Addition of Adrenaline to Chloroprocaine Provides a Moderate Duration Time for Epidural Anaesthesia in Elective Caesarean Section

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1 The Journal of International Medical Research 2012; 40: Addition of Adrenaline to Chloroprocaine Provides a Moderate Duration Time for Epidural Anaesthesia in Elective Caesarean Section SW FENG, Y CAO, WG WANG, YS LIU AND XF SHEN State Key Laboratory of Reproductive Medicine, Department of Anaesthesiology, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China OBJECTIVE: Epidural anaesthesia using chloroprocaine with or without adrenaline and lidocaine with adrenaline were compared. METHODS: Sixty parturients undergoing elective caesarean section under epidural anaesthesia were randomized to receive 3% chloroprocaine (group C), 3% chloroprocaine with adrenaline (group CA) or 2% lidocaine with adrenaline (group LA). Onset time, duration time and various maternal, fetal and neonatal parameters were monitored. Pain was assessed using a visual analogue scale. RESULTS: The onset time of analgesia in group CA was similar to that in group C but was shorter than that in group LA. Duration of analgesia, loss of cold sensation and motor blockade in group CA were prolonged compared with group C, but were shorter than those in group LA. No differences in maternal, fetal or neonatal effects were seen. A higher pain score was reported in group C than in groups CA or LA at the end of surgery. CONCLUSIONS: Epidural anaesthesia using chloroprocaine with adrenaline has a quick onset and moderate duration and is an attractive alternative to lidocaine and adrenaline or chloroprocaine alone for caesarean section. KEY WORDS: CHLOROPROCAINE; ADRENALINE; LIDOCAINE: CAESAREAN SECTION; EPIDURAL ANAESTHESIA; DURATION OF ANAESTHESIA; ONSET OF ANAESTHESIA Introduction Chloroprocaine is particularly suited to epidural anaesthesia, with a rapid onset time, excellent sensory and motor block, and rapid hydrolysis in the blood stream by pseudocholinesterase. The time to achievement of discharge criteria with chloroprocaine for ambulatory patients has been reported to be shorter than that with lidocaine, 1 bupivacaine, 2,3 articaine 4 and procaine 5 in spinal anaesthesia. In pregnancy, the activity of plasma pseudocholinesterase is decreased by 40 50%, but this seems to have little clinical effect on the metabolism of chloroprocaine. 6 The half-life of chloroprocaine in maternal plasma is < 60 s, 7,8 reducing systemic toxicity and fetal anaesthetic exposure. These characteristics of chloroprocaine account for its popularity in obstetrics. 1099

2 However, intraoperative analgesic supplementation as a result of insufficient duration of epidural anaesthesia may be required in parturients undergoing prolonged operation after delivery because of complications or accompanying diseases such as abnormal uterine bleeding or hysteromyoma. In such cases, repeat administration of epidural anaesthesia is disadvantageous to early recovery after childbirth because of prolonged motor block. A number of different drugs have been combined with chloroprocaine in order to determine which anaesthetic agents can maintain the rapid onset time whilst providing increased analgesic efficacy for epidural anaesthesia Although the addition of adrenaline to chloroprocaine for epidural anaesthesia in the normal parturient has been shown to have no adverse effects on mother, fetus, neonate or labour progress and to prolong significantly the duration of anaesthesia, 15 few studies have compared the effects of chloroprocaine with and without adrenaline with those of lidocaine with adrenaline in epidural anaesthesia for caesarean section. This prospective, randomized, double-blind trial was designed to determine whether duration of anaesthesia for 3% chloroprocaine with 1 : adrenaline was more prolonged than for 3% chloroprocaine alone or for 2% lidocaine with 1 : adrenaline. Patients and methods PATIENTS American Society of Anesthesiologists (ASA) class I parturients scheduled for elective caesarean section at the Nanjing Maternity and Child Health Care Hospital, Nanjing, China, between August 2010 and July 