Anesth Pain Med 2008; 3: 22～26 ￭임상연구￭
Small Dose of Midazolam Added to Fentanyl-Ropivacaine for Patient Controlled Epidural Analgesia after Subtotal Gastrectomy
Department of Anesthesiology and Pain Medicine, Kyungpook National University School of Medicine, Daegu, Korea
Kyunghwa Kwak, M.D., Sioh Kim, M.D., Younghoon Jeon, M.D., Jeongwon Suh, M.D., Youngsoo Kim, M.D., Jaehyun Ha, M.D., and Soohyun Lee, M.D.
Background: Midazolam has been reported to have a spinally addition, intrathecal co--administration of midazolam and fentanyl mediated antinociceptive effect. In this randomized, double-blind produced better analgesia than either drug alone without increa- study, we evaluated whether a small dose of midazolam added to sing side effect.7) Therefore, we hypothesized that the addition fentanyl-ropivacaine mixture for PCEA (patient controlled epidural analgesia) improves epidural analgesia in patients underwent of small dose of midazolam into opioid-local anesthetic for elective subtotal gastrectomy. PCEA (patient controlled epidural analgesia) could provide Methods: Forty five patients, ASA physical status I and II, under- better postoperative analgesia. Therefore, this prospective, going subtotal gastrectomy were randomly allocated to receive 0.2% ropivacaine mixed with fentanyl 4μg/ml or 0.2% ropivacaine mixed randomized, double-blind, controlled trial was designed to with fentanyl 4μg/ml and midazolam 0.2 mg/ml. The infusion rate evaluate the analgesic efficacy and side effect of midazolam was set to deliver 4 ml/hr of the study solution, with a bolus of 2 added to fentanyl-ropivacaine for PCEA in patients undergoing ml per demand and a 20 minutes lockout time. elective subtotal gastrectomy. Results: Infused volume (P ＜ 0.05) and VAS scores (P ＜ 0.05) was significantly lower in the patients receiving midazolam. However, there were no differences in requiring rescue analgesics, MATERIALS AND METHODS PONV (postoperative nausea and vomiting), sedation scores, urinary retention, and pruritus between groups. This prospective, randomized, controlled study was approved Conclusions: Small dose of midazolam could augment analgesia without adverse effects when added to thoracic epidural infusion by our Hospital Ethics Committee. We enrolled forty five of fentanyl and ropivacaine. (Anesth Pain Med 2008; 3: 22∼26) ASA physical status I and II patients who were diagnosed with gastric cancer, undergoing elective subtotal gastrectomy. Key Words: fentanyl, midazolam, patient controlled epidural anal- Written informed consent was obtained from all patients. gesia, ropivacaine. Patients who had a history of alcohol or drug abuse, who had psychiatric problems, or who had respiratory, hepatic, circula- tory or renal dysfunction were excluded. On the night before surgery, all patients were instructed to use the PCEA device. INTRODUCTION No premedication was given, and the anesthetic regimen and A short-acting water soluble benzodiazepine, midazolam has postoperative pain management were standardized in all pa- been used for sedation or anesthesia. In recent years, midazo- tients. In the operating room patients were placed in the sitting lam has been shown to improve analgesia when added to an position and an epidural catheter was inserted via 18-gauge 1-6) intrathecal or epidural administration of local anesthetic. In Tuohy needle at the T8-T9 interspace and was advanced 3－4 cm into the epidural space in a cephalad direction. A test dose of 2 ml of lidocaine 2% with epinephrine 5μg/ml was in- 논문접수일：2007년 10월 8일 jected to rule out intrathecal or intravascular position of the 책임저자：김시오, 대구시 중구 삼덕 2가 50번지 경북대학교병원 마취통증의학과, 우편번호: 700-721 catheter. Sensory block (by pin prick test) covering the area of Tel: 053-420-5875, Fax: 053-426-2760 the proposed incision was induced by injecting 8 to 12 ml of E-mail: [email protected] 0.375% ropivacaine. General anesthesia was induced with This research was supported by Kyungpook National University Research Fund, 2002. propofol (2 mg/kg) and rocuronium (1.0 mg/kg) and main-
