Effect of Preincisional Epidural Fentanyl and Bupivacaine on Postthoracotomy Pain and Pulmonary Function

Effect of Preincisional Epidural Fentanyl and Bupivacaine on Postthoracotomy Pain and Pulmonary Function Yasser Mohamed Amr, MD, Ayman Abd Al-Maksoud Yousef, MD, Ashraf E. Alzeftawy, MD, Wail I. Messbah, MD, and Ahmed Mohamed Saber, MD Department of Anesthesiology, Faculty of Medicine, Tanta University Hospital, Tanta, Egypt Background. This study attempts to determine whether preemptive thoracic epidural analgesia (TEA) initiated before surgical incision would reduce the severity of acute post-thoracotomy pain, its effects on pulmonary function and stress response. Methods. Forty patients undergoing posterolateral thoracotomy received TEA either before (preoperative-tea group) or after (postoperative-tea group) surgery. Postoperative analgesia was maintained with epidural infusion of bupivacaine and fentanyl. Pain scores, pulmonary functions, arterial blood gases, plasma glucose, cortisol levels and epidural fentanyl consumption were compared for 48 hours after surgery. Results. The preoperative-tea group demonstrated significantly reduced pain scores at 2, 4, 8, 12, 24, and 48 hours at rest (p 0.001, p 0.002, p 0.004, p < 0.001, p 0.006, and p 0.001, respectively) and at 4, 8, 12, 24, 48 hours on coughing (p 0.001, p 0.001, p 0.001, p 0.001, p 0.004, respectively), and a significant reduction in epidural fentanyl consumption (208.6 49.3 ml, versus 260 28.8 ml, p 0.001). The preoperative-tea group showed significant improvement in pulmonary functions as compared with the postoperative-tea group (p < 0.05), except forced expiratory volume in one second at 24 hours (p 0.061) and peak expiratory flow rate at 48 hours (p 0.188). The postoperative-tea treated patients were more likely to have a higher arterial carbon dioxide pressure at 4, 8, 12, and 24 hours (p 0.017, p 0.001, p 0.003, p 0.001), respectively. However, we could not demonstrate a statistical difference in oxygenation, cortisol, or glucose level. Conclusions. Though preemptive TEA appeared to reduce the severity of acute pain, preserve pulmonary function, and reduce analgesic requirements, these statistically significant differences were not enough to conclude a clinical significant difference between groups. (Ann Thorac Surg 2010;89:381 6) 2010 by The Society of Thoracic Surgeons Thoracotomy is often performed in patients with preexisting lung disease and is associated with the potential for severe pain, further impairment of lung function, and the occurrence of chronic pain [1, 2]. The provision of pain relief is a major consideration and thoracic epidural analgesia is often regarded to be the gold standard [3]. The concept of preemptive analgesia to reduce postoperative pain was founded on a series of successful animal experimental studies that demonstrated central nervous system plasticity and sensitization after nociception [4]. Preemptive analgesia is defined as an antinociceptive treatment that prevents the establishment of altered central processing of afferent input, which amplifies postoperative pain [5]. By decreasing the altered central sensory processing, preemptive analgesia is thought to consequently decrease the incidence of hyperalgesia and allodynia after surgery [6]. Whether preemptive analgesic interventions are more effective than conventional regimens in managing acute postoperative Accepted for publication Oct 27, 2009. Address correspondence to Dr Amr, Department of Anesthesiology, Tanta University Hospital, Tanta, 31527, Egypt; e-mail: yasser.amr@ gmail.com. pain remains controversial [7]. This study attempts to determine if there is an advantage to giving preoperative TEA compared to postoperative administration after thoracic surgery on postthoracotomy pain, pulmonary function, stress response, and total opioids consumption. Material