Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, PB 340, FIN-00029 Helsinki, Finland
* Corresponding author. E-mail: johannes.forster{at}hus.fi
Accepted for publication July 4, 2004.
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Abstract |
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Methods. In this randomized, double-blinded study, patients (85 yr, ASA IIII) underwent total knee arthroplasty (TKA) performed under spinal anaesthesia. After the operation, patients received an epidural infusion consisting of ropivacaine 2 mg ml1 and fentanyl 5 µg ml1 either without (Group RF, n=33) or with clonidine 2 µg ml1 (Group RFC, n=36). The infusion rate was adjusted within the range 37 ml h1.
Results. Average rate of infusion was slightly smaller in Group RFC than in Group RF (mean (SD) 4.7 (0.72) vs 5.2 (0.8) ml h1, P=0.004). Compared with the RF group, patients in the RFC group required significantly less rescue pain medication, that is i.m. oxycodone (median (25th, 75th percentile) 0 (0, 7) vs 7 (0, 12) mg, P=0.027). Arterial pressure and heart rate were slightly lower in Group RFC throughout the study period (mean difference between the groups 5 mm Hg (P<0.002) and 3 min1 (P=0.12), respectively). The groups did not differ statistically with respect to nausea, motor block, and sedation.
Conclusions. The small amount of clonidine added to the low-dose ropivacainefentanyl mixture reduced the need for opioid rescue pain medication after TKA. Clonidine slightly decreased arterial pressure and heart rate without jeopardizing haemodynamics. Otherwise, the side effect profiles were comparable in both groups.
Keywords: anaesthetic techniques, epidural, lumbar ; anaesthetics, local, ropivacaine ; analgesia, postoperative ; analgesics opioid, fentanyl ; clonidine
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Introduction |
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Methods |
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We enrolled 72 patients, aged 85 yr, ASA physical status IIII, undergoing primary, unilateral TKA. Exclusion criteria were contraindications to neuraxial anaesthesia and non-steroidal anti-inflammatory drugs, myocardial (NYHA class IIIIV), renal or hepatic impairment, psychiatric illness, and BMI more than 36 kg m2. Treatment allocation to the two study groups was by blocked randomization (closed envelope method). Block sizes were 20, 28, and 24. Randomization was performed by a third party not involved in the study. All investigators were kept unaware of the block sizes throughout the whole study period. All physicians and nurses involved in the treatment of the patients as well as the patients themselves were blinded concerning the study group allocation throughout the whole study period.
All patients received their normal morning medication before the operation, except angiotensin-converting enzyme inhibitors, diuretics, and diabetes mellitus medication. Pre-medication consisted of oral diazepam 515 mg. Intraoperative monitoring included pulse oximetry, ECG, non-invasive arterial pressure, and hourly urine output.
After local anaesthesia of the skin at the L2L3 or L3L4 inter-space, an epidural catheter (Portex Ltd, 18-gauge epidural minipack) was advanced 35 cm into the epidural space. A test dose of 3 ml of ropivacaine 7.5 mg ml1 (Naropin®, AstraZeneca) was given through the epidural catheter. After that, spinal anaesthesia was given one lumbar inter-space below that of the epidural puncture site using 34 ml ropivacaine 7.5 mg ml1. In case of early spinal block regression, anaesthesia was continued by intermittent injections of epidural ropivacaine 7.5 mg ml1. As required, the patients received i.v. midazolam and fentanyl as additional pre-medication before the spinal and epidural punctures, or for sedation or pain during the operation (e.g. position related discomfort in the back or shoulder). Glycopyrrolate or atropine for bradycardia, as well as fluid challenge and ephedrine for hypotension were given as clinically indicated.