22 Kyunghwa Kwak, et al：Midazolam in Patient Controlled Epidural Analgesia 23 tained with 66% nitrous oxide in oxygen with a small Respiratory depression was defined as bradypnoeic episodes (a concentration (0.5－0.9%) of isoflurane. Within 30 minutes of ventilation frequency ＜ 10/min) lasting ＞ 10 minutes. A induction, a continuous epidural infusion of 0.375% ropivacaine sedation score 3 or respiratory depression was regarded as at 0.1 ml/kg/h was commenced. Ventilation was mechanically unacceptable complication in this context, and was to be controlled maintaining an end tidal carbon dioxide concen- assessed and reported by any health care personnel with the tration of 35 to 40 mmHg throughout surgery. No opioids subject then being switched to an alternate analgesic modality. were administered during surgery. An infusion of Ringer’s Occurrence of clinically relevant hemodynamic adverse events, solution (10 ml/kg/h) was given intravenously (i.v.) together including hypotension (systolic arterial blood pressure decrease with 4 mg boluses of ephedrine to maintain mean arterial ＜ 90 mmHg) and bradycardia (heart rate decrease ＜ 45 pressure within 20% of baseline values throughout surgery. At bpm), requiring treatment was recorded. In addition, patients the end of surgery, glycopyrrolate 7μg/kg and pyridostigmine were asked whether they had suffered from postoperative 30μg/ kg were administered i.v. for antagonism of residual nausea and vomiting (PONV), pruritus, urinary retention and neuromuscular blockade and the epidural infusion of 0.375% of any complication at any time point between the previous and ropivacaine was stopped. Postoperative pain relief was provided the present interview. PONV was scored on a three-stage (no, by using PCEA with a standard pump (Abbott Ambulatory feeling nauseated, retching or vomiting). Ⓡ Infusion Manager plus, Abbott Laboratories, North Chicago, Based on our experience of the need for epidural solution USA). According to computer-generated random number table, for postoperative pain, we calculated that to detect a 22% patients were randomly to receive 0.2% ropivacaine mixed difference in consumption of ropivacaine and fentanyl, 20 patients with fentanyl 4μg/ml (group FR) or 0.2% ropivacaine mixed in each group were required to obtain a 0.05 level of alpha with with fentanyl 4μg/ml and midazolam 0.2 mg/ml (group a power of 0.8. MFR). Analgesic solutions were prepared by one of the Data are presented as mean ± SD or number (%). authors not taking further part in data collection and patient Demographic data, intraoperative ropivacaine usage, and care. All patients also blinded to the drugs of PCEA. The duration of surgery were analyzed using the unpaired t-test. PCEA infusion was set to deliver 4 ml/hr of the study Statistical methods included 2-way analysis of variance solution, with a bolus of 2 ml per demand and a 20 minutes (ANOVA) for VAS values and consumption of PCEA solution. lockout time. Nishiyama et al6) have demonstrated that adding Ordinary data were analyzed by using the contingency table midazolam (10 mg to 20 mg for 12 hours) to continuous analysis with Chi square test or Fisher’s exact tests. P ＜ 0.05 epidural infusion of bupivacaine for postoperative pain provided was considered significant. a better analgesia than bupivacaine alone without deep sedative 6) effect. Therefore, based on a previous report, midazolam 0.2 RESULTS mg/ mL was chosen in our study. Assessments of pain, sedation, nausea, vomiting, pruritus, Of the 45 patients originally enrolled in the study, two and urinary retention as well as any noted side