and Methods This study was approved by our local Medical Research Ethics Committee. Written informed consent was obtained from all patients enrolled in the study. Forty patients, American Society of Anesthesiologists (ASA) classification II-III, undergoing elective posterolateral thoracotomy, were allocated randomly to one of two groups. A prospective, randomized (sealed envelopes), double-blind design was used, with both patients and postoperative assessors blinded to analgesic management. Exclusion criteria were age (younger than 18 years), previous opioids, corticosteroids, or nonsteroidal antiinflammatory drugs within one week of surgery, previous chronic anticoagulation therapy, allergy to local anesthetics or opioids, inability to understand or perform verbal or physical assessments or use patient controlled epi- 2010 by The Society of Thoracic Surgeons 0003-4975/10/$36.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2009.10.060

382 AMR ET AL Ann Thorac Surg PREINCISIONAL THORACIC EPIDURAL ANALGESIA 2010;89:381 6 Table 1. Demographic, Operative Data and Preoperative Pulmonary Function in the Study Groups Variable Preoperative-TEA Group (n 20) Postoperative-TEA Group (n 20) Age (years) 50.8 7.1 49.7 5.6 Sex: male female 15 5 14 6 Weight kg 75.33 12 74.3 14 Height in cm 166.7 16.2 175.4 13.4 ASA status II-III 15 5 16 4 Pulmonary function: FVC (liter) 2.79 0.66 2.78 0.59 FEV 1 (liter) 2.21 0.62 2.10 0.61 PEFR (liter/second) 3.79 1.27 3.68 1.1 Type of surgery: Pulmonary 11 10 lobectomy Lung decortication 8 8 Pulmonary 1 2 metastatectomy Mean duration of surgery in minutes 174 59 173 62 ASA American Society of Anesthesiologists; FEV 1 forced expiratory volume in one second; FVC forced vital capacity; PEFR peak expiratory flow rate; dural analgesia (PCEA), neurologic disorders, previous surgery to (or severe deformity of) the thoracic spine, and forced expiratory volume in one second (FEV 1 ) less than 60% of the reference value. After the preoperative visit, all patients received a thoracic epidural catheter placed two hours before operation at the T5-7 interspaces and advanced 3 to 4 cm cephalad. A test dose of 1% lidocaine (10 ml) was used to confirm the location of the catheter. If the epidurals did not function, patients were excluded from this trial; the process of inclusion into the study went on until the requested number of patients was reached. Patients were familiarized with the visual analogue scale (VAS). Patients were allocated randomly to receive one of two analgesic regimens. For the preoperative-tea group, 8 ml of 0.25% bupivacaine plus fentanyl 50 g in2mlwas administered preoperatively. For the postoperative-tea group, no medication was administered through the epidural catheter preoperatively and intraoperatively. Twenty minutes after the epidural injection, general anesthesia was induced with an intravenous (IV) administration of fentanyl (2 g/kg), atracurium (0.5 mg/kg), propofol (2 mg/kg), and lidocaine (1.5 mg/kg). Tracheal intubation was with a double lumen tube and anesthesia was maintained with isoflurane in oxygen and nitrous oxide (40% and 60%, respectively). Respiratory rate and tidal volume were adjusted to maintain the end-tidal carbon dioxide level at 35 to 45 mm Hg. For fluid therapy all patients received balanced salt solution. No additional opioids were given during the operation. Standard monitors included pulse oximetry, electrocardiography, end-tidal carbon dioxide, and noninvasive arterial blood pressure. At the end of surgery, residual neuromuscular block was reversed with neostigmine (0.04 mg/kg) and atropine (0.01 mg/kg), and the endotracheal tube was removed when the patient met the criteria for extubation. Immediately after arrival to intensive care unit; an epidural infusion of fentanyl was initiated using a continuous basal infusion with a superimposed PCEA bolus