2011 were recruited to the study. Exclusion criteria included general contraindications for epidural anaesthesia, body weight > 80 kg or < 60 kg, height > 175 cm or < 150 cm, gestational age > 40 weeks or < 38 weeks, pre-eclampsia, hypertension of pregnancy, placental presentation, fetal distress, diseases of the heart, lung, liver or kidney, metabolic disorders, dehydration, electrolyte disorders, diseases of the central nervous system, neuromuscular disorders, and inability of the parturient to indicate pain severity using a visual analogue scale. In addition, women who subsequently required general anaesthesia before delivery or treatment with intravenous alfentanil after delivery for pain were also excluded from the study. Prior written informed consent was obtained from all the parturients and the study protocol was approved by the Ethical Committee of Nanjing Maternity and Child Health Care Hospital, Nanjing, China. RANDOMIZATION AND BLINDING Parturients were randomly allocated to one of three groups using sealed envelopes prepared before the start of the study: group C received 3% plain chloroprocaine (Kepunuo, Haisi Pharmaceuticals, Jincheng, Shanxi, China), group CA received 3% chloroprocaine with 1 : adrenaline, and group LA received 2% lidocaine with 1 : adrenaline. The parturient and the anaesthetists performing the block and monitoring the outcome measures were all blinded to the drug composition used. ANAESTHESIA TECHNIQUES In the operating room, parturients were connected to a bedside monitor (BSM-4113; Nihon Kohden, Tokyo, Japan) and the electrocardiogram, heart rate, pulse oximetry saturation, respiratory rate and invasive blood pressure via left radial artery cannulation were monitored continuously. After left cephalic vein cannulation, intravenous Ringer s lactate warmed to body 1100

3 temperature was infused at a rate of 15 ml/kg per h. Oxygen was supplied to all patients via a nasal catheter at a flow rate of 2 l/min. Epidural anaesthesia was performed in the right lateral decubitus position via the interspace between the second and third lumbar vertebrae using a midline approach. After insertion of an epidural catheter, the parturient was laid down in the 15 left lateral supine position and a 3 ml test dose of local anaesthetic was injected into the catheter by an anaesthesiologist. If no sign of spinal block was seen after 5 min, 12 ml of local anaesthetic solution was injected over 30 s. OUTCOME MEASURES Assessment of the outcome measures was undertaken by a second anaesthesiologist who was blinded to the anaesthetic combination used. The end of injection of the test dose was defined as the start of anaesthesia. Analgesia, loss of cold sensation and motor block At 1-min intervals, parturients were assessed for the onset of analgesia to pinprick, loss of cold sensation from 70% ethanol application to the 12th thoracic segment and motor block indicated by a score of 1 using the modified Bromage scale 16 (0, no motor block; 1, hip blocked; 2, hip and knee blocked; 3, hip, knee and ankle blocked). The highest level of anaesthesia was assessed by recording three consecutive pinprick measurements. The time to the highest level of anaesthesia was defined as the time taken to the first of three consecutive similar recordings. If the highest thoracic level of anaesthesia was below the tenth thoracic dermatome or above the second thoracic dermatome, the parturient was excluded from the study. Duration of analgesia, loss of cold sensation and motor block were assessed every 5 min from 20 min after the start of anaesthesia; these were defined as the time from the start of anaesthesia to the recovery of pinprick sensation, cold sensation from 70% ethanol or a modified Bromage scale score of 0, respectively. The time from the start of anaesthesia to the start of surgery was also noted. Blood pressure, heart rate and oxygen saturation If systolic blood pressure decreased to < 25% of baseline or < 90 mmhg, or if parturients complained of nausea or dizziness related to hypotension, 5 mg ephedrine was given as an intravenous bolus. This was repeated if blood pressure did not normalize within 2 min. The need for one or