The patients received about 8 ml kg1 of i.v. Ringer's acetate before the spinal anaesthesia. The intraoperative infusion therapy regimen consisted of Ringer's acetate and hydroxyethyl starch 60 mg ml1. For thromboprophylaxis, we used s.c. dalteparin (Fragmin®, Pharmacia/Pfizer), 2500 IU 1 h after the administration of the spinal anaesthesia, followed by 2500 IU in the evening of the day of surgery, and after this 5000 IU day1. A thigh tourniquet was used during surgery (320 mm Hg on average). Tranexamic acid (Caprilon®, Leiras, Finland) 0.51.0 g i.v. was given at the discretion of the surgeon for reduction of wound bleeding. After surgery, Ringer's acetate, hydroxyethyl starch, and packed red cells were given as clinically required.
Epidural infusion
After surgery, the patients were transferred to the recovery room. The epidural infusion was started when the sensory block had descended to Th10L1 and motor function of the lower extremities started to recover (first voluntary contraction of thigh muscles). An anaesthesia nurse, who was not involved in the treatment of the patients otherwise, prepared the study solution. In the study group (RFC, n=36), the epidural mixture consisted of ropivacaine 2 mg ml1, fentanyl 5 µg ml1, and clonidine 2 µg ml1 (Catapresan®, Boehringer Ingelheim, Ingelheim, Germany). A similar infusion without clonidine was used in the control group (RF, n=36). Initially, an epidural bolus of the study solution (5 ml) was given, after which the infusion was started at a rate of 5 ml h1. The rate of the infusion was adjusted as required within the range 37 ml h1. The infusion rate was increased in steps of 12 ml h1 if the pain score was more than 3 evaluated on a visual analogue scale (VAS) from 0 (no pain) to 10 (worst pain imaginable). Similarly, it was increased on patients' request even though VAS was only 13. Infusion speed was decreased if motor block was grade 23, or in the presence of pronounced hypotension or bradycardia. Trigger values for hypotension and bradycardia were not standardized but were considered to be a matter of the individual clinical setting (taking into account the age of the patient, possible cardiovascular diseases, and the actual well-being of the patient). When the transition from spinal anaesthesia to epidural analgesia had been accomplished in a clinically satisfying way, the patients were transferred to the orthopaedic ward. The infusion was to continue until 12:00 on the first postoperative day (POD).
Study parameters
Study parameters were recorded in a double-blinded fashion by one of the authors (J.F.), a trained study assistant, or by the nurse on duty during night shift. Parameters were written down on the day of surgery at 18:00 and 24:00, and on the first POD at 06:00 and 12:00 (±30 min). Arterial pressure, heart rate, and pulse oximetry were recorded at these predetermined times. Patients were asked whether they had suffered from pruritus or from nausea and vomiting (PONV) at any time point between the previous and the present interview. PONV was scored on a three-step scale (no, feeling nauseated, retching or vomiting). At each of the four predefined interview times, the worst or greatest value of pain intensity, motor block, and sedation observed after the previous interview was recorded. Pain intensity at rest and during motion (flexion of the knee, about 30°) was evaluated on the VAS for pain intensity (see previous section). Motor block was assessed using a modified Bromage scale10 (0=full flexion of knees and feet, 1=just able to move knees, 2=able to move feet only, 3=unable to move feet or knees). In addition, the degree of sedation was recorded (sleep=sound sleep at night, but no problem waking up, 0=awake, 1=snoozing and easy to wake up, 2=drowsy, 3=sleeping and difficult to wake up). At the end of the study infusion, each patient was asked whether he or she had felt drowsy to a disturbing extent at some time during the study period (i.e. subjective estimate by the patients: yes, no, cannot say). Finally, patients were asked about their overall satisfaction concerning the pain management regimen on a scale from 0 (worst) to 10 (best), and whether they would choose the same kind of pain treatment for a similar type of surgery in the future.