dose. The standard setting used was fentanyl concentration (10 mcg/ml) and bupivacaine (1 mg/ml) [8]. Continuous basal epidural infusion 5 bml/hour (50 mcg/hour fentanyl plus 5 mg bupivacaine), superimposed PCEA bolus dose of 1 ml (containing 10 mcg fentanyl plus 1mg bupivacaine) every 15 minutes with a 4-hour lockout of 40 ml. Fentanyl infusion was maintained for 48 hours while the patient was placed in the intensive care unit. Analgesia was assessed at both rest and with cough at 2, 4, 8, 12, 24, and 48 hours after surgery by an observer blinded to treatment groups using a 100 mm VAS. Total amount of fentanyl consumption was recorded. Pulmonary function tests including forced vital capacity (FVC), FEV 1, and peak expiratory flow rate (PEFR) were performed preoperatively as a baseline, 24 and 48 hours after surgery. Arterial blood gases were performed at 4, 8, 12, 24, 36, and 48 hours after surgery. Stress response was assessed by measurement of blood glucose Table 2. Data on Postoperative Pain at Rest Time Preoperative TEA Postoperative TEA 2h 37 8 48 8 0.001 c Preoperative-TEA 0.031 d 4h 30 8 40 4.5 0.009 a 0.003 b 0.002 c Postoperative-TEA 0.043 e 8 h 24.5 8.3 31.5 6 0.001 a 0.001 b 0.004 c 12 h 22 6.4 34 4 0.001 a 0.001 b 0.001 c 24 h 22.8 8 30.4 4.5 0.001 a 0.001 b 0.006 c 48 h 20.4 5.6 27.5 3 0.002 a 0.001 b 0.001 c a Significant over 2 hours measurement in preoperative-tea group. b Significant over 2 hours; measurement in postoperative-tea group. c Significant in comparison to preoperative-tea, p 0.05. d Significant in preoperative-tea group. e Significant in postoperative-tea group. h hours;

Ann Thorac Surg AMR ET AL 2010;89:381 6 PREINCISIONAL THORACIC EPIDURAL ANALGESIA Table 3. Data on Postoperative Pain at Cough Time Preoperative TEA Postoperative TEA 383 2h 50 7.8 52 8 0.428 Preoperative-TEA 0.049 d 4 h 43.6 8.2 55 8.1 0.150 0.245 0.001 c Postoperative-TEA 0.024 e 8 h 37.6 8.3 54 8.4 0.001 a 0.445 0.001 c 12 h 35.2 6.2 46.8 6.4 0.001 a 0.028 b 0.001 c 24 h 36 8 47.4 8 0.002 a 0.076 0.001 c 48 h 34.4 5.5 41.2 5.6 0.001 a 0.002 b 0.004 c a Significant over 2 hour measurement in preoperative-tea group. b Significant over 2 hour measurement in postoperative-tea group. c Significant in comparison to preoperative-tea, p 0.05. d Significant in preoperative-tea group. e Significant in postoperative-tea group. h hour; and serum cortisol levels one day preoperatively as a baseline 4, 24, and 48 hours postoperatively. Statistical Analysis Data were presented in the form of mean SD. Two-way analysis of variance with correction for repeated measurements was used to compare groups. The Mann- Whitney U test was for pain scores. Results This study was completed on 40 patients; each group contains 20 patients. The characteristics of these patients are shown in Table 1. Statistical analysis revealed no differences between groups regarding demographic data, type and duration of the operative procedure or the preoperative pulmonary function. The data on postoperative pain at rest are shown in Table 2. Postoperative pain scores at rest 2, 4, 8, 12, 24, and 48 hours were statistically significantly higher in the postoperative-tea group than those in the preoperative- TEA group (p 0.05). The data on postoperative pain at cough are shown in Table 3. There were statistically significant differences between the postoperative-tea and preoperative-tea groups at 4, 8, 12, 24, and 48 hours postoperatively (p 0.05). The total epidural fentanyl consumption over 48 hours postoperatively was significantly lower in the preoperative-tea group compared with the postoperative-tea group (mean SD: 208.6 49.3 ml vs 260 28.8 ml) (p 0.001). Thoracotomy resulted in a significant decrease (p 0.05) of FVC, FEV 1, and PEFR. Thereafter, a steady recovery on the second postoperative day of parameters was observed in both groups but complete normalization