effects, were made at 2 and 6 hours after the end of surgery, and then at Table 1. Demographic Data, Intraoperative Usages of Ropivacaine, 08:00 and 20:00 on the first and second postoperative day by and Duration of Surgery a study-blinded anesthesiologist. Consumption of local Variables Group FR (n = 21) Group MFR (n = 21) anesthetic solution at 24, 48, 72 hours after operation was measured. The epidural catheter was removed on the third Age (yr) 57.1 ± 7.7 60.2 ± 7 postoperative day. Pain intensity scores during coughing were Sex (female/male) 13/8 11/10 Height (cm) 167.1 ± 4.4 168.4 ± 4.8 measured with a 100-mm visual analog scale (VAS). Rescue Weight (kg) 63.8 ± 8.2 62.8 ± 10.3 analgesia was provided with ketorolac 50 mg i.v if the pain Intraoperative ropivacaine (mg) 117.8 ± 17.9 111.9 ± 17.1 score was more than 4 or patient asked for rescue analgesics. Duration of surgery (min) 260.5 ± 37.6 249.1 ± 31.7 Sedation levels were assessed using a 4-point scale (0 = Values are expressed as means (SD) or numbers of patients. There awake, 1 = mildly sedated, easy to wake up when spoken to, were no significant differences between groups. Group FR: 0.2% 2 = moderately sedated, easy to wake up when slightly ropivacaine mixed with fentanyl 4μg/ml, Group MFR: 0.2% ropi- shaken, 3 = deep sedated, difficult to wake up when shaken). vacaine with fentanyl 4μg/ml and midazolam 0.2 mg/ml. 24 Anesth Pain Med Vol. 3, No. 1, 2008
Table 2. Consumption of Epidural Analgesic Solution and Side Effects
Group FR (n = 21) Group MFR (n = 21)
Infused volume of 423.8 ± 68.9 328.3 ± 34.2* PCEA solution (ml) Fentanyl consumption (μg) 1,695 ± 190.9 1,313.1 ± 136.7* Ropivacaine consumption (mg) 847.5 ± 95.4 656.6 ± 68.4* Patients requiring ketorolac 4 (19) 1 (5) PONV Absent 15 (71) 19 (90) Nausea 5 (24) 2 (10) Vomiting 1 (5) 0 Sedation (0/1/2/3) 19/2/0/0 17/4/0/0 Urinary retention 10 (48) 6 (29) Pruritus 9 (43) 5 (24) Fig. 1. Cumulative volume (ml) of epidurally administered study solutions. Group FR: 0.2% ropivacaine mixed with fentanyl 4μg/ml, Group MFR: Values are in mean ± SD or number (%) of patients. PCEA: 0.2% ropivacaine with fentanyl 4μg/ml and midazolam 0.2 mg/ml.l. Data patient controlled epidural analgesia, PONV: postoperative nausea are presented as mean ± SD. *P ＜ 0.05 compared with Group FR. and vomiting; Group FR: 0.2% ropivacaine mixed with fentanyl 4μg/ ml, Group MFR: 0.2% ropivacaine with fentanyl 4μg/ml and mida- zolam 0.2 mg/ml. Sedation level: 0 = awake, 1 = mildly sedated, easy to wake up when spoken to; 2 = moderately sedated, easy to wake up when slightly shaken; 3 = deep sedated, difficult to wake up when shaken. *P ＜ 0.05 compared with Group FR. patients in group FR were excluded due to failure of epidural catheterization and one patient of MFR group were excluded due to disconnection of the epidural catheter. There were no significant differences between groups in demographic data, intraoperative usages of ropivacaine, and duration of anesthesia (Table 1). Table 2 showed that consumption of volume, fentanyl and ropivacaine of PCEA, patients requiring rescue analgesic and adverse effects such as PONV, pruritus and urinary retention. Patients in the group MFR consumed less Fig. 2. Pain scores on coughing. POD1: first postoperative day, POD2: second postoperative day. Group FR: 0.2% ropivacaine mixed with ＜ analgesic solutions of PCEA (P 0.05). Infused volume of fentanyl 4μg/ml, Group MFR: 0.2% ropivacaine with fentanyl 4μg/ml and PCEA was less in the MFR group than in the FR group at midazolam 0.2 mg/ml, VAS: visual analogue scale. Data are expressed 24, 48, and 72 hours after surgery (P ＜ 0.05) (Fig. 1). VAS as mean ± SD. *P ＜ 0.05 compared with Group FR. pain scores on coughing were lower in the MFR group than in the FR group at 2 and 6 hours after surgery and 8:00 and treatment. With