Supplemental analgesics and other drugs
All patients received propacetamol (ProDafalgan®, Bristol-Myers Squibb) 2 g i.v. at the time when the epidural infusion was started in the recovery room, and thereafter, paracetamol 1 g orally every 8 h. Rofecoxib (Vioxx®, MSD) 25 mg orally twice a day was started in the evening after the operation. Rescue pain medication was oxycodone 0.03 mg kg1 i.v. (in the recovery room) or 0.050.07 mg kg1 i.m. (after transfer to the orthopaedic ward). If two successive oxycodone doses, given shortly one after another, did not provide sufficient pain relief (VAS 3), the anaesthetist on call injected an epidural bolus of ropivacaine 7.5 mg ml1 (37 ml) in order to test the function of the epidural catheter. PONV was treated as required with tropisetron (Navobane®, Novartis) 2 mg i.v., and additionally, as needed, with metoclopramide 10 mg i.v. Pruritus was treated with hydroxyzine (Atarax®, UCB) 1025 mg orally.
Statistical analyses
Groups were compared with 2-analysis or Fisher's exact test for categorical data, t-test, or two-way repeated-measures analysis of variance (RM ANOVA) for continuous, normally distributed data, and with MannWhitney U-test for non-parametric data. A P value <0.05 was considered statistically significant. We calculated the sample size based on estimations of the primary end point, that is the amount of the rescue medication i.m. oxycodone. Using previous experience (mean 11 mg, SD 8 mg) and assuming a mean reduction of 50% (5.5 mg) as clinically significant, 34 patients per group were considered necessary to detect statistical significance (
=0.05, two-sided, power=80%). All statistical calculations were performed using the StatView® for Windows® Version 5.0.1. computer program (SAS Institute Inc., Cary, NC, USA).
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Results |
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Compared with patients in Group RF, patients in Group RFC received smaller doses of epidurally infused ropivacaine and fentanyl (Table 3). At the same time, they required significantly less i.m. oxycodone as rescue medication (Fig. 1). The median amount (25th, 75th percentile) of i.m. oxycodone was 0 (0, 7) mg in RFC, compared with 7 (0, 12) mg in RF (P=0.027). One patient in Group RFC received an epidural bolus of ropivacaine as rescue medication compared with three patients in Group RF requiring altogether six boluses. Each epidural bolus improved pain relief, indicating an appropriate epidural position of the catheter. VAS pain scores at the interview time points did not differ statistically between the groups except at 24:00, in favour of the RFC group (Table 3).
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Technical problems and complications
Technical problems occurred in five patients. In one instance, the infusion pump had to be replaced (infusion interrupted for 40 min). In two cases, catheter occlusion was overcome by rearranging the attachment tapes of the epidural catheter. There was one disconnection and another case of occlusion, which led to withdrawal from the study (Table 1, no. 26 and no. 64).
One patient (76 yr, Group RFC) presented with postoperative confusion in the afternoon and evening of the 1st POD; that is after the study infusion was turned off. The next day, this patient was again cooperative but he had no recall of the previous day. One patient (70 yr, Group RFC) suffered from a bad headache during the morning of the 1st POD. The headache became worse and a computer tomogram of the head was taken in order to exclude major complications. Nothing exceptional was seen in the tomogram, and the headache disappeared after a small dose of i.v. diazepam.
Patient satisfaction
Overall satisfaction concerning the pain management regimen was good to excellent in both groups (Table 3). The majority of all patients said that they would choose the same kind of pain treatment for a similar type of surgery in the future (yes/no/cannot say; 33/1/1 in RFC vs 28/2/3 in RF).