was not reached within the extended period of observation. The preoperative-tea group showed a significant improvement in pulmonary functions compared with the postoperative-tea group (p 0.05) except for FEV 1 at 24 hours (p 0.061) and PEFR at 48 hours (p 0.188) (Table 4). Oxygenation was satisfactory in all patients during the study. However, mean arterial oxygen pressure was lower in postoperative-tea group at 4, 8, and 12 after extubation in comparison with the preoperative-tea group ([110 47, 118 42], [107 42, 114 39], and [100 17, 105 22]), respectively), but was not statistically significant (p 0.573, p 0.588, p 0.426, respectively). Four hours after extubation arterial carbon dioxide Table 4. Pulmonary Function Tests as Percent Reduction From Preoperative Baseline Pulmonary Function Preoperative TEA Postoperative TEA 24 hour: Preoperative FVC 1.40 0.35 1.17 0.35 0.001 a 0.001 b 0.036 c 0.011 d FEV 1 1.28 0.31 1.10 0.28 0.001 a 0.001 b 0.061 0.032 d PEFR 2.27 0.39 1.99 0.38 0.001 a 0.001 b 0.027 c 0.021 d 48 hour: Postoperative FVC 1.79 0.27 1.61 0.26 0.001 a 0.001 b 0.038 c 0.019 e FEV 1 1.48 0.24 1.26 0.23 0.001 a 0.001 b 0.005 c 0.045 e PEFR 2.65 0.66 2.36 0.71 0.001 a 0.002 b 0.188 0.039 e a Significant in comparison to preoperative values in preoperative-tea group. b Significant in comparison to preoperative values in postoperative- TEA group. c Significant in comparison to preoperative-tea group, p 0.05. d Significant in preoperative-tea group. e Significant in postoperative-tea group. FEV 1 forced expiratory volume in one second; FVC forced vital capacity; PEFR peak expiratory flow rate; TEA thoracic epidural analgesia.

384 AMR ET AL Ann Thorac Surg PREINCISIONAL THORACIC EPIDURAL ANALGESIA 2010;89:381 6 Table 5. Arterial Carbon Dioxide Pressure Values (mm Hg) Time Preoperative TEA Postoperative TEA 4 h 41.7 3.2 44.6 4.1 0.017 a Preoperative-TEA 0.523 8 h 42.2 2.3 44.7 2.4 0.573 0.925 0.001 a Postoperative-TEA 0.982 12 h 42.1 2,2 44.4 2.4 0.647 0.851 0.003 a 24 h 41.4 2 44.9 1.4 0.724 0.758 0.001 a a Significant in comparison to preoperative-tea group, p 0.05. h hour; pressure values (mm Hg) demonstrated significant reduction in the preoperative-tea group. The significant difference between both groups persisted at 8, 12, and 24 hours after extubation (p 0.05) (Table 5). The cortisol and blood glucose increased during the postoperative period; postoperative blood glucose level was significantly higher at 4 hours in the preoperative- TEA group. Cortisol levels were significantly higher at 4 and 24 hours in the preoperative-tea group and at 4, 24, and 48 hours in the postoperative-tea group in comparison with the preoperative baseline values (p 0.05). Serum cortisol or blood glucose levels were comparable in both the groups (p 0.05) (Table 6). Comment Thoracotomy produces one of the most damaging surgical insults that are possible to inflict on respiratory mechanics and gas exchange [9]. It is widely assumed that respiratory function is improved if the patient is relatively pain free in the postoperative period. Thoracotomy pain arises as a result of severe chest wall trauma, including fractured ribs, damaged peripheral nerves, and central nervous system hyperexcitability [10]. Poor analgesia after thoracotomy can lead to impaired coughing, reduced clearance of secretions, and respiratory failure. This is associated with a prolonged intensive care unit stay and delay in discharge from hospital [11]. Provision of effective postoperative analgesia is an integral part of anesthetic practice. Regional analgesia by continuous epidural infusion offers benefits over conventional opioid analgesia, particularly for thoracic surgery [12]. This is a small prospective randomized trial on 40 patients. The authors report statistically significant decreased pain in the group with the preoperative epidural drugs compared