two doses of ephedrine was defined as mild or moderate hypotension, respectively. The need for three or more ephedrine injections or phenylephrine infusion was defined as sustained hypotension. If the heart rate fell to < 50 beats/min, 0.25 mg atropine was given as an intravenous bolus. This was repeated if the heart rate did not normalize within 2 min. Hypoxia was defined as a pulse oximetry saturation of < 95% for > 30 s or any reading < 90%. Pain Parturients were asked to evaluate any pain using a visual analogue scale (VAS), with 0 indicating no pain and 10 indicating the worst possible pain. The VAS score was recorded at the start of surgery, after delivery, after replacement of the uterus and at the end of surgery. For the purposes of the study, the presence of pain was defined as a VAS score of

4 Fetal and neonatal status and postdelivery uterine contraction Fetal heart rate was directly monitored via a scalp electrode. Neonates were evaluated using 1- and 5-min Apgar scores, umbilical venous and arterial blood acid base status at delivery, and assessment using the Neurologic and Adaptive Capacity Scoring System (NACS) 17 at 15 min, 2 h and 24 h postdelivery. Uterine contraction after delivery was classified as highly satisfactory (stiff uterus), satisfactory (moderately stiff uterus, additional oxytocin needed) or unsatisfactory (atonic uterus, additional oxytocin or operation needed). Complications All parturients received 100 µg sufentanyl in 100 ml of saline intravenously for postoperative pain relief, with a starting dose of 2.5 ml/h. Pain, nausea or itching after surgery were recorded. Parturients were assessed for the presence of neurological complications, including residual paraesthesia/dysaesthesia in the lower limbs or buttocks, until hospital discharge (normally 7 10 days postoperatively). STATISTICAL ANALYSES In order to detect a predicted difference of 2 min in the duration of analgesia among the three groups, a sample size of 18 patients per group was determined prospectively to give 90% power at a 5% significance level. Parametric variables were analysed using one-way analysis of variance. Categorical data were expressed as a percentage and were analysed using the χ 2 -test. A P-value of < 0.05 was considered to be statistically significant. Statistical analyses were performed using SPSS for Windows software, version 10.0 (SPSS Inc., Chicago, IL, USA). Results A total of 60 parturients were recruited to the study and assigned randomly to the three groups (n = 20 for each). Baseline demographic characteristics and surgical parameters are given in Table 1. There were no significant differences in demographic data, duration of surgery, blood loss or the volume of intravenous Ringer s lactate administered between the three groups. No women required general anaesthesia before delivery or treatment with intravenous TABLE 1: Baseline demographic characteristics and surgical parameters for the 60 parturients undergoing elective caesarean section under epidural anaesthesia with chloroprocaine (group C), chloroprocaine plus adrenaline (group CA) or lidocaine plus adrenaline (group LA) Characteristic or parameter (n = 20) (n = 20) (n = 20) Maternal height, cm 163 ± ± ± 6 Maternal weight, kg 69 ± 6 72 ± 6 70 ± 7 Maternal age, years 28 ± 3 30 ± 3 31 ± 4 Maternal gestational age, weeks 39.1 ± ± ± 0.6 Infant weight, g 3336 ± ± ± 388 Duration of surgery, min 40 ± ± 9 38 ± 11 Blood loss, ml 333 ± ± ± 51 Intravenous Ringer s lactate, ml 969 ± ± ± 212 Data presented as mean ± SD. 1102

5 alfentanil after delivery. Onset times of analgesia and motor block in group CA were similar to those in group C, but were significantly shorter than those in group LA (P < 0.01 for both; Table 2). The onset time of loss of cold sensation was similar in all three groups. Duration of analgesia, loss of cold sensation and motor block in group CA were significantly longer than for patients in group C, but were significantly shorter than for group LA (P < 0.01 for all; Table 2). Times from the start of anaesthesia to the start of operation and to the highest level of anaesthesia in group CA were comparable to those in group C, but were significantly