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Discussion |
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Clonidine produces dose-dependent spinal cord antinociception mainly through stimulation of 2-adrenoreceptors in the dorsal horn, mimicking the activation of descending inhibitory pathways.11112 When clonidine was used alone for continuous epidural analgesia, doses as high as 100150 µg h1 were required to obtain satisfactory analgesia.13 Such high doses cause hypotension, bradycardia, and sedation. In combination with either opioids or local anaesthetics, epidural clonidine has been used in single bolus doses of 75800 µg or continuous infusion dosages of 2050 µg h1.2 However, these dosages of clonidine have also commonly been associated with hypotension, bradycardia, and sedation.2 Although usually well tolerated by patients, these side effects have been considered worrisome in the postoperative setting. Thoracic epidural analgesia was improved by administering clonidine at a rate of 18.75 µg h1 together with a mixture of bupivacaine (5 mg h1) and morphine (0.1 mg h1) after hysterectomy,6 or by administering clonidine at a rate of 20 µg h1 in a mixture of bupivacaine (6.25 mg h1) and fentanyl (10 µg h1) after abdominal gynaecological surgery.7 In these two studies,67 haemodynamic changes were observed. Compared with these above-mentioned studies, the clonidine dose used in our study (on average 9 µg h1, i.e. approximately 220 µg days1) was low. Unfortunately, the design of our study does not allow conclusions about whether clonidine supplemented analgesia just in an additive or, perhaps, a synergistic way.
Arterial pressure and heart rate were slightly lower in the clonidine group than in the control group. Similar modest haemodynamic changes have been described consistently in many previous studies utilizing clonidine for postoperative analgesia.167 Obviously, in addition to clonidine there are several other factors, which may have influenced arterial pressure and heart rate in our patients, such as fluid loss as a result of bleeding and diuresis, the amounts of administered fluids, and use of diuretics. Nevertheless, in the clinical sense, the lower arterial pressure and heart rate had no obvious deleterious impact on our patients.
The groups did not differ statistically concerning PONV and antiemetic drug consumption. This in spite of the fact, that patients in the clonidine group received fewer opioids. In fact, our results may suggest that clonidine may somehow be associated with the occurrence of nausea and vomiting (Table 4), which has been observed in animal research.14 In contrast, there are recent reports that 2-adrenergic agonists might be useful in the treatment of nausea and vomiting.1516 About one-third of our patients suffered from PONV, which is comparable with or even slightly less than in other reports using epidural analgesia with opioids (on average 42%17).
Sedation is a side effect frequently associated with the use of clonidine in postoperative analgesia, often in conjunction with opioids.12 Probably the low dose of clonidine used here does not contribute to sedation. The confusion that occurred in one of the elderly patients after the end of the study period may not be related to the study drugs, but rather to the type of surgery. Postoperative delirium in elderly patients is relatively common particularly after major orthopaedic surgery.18 The degree of motor block decreased over time. With the low-dose epidural infusions used here, motor block was slight overall, allowing early postoperative mobilization therapy in all but two patients.
Mixtures of ropivacaine and fentanyl, as well as of ropivacaine and clonidine have been shown to be stable for up to 30 days,19 and a combination of bupivacaine, morphine, and clonidine for up to 90 days.20 Triple combinations of local anaesthetic, opioid, and clonidine have been used as intrathecal boluses, either without2122 or with slight improvement of analgesia.23 Clonidine doses have ranged between 15 and 75 µg. In all these studies, the addition of clonidine caused significant hypotension. The advantage of such a single-shot technique may be that no spinal or epidural catheter is required but, on the other hand, hypotension seems to be a problem with the large intrathecal clonidine doses. The continuous administration of a ropivacainefentanylclonidine triple combination via a spinal catheter might be an interesting subject of future studies.
In conclusion, clonidine 2 µg ml1 augmented analgesia when added to a continuous lumbar epidural infusion of ropivacaine 2 mg ml1 and fentanyl 5 µg ml1 after TKA at a rate of 37 ml h1. However, the use of this low-dose epidural clonidine together with a multi-modal analgesic regimen consisting of paracetamol, rofecoxib, epidural ropivacaine, and fentanyl had no major clinical benefits. In particular, the reduced opioid consumption in the clonidine group did not translate into reduced side effects, for example PONV. The small clonidine dose did not cause sedation. The levels of arterial pressure and heart rate were slightly lower in the clonidine group as compared with the control group. Increasing the clonidine dose may further improve the quality of the pain management regimen, but it may also increase the risk of hypotension.
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Acknowledgments |
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Footnotes |
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References |
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