three groups had significantly smaller values for pain compared with the morphine group (table III). No patient was unable to co-operate with the VAS scoring system. The time from administration of the bolus extradural dose to the first self administration of analgesia via the PCAS was taken as an indication of the duration of action of the bolus dose. This period in the clonidine 50 ug and combination groups was significantly longer than in both the clonidine ug and the morphine groups (table III). Total morphine administered via the PCAS was recorded for the first 24 h after surgery. Morphine requirements in the combination group were significantly less than the morphine and clonidine ug group. PCAS requirements in the clonidine 50 ug group were significantly less than in the extradural morphine group. There were no other significant differences between the groups (table III). There were no significant differences between the groups in the incidence of emetic symptoms or urinary retention requiring catheterization (table IV). One patient in each of the morphine and combination groups had a ventilatory frequency of less than 10 b.p.m. during the study period. In the patient in the morphine group, this was associated with a decrease in haemoglobin oxygen saturation to 88 %, and occurred 5 min after use of the PCAS. Five patients in the clonidine ug and seven patients in the clonidine 50 ug groups experienced dryness of the mouth. No patient in either the morphine or combination group reported a dry mouth. DISCUSSION In the combination and clonidine 50 ug groups, PCAS requirements were least and the duration of analgesic effect of the bolus doses was greatest. Postoperative pain scores and PCAS requirements were greatest in the extradural morphine group. The dose of extradural morphine used here was small (0.1 mgh" 1 ) and the PCAS was provided to ensure adequate analgesia after operation. By choosing such a small dose of morphine, the demonstration of increased analgesia by the addition of clonidine was possible. Potentiation of both local anaesthetic agents and opioids by clonidine has been suggested

5 342 BRITISH JOURNAL OF ANAESTHESIA by other workers [15, 16] and, although the evidence is often conflicting [17], the clinical implications are demonstrated in this study. The effect of an inadequate bolus dose and subsequent infusion of extradural morphine was improved significantly by the addition of clonidine to the bolus dose. Although the work of Reddy, Maderdrut and Yaksh has presented a clearer picture of the interactions at a spinal cord level [18], the exact mechanism of the interaction between the alpha 2 adrenergic agonists and other drug groups is still unclear. Other agents such as serotonin may also be important [19], although it is possible that they act by sharing common final pathways with the alpha 2 adrenergic agonists [20]. It has been suggested that analgesia attributable to the alpha 2 adrenergic agonists alone is insufficient, and that their role lies in reducing the dose requirements of other agents [21]. Analgesia associated with bolus extradural doses has been shown to be dose related, although the cardiovascular effects are less predictable at the extremes of the dosing range [22]. In addition, the variability in duration of analgesic effect has led to the suggestion that extradural clonidine may be more effectively administered by infusion rather than bolus doses. It would appear from our study that clonidine infusions used alone can provide satisfactory postoperative analgesia and with the greater dose infusion the systemic analgesic requirements were less than in the low-dose group. One of the commonest side effects associated with clonidine is sedation, but this was not apparent in our study, even with the greater infusion rate. However, the dry mouth often associated with oral clonidine used for hypertension [23] was noted in both the clonidine groups. The smaller arterial pressure in both clonidine groups compared with baseline readings are probably attributable to the reduction in central sympathetic outflow [24]. Heart rate changes with clonidine are less predictable and there was no apparent dose related reduction in heart rate noted here. Blood loss was monitored in the perioperative period and replaced promptly, so the cardiovascular changes that occurred after the extradural bolus dose were caused probably by the drug administered rather than inadequate fluid balance. The cardiovascular changes associated with the combination group were less marked than in the clonidine groups, which reflects the smaller plasma concentration of clonidine in this group. One of the disadvantages associated with the use of spinal and extradural opioids is the relatively high incidence of urinary retention leading to catheterization []. As the urinary tract has been implicated as a source of infection after joint replacement surgery [26], avoidance of urinary catheterization is desirable. Although it might be anticipated that the incidence of catheterization would be less in the clonidine group, the results of the present study do not support this, but other factors may have had an influence on the catheterization rate, as patients with a history of urinary symptoms were not excluded from the study. On the basis of haemoglobin oxygen saturation readings and ventilatory frequency, the results of this study are in agreement with the findings of Bailey and co-workers [27]. They noted that clonidine did not produce respiratory depression when used alone, and its addition to morphine did not increase the risk of respiratory depression. ACKNOWLEDGEMENT This study was supported by a grant from the Department of Health and Social Services for N. Ireland. REFERENCES 1. Yaksh TL. 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6 EXTRADURAL CLONIDINE Reddy SVR, Maderdrut L, Yaksh TL. Spinal cord pharmacology of adrcnergic agonist-mediated antinociception. Journal of Pharmacology and Experimental Therapeutics 1980; 213: Svensson TH, Bunney BS, Aghajanian GK. Inhibition of both noradrenergic and serotonergic neurons in brain by alpha adrcnergic agonist clonidine. Brain Research 1975; 92: Nakagawa I, Omote K, Kitahata L, Collins JG, Murata K. Serotonergic mediation of spinal analgesia and its interaction with noradrenergic systems. Anesthesiology 1990; 73: Motsch J, Graber E, Kudwig K. Addition of clonidine enhances postoperative analgesia from epidural morphine: A double blind study. Anesthesiology 1990; 73: Eisenach JC, Lysak SZ, Viscomi CM. Epidural clonidine analgesia following surgery: phase I. Anesthesiology 1989; 71: Wing LMH, Reid JL, Davies DS, Neill EM, Tippett P, Dollery CT. Pharmacokinetic and concentration effect relationships of clonidine in essential hypertension. European Journal of Clinical Pharmacology 1977; 12: 463-^ Lowenthal DT, Matzek KM, Mac Gregor TR. Clinical pharmacokinetics of clonidine. Clinical Pharmacokinetics 1988; 14: Barron DW, Strong JE. Postoperative analgesia in major orthopaedic surgery. Epidural and intrathecal opiates. Anaesthesia 1981; 36: Artz TD. Haematogenous infection of total hip replacement: A report of four cases. Journal of Bone and Joint Surgery 1975; 57A: Bailey PL, Sperry RJ, Johnson GK, Eldredge SJ, East KA, Pace NL, Stanley TH. Respiratory effects of clonidine alone and combined with morphine, in humans. Anesthesiology 1991; 74: 43-^8.