with the postoperative. As expected, pulmonary function was significantly decreased at all postoperative measurement times, and the reduction was more in the postoperative epidural group than in the preoperative epidural group. There are several problems with the study. The difference in total epidural fentanyl consumption between the two groups is 52 ml. This is statistically significant but clinically this is a small difference. Similarly, with the VAS scores, the differences are small although clinically significant. To support the argument that these results are not clinically significant is the finding that there was no clinically significant difference in the pulmonary function testing. We found the FEV 1 in the preoperative group was 58% of predicted and 52% of predicted in the postoperative group. This small percent difference is not enough to conclude a clinical significant difference in the Table 6. Blood Glucose (mg/dl) and Cortisol Levels (mcg/dl) in Both Groups, Values Are Mean SD Time Blood glucose: 0.056 Preoperative 103.5 20.29 107.75 19.5 0.503 0.063 4 hours 124.1 23.8 114.2 16.2 0.006 0.262 0.132 24 hours 119.4 36.1 112.4 24.2 0.093 0.491 0.475 48 hours 118.4 22.6 112.58 24.4 0.34 0.493 0.438 Cortisol level: Preoperative 17.2 7.5 18.5 3.3 0.482 0.045 c 4 hours 24.4 5.3 22.3 6.2 0.002 a 0.020 b 0.256 0.056 24 hours 22.5 0.2 21.4 0.32 0.03 a 0.001 b 0.113 48 hours 22.5 0.7 21.7 0.7 0.05 0.001 b 0.071 a Significant in comparison to preoperative values in preoperative-tea group. TEA group. c Significant in preoperative- TEA group. b Significant in comparison to preoperative values in postoperative-

Ann Thorac Surg AMR ET AL 2010;89:381 6 PREINCISIONAL THORACIC EPIDURAL ANALGESIA two groups. As proof that there is no physiologic advantage and the stated benefits are all statistical is the data on the blood glucose and cortisol levels that do not show any difference. Oxygenation was satisfactory in all patients during the study. The values of arterial carbon dioxide pressure was significantly higher in the postoperative-tea group during the first 24 hours after surgery as compared with the preoperative-tea group. Senturk and colleagues [2] compared the effects of preoperative and postoperative initiation of TEA. They showed that preoperative initiation of TEA is more effective in controlling acute pain after thoracotomy compared with postoperative initiation. Obata and colleagues [13] have shown that an epidural block with mepivacaine before surgery reduces acute and long-term postthoracotomy pain. There are two major differences between that study and the present study. Obata and colleagues used only a local anesthetic drug (mepivacaine) for epidural block (without opioid supplementation), and that study included long-term postthoracotomy pain, which is out of the scope of our study. Akural and colleagues [14] concluded that, preemptive epidural sufentanil administration had a short-term opioid-sparing effect, reduced wound touch, and pain sensitivity in patients with a Pfannenstiel incision, and reduced adrenocorticotropic hormone and cortisol concentrations compared with patients who received epidural sufentanil at the end of surgery. This may be explained by the nature of the surgery as patients in that study were undergoing hysterectomy, while in our study they were undergoing thoracotomy which is characterized by the most severe type of pain. In contrary, Aguilar and colleagues [15] found that, there was no significant difference between groups, either in PCEA requirements or in VAS scores (either at rest, during mobilization of the ipsilateral arm of surgery, or after cough) in a study carried out by using (mepivacaine) as a preemptive epidural analgesia. In another study, no significant difference in dynamic pain relief was seen when bupivacaine and morphine were given before and after incision and