shorter in both these group than in group LA (P < 0.05 for both; Table 3). The highest TABLE 2: Onset times and durations of analgesia, loss of cold sensation and motor blockade in the 60 parturients undergoing elective caesarean section under epidural anaesthesia with chloroprocaine (group C), chloroprocaine plus adrenaline (group CA) or lidocaine plus adrenaline (group LA) Parameter (n = 20) (n = 20) (n = 20) Onset Analgesia, min 3.8 ± ± ± 2.2 a,b Loss of cold sensation, min 6.4 ± ± ± 1.9 Motor block, min 12.8 ± ± ± 4.0 a,b Duration Analgesia, min 58 ± ± 18 a 136 ± 22 a,b Loss of cold sensation, min 57 ± ± 12 a 140 ± 25 a,b Motor block, min 46 ± 7 74 ± 20 a 108 ± 19 a,b Data presented as mean ± SD. a P < 0.01 compared with group C; b P < 0.01 compared with group CA (one-way analysis of variance). TABLE 3: Time course and maximum extent of anaesthesia in the 60 parturients undergoing elective caesarean section under epidural anaesthesia with chloroprocaine (group C), chloroprocaine plus adrenaline (group CA) or lidocaine plus adrenaline (group LA) Parameter (n = 20) (n = 20) (n = 20) Time from start of anaesthesia to highest 12.1 ± ± ± 2.7 a,b level of anaesthesia, min, mean ± SD Time from start of anaesthesia to start of 17.8 ± ± ± 3.1 a,b operation, min, mean ± SD Highest thoracic level of anaesthesia, 6.8 ± 1.3 (5 9) 6.8 ± 1.4 (4 9) 7.1 ± 1.3 (5 10) thoracic segment, mean ± SD (range) Maximum motor blockade (Bromage scale) 0, n (%) 0 (0) 0 (0) 0 (0) 1, n (%) 7 (35) 5 (25) 6 (30) 2, n (%) 10 (50) 12 (60) 10 (50) 3, n (%) 3 (15) 3 (15) 4 (20) a P < 0.05 compared with group C; b P < 0.05 compared with group CA (one-way analysis of variance). 1103

6 thoracic level of anaesthesia was comparable in all three groups and there were no statistically significant differences between the groups in the degree of motor block (Table 3). The results of the VAS pain assessment are given in Table 4. No parturients reported a VAS score 7 at any of the time points. VAS scores at the start of surgery, at delivery and at replacement of the uterus were similar in all three groups, but the percentage of patients reporting a VAS score of 4 6 at the end of surgery was significantly higher in group C than in groups CA and LA (P < 0.01 for both; Table 4). All parturients gave birth successfully under epidural anaesthesia. Intraoperative complications occurred with similar frequency in all three groups (Table 5). Parturients with bradycardia were successfully treated with 0.25 mg intravenous atropine. None of the fetuses developed abnormal heart rate patterns. Uterine contraction after delivery and neonatal blood acid base status were similar in the three groups (Table 6). There were also no statistically significant between-group differences in Apgar scores at TABLE 4: Visual analogue scale scores for pain in the 60 parturients undergoing elective caesarean section under epidural anaesthesia with chloroprocaine (group C), chloroprocaine plus adrenaline (group CA) or lidocaine plus adrenaline (group LA) (n = 20) (n = 20) (n = 20) Time point Start of surgery 20 (100) 0 (0) 20 (100) 0 (0) 20 (100) 0 (0) Delivery 20 (100) 0 (0) 20 (100) 0 (0) 20 (100) 0 (0) Replacement of uterus 14 (70) 6 (30) 17 (85) 3 (15) 16 (80) 4 (20) End of surgery 11 (55) 9 (45) 20 (100) a 0 (0) a 19 (95) a 1 (5) a Data presented as number (%) of patients. a P < 0.01 compared with group C (χ 2 -test). TABLE 5: Intraoperative complications in the 60 parturients undergoing elective caesarean section under epidural anaesthesia with chloroprocaine (group C), chloroprocaine plus adrenaline (group CA) or lidocaine plus adrenaline (group LA) Complication (n = 20) (n = 20) (n = 20) Hypotension 10 (50) 11 (55) 11 (55) Mild 5 (25) 6 (30) 8 (40) Moderate 5 (25) 5 (25) 3 (15) Sustained 0 (0) 0 (0) 0 (0) Bradycardia 0 (0) 1 (5) 1 (5) Nausea or vomiting 3 (15) 1 (5) 2 (10) Hypoxia 0 (0) 0 (0) 0 (0) No complications 7 (35) 7 (35) 6 (30) Data presented as number (%) of patients. 1104

