Optimal concentration of epidural fentanyl in bupivacaine 0.1% after thoracotomy

C. N. H. Tan1, A. Guha2, N. D. A. Scawn, S. H. Pennefather* and G. N. Russell

Department of Anaesthesia, The Cardiothoracic Centre, Liverpool, Thomas Drive, Liverpool L14 3PE, UK 1 Present address: Department of Anaesthesia, University Hospitals of Wales, Heath Park, Cardiff CF14 4WX, UK 2 Present address: Department of Anaesthesia, University Hospital Aintree, Longmoor Lane, Liverpool L9 7A, UK

*Corresponding author. E-mail: stephen.pennefather{at}ctc.nhs.uk

Accepted for publication: December 13, 2003


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. The aim of this prospective, double-blind, randomized controlled trial was to investigate the analgesic and adverse effects of three commonly used concentrations of thoracic epidural fentanyl with bupivacaine in patients undergoing thoracotomy for lung resection.

Methods. We studied 99 patients who were randomized to receive fentanyl 2 µg ml–1 (group 2), fentanyl 5 µg ml–1 (group 5) and fentanyl 10 µg ml–1 (group 10) in bupivacaine 0.1% via a thoracic epidural. Postoperatively, pain on coughing was assessed using a visual analogue scale (VAS) and an observer verbal rating score (OVRS) at 2, 8, 16 and 24 h. At the same times, sedation, pruritus and nausea were assessed.

Results. Of 29, 28 and 32 patients who completed the study in groups 2, 5 and 10 respectively, there was no significant difference in baseline characteristics between the three groups. The number of patients with episodes of unsatisfactory pain, i.e. VAS scores >30 mm and OVRS >1, at each of the four assessments postoperatively was significantly (P<0.01) higher in group 2 than in groups 5 and 10. In group 10, 16 patients had sedation scores >1 compared with 10 each in groups 2 and 5. In addition, 19 patients in group 10 experienced pruritus compared with 12 each, in groups 2 and 5. These differences were not significant. Nausea was not significantly different between the three groups.

Conclusion. We conclude that thoracic epidural fentanyl 5 µg ml–1 with bupivacaine 0.1% provides the optimum balance between pain relief and side effects following thoracotomy.

Br J Anaesth 2004: 92: 670–4

Keywords: anaesthesia, regional; anaesthetic techniques, thoracic epidural; analgesics opioid, fentanyl; surgery, thoracotomy


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After thoracotomy, patients may experience severe pain that prevents deep breathing and effective coughing, leading to the likelihood of pulmonary atelectasis.1 2 To manage post-thoracotomy pain, it is common practice to administer combinations of opioids and local anaesthetics into the epidural space for their synergistic effects.3 4 Epidural local anaesthetics can cause hypotension4 5 and opioids can cause sedation, respiratory depression, pruritus, nausea and vomiting.6 7 As they are dependent on dose, these adverse effects may be minimized by using epidural solutions of low drug concentration.8

Epidural bupivacaine 0.1% is commonly used with a wide range of fentanyl concentrations (1 to 15 µg ml–1).3 The important clinical question is what concentration of fentanyl in bupivacaine 0.1% will provide effective analgesia with minimal adverse effects after invasive thoracic surgery. The aim of this study was to investigate the analgesic and adverse effects of three concentrations of epidural fentanyl (2, 5 and 10 µg ml–1) in bupivacaine 0.1%.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After obtaining local research Ethics Committee approval and informed patient consent, we studied 99 ASA I–III patients, aged 20–80 yr, for pulmonary resection via a thoracotomy (Fig. 1). Patients were excluded if there were contra-indications to an epidural and if they were not able to understand postoperative measurements (e.g. VAS pain scores).



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Fig 1 Enrolment, intervention allocation, follow-up and data analysis.

 
Patients were randomized to receive one of three epidural solutions: bupivacaine 0.1% with either fentanyl 2 µg ml–1 (group 2) or fentanyl 5 µg ml–1 (group 5) or fentanyl 10 µg ml–1 (group 10). Randomization and drug preparation was performed by the hospital Pharmacy. The study solution was provided in 50 ml syringes labelled with the patient’s name and trial code. Thus, patients as well as staff in theatre and on the ward were blind to the study solution. The study solution was administered at 0.1 ml–1 kg–1 h–1 after a loading dose of 0.1 ml kg–1 via an epidural catheter inserted at T4/ 5 or T5/ 6 inter-space, prior to surgery.