continued into the postoperative period [16] or when bupivacaine alone was given followed by PCEA with fentanyl and bupivacaine [17]. Two studies have demonstrated a preemptive effect; Wu and colleagues [18] used a mixture of ketamine, bupivacaine, and morphine, and demonstrated a statistically significant improvement in analgesia in the preincisional group after upper abdominal surgery during the first postoperative day. Also, Gottschalk and colleagues [19] demonstrated that, patients recovering from radical prostatectomy, all of whom had an aggressive postoperative epidural analgesic regimen, had significantly less pain in-hospital and 9.5 weeks later if they had epidural fentanyl or bupivacaine administered before surgical incision. Preemptive TEA appeared to reduce the severity of acute pain, preserve pulmonary function, and reduce analgesic requirements but had no effect on stress response. This statistically significant difference is not enough to conclude a clinical significant difference in the two groups. References 385 1. Ochroch EA, Gottschalk A, Augostides J. Long-term pain and activity during recovery from major thoracotomy using thoracic epidural analgesia. Anesthesiology 2002;97:1234 44. 2. Senturk M, Ozcan PE, Talu GK. The effects of three different analgesia techniques on long term postthoracotomy pain. Anesth Analg 2002;94:11 5. 3. Swanevelder J. Pain relief after thoracotomy: is epidural analgesia the optimal technique? Br J Anaesth 2007;98: 159 62. 4. Woolf CJ, Wall PD. Morphine-sensitive and morphineinsensitive actions of C-fiber input on the rat spinal cord. Neurosci Lett 1986;64:221 5. 5. Kissin I. Preemptive analgesia. Anesthesiology 2000;93: 1138 43. 6. Wilder-Smith OH. Pre-emptive analgesia and surgical pain. Prog Brain Res 2000;129:505 24. 7. Cliff KS, Lirk P, Seymour RA, Jenkins BJ.The efficacy of preemptive analgesia. Analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg 2005;100: 757 73. 8. Lubenow TR, Ivankovich AD, McCarthy RJ. Management of acute postoperative pain. Barash P, Cullen BF, Stoelting RK, eds. In: Clinical anesthesia. 4th ed. Philadelphia, PA: Lippincott; 2000:1403 34. 9. Warner DO. Preventing postoperative pulmonary complications. Anesthesiology 2000;92:1467 72. 10. Sabanthan AS, Richardson J, Mearns AJ. Management of pain in thoracic surgery. Br J Hosp Med 1993;50:114 20. 11. Hughes R, Gao F. Pain control for thoracotomy in children. Contin Educ Anaesth Crit Care Pain 2005;5:56 60. 12. Kotzé A, Hinton W, Crabbe DCG, Carrigan BJ. Audit of epidural analgesia in children undergoing thoracotomy for decortication of empyema. Br J Anaesth 2007;98:662 6. 13. Obata H, Saito S, Fujita N. Epidural block with mepivacaine before surgery reduces long-term post-thoracotomy pain. Can J Anaesth 1999;46:1127 32. 14. Akural TE, Salomki AH, Tekay AH, Alahuhta SM. Preemptive effect of epidural sufentanil in abdominal hysterectomy. Br J Anaesth 2002;88:803 8. 15. Aguilar JL, Rincon R, Domingo V, Espachs P, Preciado MJ, Vidal F. Absence of an early pre-emptive effect after thoracic extradural bupivacaine in thoracic surgery. Br J Anaesth 1996;76:72 6. 16. Dahl JB, Hansen BL, Hjortso NC, Erichsen CJ, Moiniche S, Kehlet H. Influence of timing on the effect of continuous extradural analgesia with bupivacaine and morphine after major abdominal surgery. Br J Anaesth 1992;69:4 8. 17. Aguilar JL, Cubells C, Rincon R, Preciado MJ, Valldeperas I, Vidal F. Pre-emptive analgesia following epidural 0.5% bupivacaine in thoracotomy. Reg Anesth 1994;19:72. 18. Wu CT, Yeh CC, Yu JC. Pre-incisional epidural ketamine, morphine and bupivacaine combined with epidural and general anaesthesia provides pre-emptive analgesia for upper abdominal surgery. Acta Anaesthesiol Scand 2000;44: 63 8. 19. Gottschalk A, Smith DS, Jobes DR. Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial. J Am Med Assoc 1998;279:1076 82.