7 TABLE 6: Uterine contraction after delivery and neonatal blood gas data in the 60 parturients undergoing elective caesarean section under epidural anaesthesia with chloroprocaine (group C), chloroprocaine plus adrenaline (group CA) or lidocaine plus adrenaline (group LA) Parameter (n = 20) (n = 20) (n = 20) Uterine contraction after delivery Highly satisfactory 14 (70) 16 (80) 15 (75) Satisfactory 6 (30) 4 (20) 5 (25) Unsatisfactory 0 (0) 0 (0) 0 (0) Umbilical vein blood gases ph 7.33 ± ± ± 0.05 PO 2, mmhg ± ± ± 2.91 PCO 2, mmhg ± ± ± 2.61 Base excess, mmol/l 5.23 ± ± ± 0.53 Umbilical artery blood gases ph 7.23 ± ± ± 0.03 PO 2, mmhg ± ± ± 2.52 PCO 2, mmhg ± ± ± 3.33 Base excess, mmol/l 6.13 ± ± ± 0.79 Data presented as number (%) of patients or mean ± SD. PO 2, partial pressure of oxygen; PCO 2, partial pressure of carbon dioxide. 1 and 5 min, NACS scores at 15 min, 2 h and 24 h or oxytocin consumption (data not shown). No serious postoperative side-effects or complications were recorded. Discussion Although the addition of adrenaline has been shown significantly to prolong the duration of epidural anaesthesia with both chloroprocaine 15 and lidocaine, 18 the effect of adding adrenaline has not been directly compared for these two anaesthetics. A short duration of analgesia may be insufficient for surgery, whereas a long duration may be unfavourable for quick recovery after childbirth. The aim of the present study was to compare the duration of anaesthesia following a single dose of different anaesthetic agents. The findings demonstrated that the addition of adrenaline to chloroprocaine provided a moderate duration of analgesia, loss of cold sensation and motor blockade that was shorter than that produced by lidocaine with adrenaline but longer than that provided by chloroprocaine alone. Abboud et al. 15 reported that 2% chloroprocaine with 1 : adrenaline significantly prolonged the duration of analgesia compared with 2% chloroprocaine alone (time from onset of pain relief until onset of discomfort was 76.4 ± 3.8 min and 42.9 ± 1 min, respectively). In the present study, the duration of analgesia, loss of cold sensation and motor blockade in group CA were longer than in group C but shorter than in group LA. On the basis of the present results, if the time from anaesthesia to operation is 20 min and the duration of surgery is 40 min, with complications or accompanying diseases possibly prolonging surgery by a further 20 min, 3% chloroprocaine with 1 : adrenaline would provide an appropriate length of anaesthesia, whereas the duration of anaesthesia provided by 3% plain 1105

8 chloroprocaine would be too short and that provided by 2% lidocaine with 1: adrenaline would be too long. In a study by Bjørnestad et al., 9 2% lidocaine with 5 µg/ml adrenaline and 3% chloroprocaine had similar rapid onset times to achieve loss of cold sensation at the level of the fifth thoracic segment for epidural anaesthesia in elective caesarean section. This is consistent with the results of the present study, which showed that there were no significant differences in the loss of cold sensation onset times between the three groups. However, the onset times of analgesia and motor blockade were significantly longer in group LA than in groups C and CA, but with similar highest thoracic level of anaesthesia and maximum degree of motor blockade. At the end of surgery, 45% of the parturients receiving chloroprocaine (group C) experienced moderate pain (VAS score 4 6), indicating that when used alone this narcotic provided insufficient duration of analgesia. Although 10 parturients in group C, 11 in group CA and 11 in group LA developed intraoperative hypotension, and one parturient in each of group CA and group LA had bradycardia at delivery, these complications were not serious and were easily treated with ephedrine or atropine, respectively. There were no other serious maternal, fetal or neonatal complications. Placental transfer of chloroprocaine is not influenced by fetal acidosis 19 and chloroprocaine with adrenaline has been demonstrated to be safe for epidural anaesthesia in elective caesarean section, with no adverse effects on mother, fetus, neonate or the progress of labour. 15 In contrast, lidocaine has been reported to increase arterial carbon dioxide tension and decrease ph, mean arterial blood pressure and blood flow to the brain, heart and adrenals in asphyxiated baboon fetuses. 