All patients received a standardized anaesthetic comprising diazepam 10 mg po, propofol 1–2 mg kg–1 i.v., fentanyl 1.5 µg kg–1 i.v. and atracurium 0.5 mg kg–1 i.v. Their lungs were ventilated with isoflurane 1–2% in oxygen enriched air via a double lumen endobronchial tube. Blood pressure was monitored invasively and hypotension was treated with incremental doses of ephedrine and intravenous fluids as required. Surgical incisions were made through the bed of the 6th rib on the appropriate side. At the end of the procedure after reversal of residual neuromuscular blockade with neostigmine 2.5 mg and glycopyrolate 500 µg, patients were extubated and nursed in a high dependency unit.

In the postoperative period, assessments were made at 2, 8, 16 and 24 h, by one of the authors or nursing staff, blinded to the treatment. Pain on coughing was assessed using a visual analogue scale (VAS) comprising a horizontal 100 mm line representing ‘no pain’ on the left and ‘worst pain imaginable’ on the right. In addition, the observer verbal response score (OVRS) scale was used to demonstrate practical endpoints relating to the ability to cooperate with physiotherapy (Table 1).


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Table 1 Observers Verbal Rating Scores (OVRS)
 
The epidural was adjusted by the nursing staff in an attempt to obtain pain VAS <=30 mm. If pain exceeded this target, a bolus of 0.1 ml kg–1 of the treatment solution was administered and the infusion rate increased by one third.

At the same postoperative times, patients were assessed for adverse effects. Sedation was measured on a scale of 0, 1, 2, 3 and 4 representing: awake, not sedated; mild sedation; moderate sedation easily arousable; heavily sedated difficult to rouse; over sedated unarousable, respectively. Also, the presence of nausea and pruritus were assessed at 2, 8, 16 and 24 h postoperatively. Arterial blood gases breathing room air were measured prior to induction and at 2 h postoperatively. The total volume of epidural solution was noted at the end of the 24 h period.

From a pilot study, we showed that 20% of patients receiving bupivacaine 0.1% with fentanyl 5 µg ml–1 for post-thoracotomy pain had no episodes when their pain VAS exceeded 30 mm. A clinically important result was judged to be when this proportion was at least 50%. In order to detect the difference with 80% power at the 5% significance level, we estimated that we had to study 30 patients per group.

Data were tabulated in Excel 2000 and analysed using SPSS v.10 for Windows. They were tested for normality using the Kolmogorov–Smirnov test. One-way ANOVA with Bonferroni correction for multiple comparisons was used to test normally distributed data for significance. We considered that patients were comfortable when their pain VAS scores were <=30 mm and OVRS<=1. Thus, over the four assessments postoperatively, we noted the number of times when the VAS scores were >30 mm and OVRS>1, for each patient. These frequencies were compared using Chi-squared or Fisher’s Exact tests, as appropriate.

Similarly, a sedation score of >1 was deemed unsatisfactory and the numbers of patients in each treatment group exceeding this score were compared. A similar analysis was performed for nausea and pruritus using the Chi-squared test. A value of P<0.05 was taken to be significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Of 99 patients, four, five and one in groups 2, 5 and 10, respectively, did not complete the study (Fig. 1). Of 89 patients who remained in the study, there was no significant difference in age, sex, weight, ASA status, lung function and type of operation between the three treatment groups (Table 2). In accordance with the volume of epidural solution infused in 24 h, the dose of bupivacaine was highest in group 2 and lowest in group 10 (Table 2). Conversely, of the three treatment groups, 24 h dose of fentanyl was lowest in group 2 and highest in group 10.


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Table 2 Patient and surgical details. Epidural solutions contained bupivacaine 0.1% with either fentanyl 2 µg ml–1 (group 2) or fentanyl 5 µg ml–1 (group 5) or fentanyl 10 µg ml–1 (group 10). Age, weight, FEV1, FVC, PaCO2, total doses of bupivacaine and fentanyl are expressed as mean (95% CI). Sex, ASA and type of operation are expressed as number of patients. FEV1=forced expiratory volume in 1 s (% expected). FVC= forced vital capacity (% expected). No significant difference between groups except: *total 24 h bupivacaine (group 2 vs group 10, P<0.05); **total 24 h fentanyl (all groups, P<0.01)
 
At each of the four assessments postoperatively, the number of patients with unsatisfactory pain (i.e. pain VAS >30 mm or OVRS >1) was significantly (P<0.01) higher in group 2 compared with that in groups 5 or 10 (Table 3). In addition, we found that the fraction of patients of 16/32 (50%) in group 10, with sedation scores >1 was higher but not significantly so, compared with that of 10/28 (35%) and 10/29 (34%) in groups 5 and 2, respectively. The fraction of patients of 19/32 (59%) in group 10 with pruritus was higher but not significantly so compared with that of 12/28 (43%) and 12/29 (41%) in groups 5 and 2, respectively. Nausea and PaCO2 did not differ between the three groups.