respect to other complications such as PONV, 20:00 on the second day after surgery (P ＜ 0.05) (Fig. 2). urinary retention and pruritus, there were no significant More patients in group FR required rescue analgesics than in differences between the groups. group MFR, but difference did not reach significance. There was no difference in the level of sedation between two groups. DISCUSSION Two patients in the FR group and four patients in the MFR group were mildly sedated 2 hours after operation, but no In our study, compared with patients in the group FR, patients developed deep sedation or unacceptable respiratory patients in the midazolam group received, on average, smaller depression throughout observation period. In addition, no doses of epidurally infused drugs (P ＜ 0.05). In addition, patients developed clinically relevant hemodynamic adverse VAS scores in the MFR group were lower than in the FR events such as hypotension and bradycardia, requiring group at 2 and 6 hours after surgery and 8:00 and 20:00 on Kyunghwa Kwak, et al：Midazolam in Patient Controlled Epidural Analgesia 25 the second day after surgery (P ＜ 0.05). These result suggest in humans for more than 10 years for the treatment of chronic that midazolam added to fentanyl-ropivacaine PCEA would be low back pain18) and even long-term (2.5 years) administration beneficial adjunct to provide better analgesia after gastrectomy of up to 6 mg per day of intrathecal midazolam did not cause without significant adverse effects. any neurological deficits in patients with refractory Previous preclinical studies have shown a potential role of musculoskeletal pain.19) Tucker et al.7) have suggested that spinal benzodiazepine receptors in segmental antinociceptive clinically useful doses of intrathecal midazolam 2 mg did not action of intrathecal midazolam.8,9) The mechanism by which increase adverse neurological symptoms compared with midazolam provides analgesia has been explored in several conventional therapies. Nishiyama et al.20) found that epidu- recent studies. The main site of benzodiazepine action in the rally administered midazolam enters the cerebrospinal fluid, but spinal space is the presynaptic γ-aminobutyric acid (GABA) concentrations are only 3% of those in the systemic receptor in the dorsal horn of the spinal cord.10,11) GABA circulation. They suggested that epidural administration of receptors in spinal cord are involved in antinociceptive midazolam has a wide safety margin for neurotoxicity of the mechanism.12) Recent report suggests that intrathecal midazolam spinal cord.20) In the present study, Infusion rate of PCEA in is involved in the release of an endogenous opioid, acting at group MFR was 4 to 5.3 ml/h and no patients who received spinal delta-receptors.13) epidural infusion of midazolam showed neurotoxic effects. In Nishiyama et al.6) suggested that adding midazolam to conti- addition, side effects such as PONV, pruritus and urinary nuous epidural infusion of bupivacaine could be adequate to retention were comparable in the two groups. increase analgesia. However, they found that higher doses (mi- In conclusion, midazolam 0.2 mg/ml could augment analgesia dazolam 20 mg/12 hr) significantly decreased blood pressure without adverse effects when added to thoracic epidural and increased sedation compared with lower doses (midazolam infusion of fentanyl 4μg/ml and ropivacaine 2 mg/ml at a 10 mg/ 12 hr), but there were no serious complications rate of 4－5.3 ml/h in patients underwent subtotal gastrectomy. requiring treatment. Continuous epidural administration of analgesics (ropivacaine 1.9 mg/ml, fentanyl 2μg/ml) at a rate REFERENCES of 5 ml/h has been shown to provide adequate analgesia to Korean patients undergoing subtotal gastrectomy.14) In the 1. 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