20 These characteristics increase the disadvantages of lidocaine if a serious situation develops during delivery. In conclusion, the present study demonstrated that chloroprocaine with adrenaline provides a moderate duration of anaesthesia, with no serious maternal, fetal or neonatal effects, and is suitable for epidural anaesthesia for elective caesarean section. Acknowledgements This study was supported in part by grant YKK08119 from the Nanjing Municipal Medical Science Development Foundation, Nanjing, Jiangsu, China, and grant 08NMUM063 from the Science and Technology Development Foundation of Nanjing Medical University, Nanjing, Jiangsu, China. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 17 December 2011 Accepted subject to revision 29 December 2011 Revised accepted 1 March 2012 Copyright 2012 Field House Publishing LLP References 1 Hejtmanek MR, Pollock JE: Chloroprocaine for spinal anesthesia: a retrospective analysis. Acta Anaesthesiol Scand 2011; 55: Lacasse MA, Roy JD, Forget J, et al: Comparison of bupivacaine and 2-chloroprocaine for spinal anesthesia for outpatient surgery: a doubleblind randomized trial. Can J Anaesth 2011; 58: Yoos JR, Kopacz DJ: Spinal 2-chloroprocaine: a comparison with small-dose bupivacaine in volunteers. Anesth Analg 2005; 100: Förster JG, Kallio H, Rosenberg PH, et al: Chloroprocaine vs. articaine as spinal anaesthetics for day-case knee arthroscopy. Acta Anaesthesiol Scand 2011; 55:

9 5 Gonter AF, Kopacz DJ: Spinal 2-chloroprocaine: a comparison with procaine in volunteers. Anesth Analg 2005; 100: Shnider SM: Serum cholinesterase activity during pregnancy, labor and the puerperium. Anesthesiology 1965; 26: Kuhnert BR, Kuhnert PM, Prochaska AL, et al: Plasma levels of 2-chloroprocaine in obstetric patients and their neonates after epidural anesthesia. Anesthesiology 1980; 53: Kuhnert BR, Kuhnert PM, Philipson EH, et al: The half-life of 2-chloroprocaine. Anesth Analg 1986; 65: Bjørnestad E, Iversen OL, Raeder J: Similar onset time of 2-chloroprocaine and lidocaine + epinephrine for epidural anesthesia for elective Cesarean section. Acta Anaesthesiol Scand 2006; 50: Davis BR, Kopacz DJ: Spinal 2-chloroprocaine: the effect of added clonidine. Anesth Analg 2005; 100: Karambelkar DJ, Ramanathan S: 2- Chloroprocaine antagonism of epidural morphine analgesia. Acta Anaesthesiol Scand 1997; 41: Polley LS, Columb MO, Lyons G, et al: The effect of epidural fentanyl on the minimum local analgesic concentration of epidural chloroprocaine in labor. Anesth Analg 1996; 83: Johnson C, Ransil BJ, Oriol N: Comparison of onset time between 0.5% bupivacaine and 3% 2-chloroprocaine with and without 75 micrograms fentanyl. Reg Anesth 1991; 16: Brooks GZ, Donchin Y, Collins JG, et al: Epidural morphine does not affect the duration of action of epidural 2-chloroprocaine following Caesarean section. Can Anaesth Soc J 1983; 30: Abboud TK, DerSarkissian L, Terrasi J, et al: Comparative maternal, fetal, and neonatal effects of chloroprocaine with and without epinephrine for epidural anesthesia in obstetrics. Anesth Analg 1987; 66: Bromage PR: A comparison of the hydrochloride and carbon dioxide salts of lidocaine and prilocaine in epidural analgesia. Acta Anaesthesiol Scand Suppl 1965; 16: Amiel-Tison C, Barrier G, Shnider SM, et al: A new neurologic and adaptive capacity scoring system for evaluating obstetric medications in full-term newborns. Anesthesiology 1982; 56: Abboud TK, David S, Nagappala S, et al: Maternal, fetal, and neonatal effects of lidocaine with and without epinephrine for epidural anesthesia in obstetrics. Anesth Analg 1984; 63: Philipson EH, Kuhnert BR, Syracuse CD: Fetal acidosis, 2-chloroprocaine, and epidural anesthesia for cesarean section. Am J Obstet Gynecol 1985; 151: Morishima HO, Covino BG: Toxicity and distribution of lidocaine in nonasphyxiated and asphyxiated baboon fetuses. Anesthesiology 1981; 54: Author s address for correspondence Dr Shan Wu Feng State Key Laboratory of Reproductive Medicine, Department of Anaesthesiology, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, 140 Hanzhong Road, Nanjing , China. shanwufeng@163.com 1107