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Table 3 Pain and adverse effects. Epidural solutions contained bupivacaine 0.1% with either fentanyl 2 µg ml–1 (group 2), fentanyl 5 µg ml–1 (group 5) or fentanyl 10 µg ml–1 (group 10). Data are expressed as number of patients. No significant difference between groups except: *VAS on coughing (group 2 vs group 10, P<0.01) and **OVRS > 1 (group 2 vs groups 5 and 10, P<0.01)
 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Our results show that significantly (P<0.01) more patients receiving epidural fentanyl 2 µg ml–1 in bupivacaine 0.1% had pain VAS>30 mm and OVRS>1 compared with those who received fentanyl 5 µg ml–1 or fentanyl 10 µg ml–1, in bupivacaine 0.1%. In addition, there was a tendency for a higher incidence of sedation scores >1 and of pruritus, in group 10 compared with groups 5 and 2. No significant difference in nausea between the three groups was detected.

Our results concur with those of a randomized controlled trial (RCT) of thoracic epidural fentanyl 2.5, 5, 10 and 20 µg ml–1 with no local anaesthetic.9 It was shown that there was a concentration-dependent reduction in pain intensity in patients undergoing thoracotomy for lung resection. With fentanyl 2.5 µg ml–1, there was a significant decrease in proportion of patients with >50% reduction in pain scores, compared with higher concentrations (fentanyl 5, 10 and 20 µg ml–1). In another RCT comparing thoracic epidural fentanyl 1, 2 and 4 µg ml–1 in ropivacaine 0.2% in patients undergoing major abdominal surgery, it was shown that pain intensity was significantly greater in patients receiving fentanyl 1 to 2 µg ml–1 than in those having fentanyl 4 µg ml–1.10 In addition, our results are in agreement with another double-blind RCT involving 66 patients undergoing thoracotomy. It was shown that lumbar epidural fentanyl 5 and 10 µg ml–1 with no local anaesthetic provided equally effective analgesia.11

Epidural opioids can be associated with dose-dependent adverse effects e.g. sedation, pruritus, nausea and respiratory depression.7 Our study in which there was a tendency to increased sedation in patients receiving epidural fentanyl 10 µg ml–1, concurs with a study by Welchew and colleagues.9 He showed that increased sedation occurred at fentanyl 10, 20 µg ml–1 but not at fentanyl 2.5 µg ml–1. In two other RCTs of patients receiving thoracic epidural fentanyl 1, 2 and 4 µg ml–1 in ropivacaine 0.2%, sedation scores were low and no significant difference in sedation was detected.10 12

In our study, there appeared to be an increased incidence of pruritus in patients receiving epidural fentanyl 10 µg ml–1. This trend is consistent with a RCT in which the incidence of pruritus increased from 17% at fentanyl 10 µg ml–1, to 36% at fentanyl 20 µg ml–1.9 In other studies of lower fentanyl concentrations, this concentration-dependent effect was also demonstrable. For instance, the incidence of pruritus was 23%, 8%, 4% and 4% in obstetric patients receiving epidural fentanyl of concentrations 4, 3, 2 and 1 µg ml–1, respectively.13 Furthermore, in a RCT of 244 patients undergoing major abdominal surgery, thoracic epidural fentanyl 4 µg ml–1 was associated with a significantly (P<0.02) higher incidence of pruritus than fentanyl 1 µg ml–1 to 2 µg ml–1.10

No significant difference in nausea was found between the three treatment groups in our study. This concurs with Welchew’s study showing that there was no concentration-dependent nausea between the groups with epidural fentanyl 2.5, 5, 10 and 20 µg ml–1.9 In another RCT, no significant difference in nausea was shown between groups receiving epidural fentanyl at 1, 2 and 4 µg ml–1.10

In our study, assessments were made in the first 24 h postoperatively, and so our results are applicable to this period. After thoracotomy for lung resection, patients may have an epidural in situ for 5 days. Analgesic requirements are expected to be much reduced on day 5 compared with the immediate postoperative period. Thus if this study was extended beyond the first 24 h, then it is likely that we would have recorded a progressive reduction in opioid consumption in all treatment groups. By day 5, opioid consumption would be low; any possible differences in pain scores and opioid related adverse effects would not be detectable between groups 2, 5 and 10.

Patients who are listed for a thoracotomy may have underlying lung pathology such as chronic obstructive pulmonary disease and pleural disease. Their surgery may involve lung collapse and re-expansion as well as lung resection. In the postoperative period, there is a high risk of sputum retention, pneumonia and pulmonary oedema.2 Consequently, provision of high quality analgesia following thoractomy is essential. From the above discussion and our results, it would appear that higher concentrations of epidural fentanyl may increase the likelihood of opioid-related adverse effects such as sedation and pruritus. On the other hand, lower concentrations of epidural fentanyl do not provide analgesia of high quality following thoracic surgery; they appear to be more appropriate for non-incisional pain e.g. pain during labour.13 14 In patients who receive insufficient analgesia, an alternative method to increasing the concentration of epidural opioid is to consider an additional drug e.g. clonidine. Epidural clonidine prolongs analgesia,15 and by minimizing opioid administration and hence opioid-related adverse effects, it may be useful as an analgesic adjunct after major surgery.16

In conclusion, our study has shown that thoracic epidural fentanyl 5 or 10 µg ml–1 in bupivacaine 0.1% is associated with superior analgesia after thoracotomy compared with fentanyl 2 µg ml–1 in bupivacaine 0.1% in the immediate postoperative period. However, the use of fentanyl at 10 µg ml–1 does not improve analgesia compared with fentanyl 5 µg ml–1 and may increase the tendency to excessive sedation and pruritus. Therefore, epidural fentanyl 5 µg ml–1 in bupivacaine 0.1% would appear to provide the optimal balance between pain relief and adverse effects following thoracic surgery.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Tyler DC. Respiratory effects of pain in a child after thoracotomy. Anesthesiology 1989; 70: 873–4[ISI][Medline]

2 Conacher ID. Pain relief after thoracotomy. Br J Anaesth 1990; 65: 806–12[ISI][Medline]

3 Romer HC, Russell GN. A survey of the practice of thoracic epidural analgesia in the United Kingdom. Anaesthesia 1998; 53: 1016–22[CrossRef][ISI][Medline]

4 Mahon SV, Berry PD, Jackson M, Russell GN, Pennefather SH. Thoracic epidural for post-thoracotomy pain: a comparison of fentanyl-bupivacaine mixtures vs fentanyl alone. Anaesthesia 1999; 54: 641–6[CrossRef][ISI][Medline]

5 Liu S, Angel JM, Owen BD, Carpenter RL, Isabel L. Effects of epidural bupivacaine after thoracotomy. Reg Anesth 1995; 20: 303–10[ISI][Medline]

6 De Leon-Casasola OA, Lema MJ. Postoperative epidural opioid analgesia: what are the choices? Anesth Analg 1996; 83: 867–75[Abstract]

7 Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth 1995; 42: 891–903[Abstract]

8 Mourisse J, Hasenbos MA, Gielen MJ, et al. Epidural bupivacaine, sufentanil or the combination for post-thoracotomy pain. Acta Anaesthesiol Scand 1992; 36: 70–4[ISI][Medline]

9 Welchew EA. The optimal concentration for epidural fentanyl. Anaesthesia 1983; 38: 1037–41[ISI][Medline]

10 Scott D, Blake D, Buckland M, Etches R, et al. A comparison of epidural ropivacaine alone and in combination with 1, 2, and 4 µg ml–1 fentanyl for 72 hrs of postoperative analgesia after major abdominal surgery. Anesth Analg 1999; 88: 857–64[Abstract/Free Full Text]

11 Thomson C, Becker D, Messick J, de Castro M, et al. Analgesia after thoracotomy: effects of epidural fentanyl concentration/ infusion rate. Anesth Analg 1995; 81: 973–81[Abstract]

12 Liu SS, Moore JM, Luo AM, Trautman W, et al. Comparison of three solutions of ropivacaine/fentanyl for postoperative patient-controlled epidural analgesia. Anesthesiology 1999; 90: 727–32[CrossRef][ISI][Medline]

13 Lyons G, Columb M, Hawthorne L, Dresner M. Extradural pain relief in labour: bupivacaine sparing by extradural fentanyl is dose dependent. Br J Anaesth 1997; 78: 493–7[Abstract/Free Full Text]

14 Comparative Obstetric Mobile Epidural Trial (COMET) study group UK. Effect of low dose mobile versus traditional epidural techniques on mode of delivery: a randomised controlled trial. Lancet 2001; 358: 19–23[CrossRef][ISI][Medline]

15 Eisenach J, De Kock M, Klimscha W. Alpha-2 adrenergic agonists for regional anesthesia: A clinical review of clonidine (1984–1995). Anesthesiology 1996; 85: 655–74[ISI][Medline]

16 Curatolo M, Schnider T, Petersen-Felix S, et al. A direct search procedure to optimize combinations of epidural bupivacaine, fentanyl and clonidine for postoperative analgesia. Anesthesiology 2000; 92: 325–37[ISI][Medline]





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