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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENSE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES - - TRAN DUC THO EFFECTIVENESS OF LEVOBUPIVACAIN COMBINED WITH SUFENTANIL OR FENTANYL OR CLONIDIN BY PATIENT CONTROLLED EPIDURAL ANALGESIA (PCEA) IN CONTROLLING POSTOPERATIVE PAIN IN PATIENTS WITH UPPER ABDOMINAL SURGERIES Specialism: Code: Anesthesia Reanimation 62.72.01.22 THE SUMMARY OF MEDICAL DOCTORAL THESIS HANOI - 2017 THE THESIS HAS BEEN COMPLETED AT 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES Scientific supervisor: Prof.PhD NGUYEN QUOC KINH Opponent 1: Pro Ph.D NGUYEN QUOC ANH Opponent 2: Pro Ph.D NGUYEN VAN HIEU Opponent 3: Pro Ph.D NGUYEN MINH LY Doctoral thesis will be evaluated at thesis evaluation council at 108 Institute of Clinical Medical and Pharmaceutical Sciences On: ………………, ……… /………./ 2017 You can find the thesis at: The National Library Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences INTRODUCTION Upper abdominal postoperative pain (UAPP) is prolonged and intensive Many pain management methods have been deployed to control the pain, including intravenous nonsteroid drugs, intramuscular or intravenous morphine and epidural analgesia (EA) However, these methods have not brought expected outcome and also patients are passive in controlling their pain Patient Controlled Epidural Analgesia (PCEA) has been proved to be an effective method to manage posoperative pain from upper abdominal surgeries, with reduced dose of analgesics, improved respiratory functions and less postoperative adverse events Levobupivacain, an isomer of bupivacaine, had similar pain control efficacy as bupivacaine, but with less systemic side effects, especially on cardiovascular and central nervous systems Combining levobupivacain with reduced doses of other adjuvant analgesics (i.e fentanyl, sufentanil or clonidine) has been a multidisciplinary approach of pain management, preferred by renowned surgery centers in the world However, the pain control effect and adverse event profiles are various among centers, due to the differences in the mechanism of the adjuvant analgesics In Vietnam, there has been inadequate research on combining and comparing the mentioned adjuvant analgesics in UAPP management by PCEA Therefore, we conducted the study of “effectiveness of levobupivacain combined with sufentanil or fentanyl or clonidine by patient controlled epidural analgesia (PCEA) in controlling postoperative pain in patients with upper abdominal surgeries” in order to provide more scientific evidence in this issue Research objectives - To compare the efficacy of postoperative pain control of levobupivacain 0,125% in combination with sufentanil ug/ml or with fentanyl ug/ml or with clonidine ug/ml by PCEA, in patients with upper abdominal surgeries - To assess the side effects on circulatory, respiratory systems and other unexpected events of levobupivacain 0,125% in combination with sufentanil ug/ml or with fentanyl ug/ml or with clonidine ug/ml used through epidural catheter in PCEA 2 Relevance of the study Postoperative pain is considered as the fifth vital sign and as an essential part of human rights However, management of postoperative pain has not been paid adequate attention, even in major surgery centers in Vietnam - PCEA, an innovative approach in managing acute postoperative pain, has been proved to be effective and preferred among many surgical centers in the world The selection of drug combination in PCEA is based on the balance between the effectiveness of pain control and the reduction of side effects Implications from the study - This research studied extensively the epidural analgesia efficacy and compare the combination of levobupivacain with fentanyl or fentanyl or clonidine by PCEA in patients with upper abdominal surgeries - Evaluated the influence on respiratory and cardiological functions of levobupivacain in combinations with sufentanyl or fentanyl or clonidine, using PCEA in patients with upper abdominal surgeries - The results confirmed that levobupivacain PCEA is more effective when combined with fentanyl than with sufentanyl or clonidine in managing UA postoperative pain management Structure of the research report - The thesis report was 142 pages long, including pages of introduction, 38 pages of literature review, 22 pages of research methods and study populations, 33 pages of study results, 44 pages of discussion, pages of conclusion and page of recommendation sections - The research report included 33 tables, 13 charts and 17 figures The references includes 142 articles (19 in Vietnamese and 123 in English) Chapter LITERATURE REVIEW 1.1 Upper abdominal postoperative pain (UAPP) Upper abdominal postoperative pain (UAPP) is among the most intense and persistant pains It is caused by the tissue damages of the skin, muscles, ligaments and viscerals Pain signals are transmitted from the damanged tissues to the central nerves through a reflectory arch which consists of neurons This pain perception process includes mechanisms of inflamatory, visceral pain and neuronic pains 1.2 Assessment of postoperative pain 1.3 Methods of UAPP assessment To date, there has not been an optimal method for UAPP pain control Commonly used methods included using NSAID, using opioids and epidural analgesia IV-PCA and PCEA have been preferred and widely used in major surgery centers in the world Current approach in pain management deployed a multidisciplinary method to improve pain control efficacy and reduce the unwanted side effects of the analgesics Besides, other factors, including shortening the operation time, reducing tissue and neuron damages, also are relevant in the strategy of optimizing postoperative pain control 1.4 Patient controlled epidural analgesia (PCEA) in upper abdominal surgeries Patient controlled epidural analgesia (PCEA) is an innovative EA with active participation of the patients There have been a wealth of study proved the advantages of this approach, including improved effectiveness, more patient satisfaction, less medication consumption, less inhibition of sympathetic receptors and motor receptors, comparing to intermittent or contiuous i.v CEA in UAPP control Behera (2008) found that PCEA was more effective than IV-PCA in post lung surgery, both at rest and while ambulating Nightingale (2007) compared pain control efficacy of epidural analgesias by PCEA or CEI in major abdominal surgeries within 72 hours postoperative The author concluded that PCEA was more effective and induced less side effects than CEI Patient satisfactory scores were also higher in PCEA (84%) group than in CEI group (57%) 1.5 Literature review in epidural analgesia using levobupivacain combined with opioids or clonidine Kopacz (1999) conducted a double blind trial to compare postoperative analgesic effectiveness of levobupivacain in combination with fentanyl or fentanyl only using PCEA in patients with knee joints repacement The result showed that combining levobupivacain-fentanyl was more effective than single fentanyl Essam Mahran (2014), concluded that fentanyl 2µg/ml or clonidin 2µg/ ml could be used as adjuvant analgesics combining with levobupivacain 0,125% in EA pain control for patients with urine bladder surgeries, with similar results in vital signs, pain control efficacy, sedative effects and safety profile De Cosmo (2007) used levobupivacain 0,125% combined with sufentanil µg/ml and gained satisfactory pain control results, with mean VAS scores of 1.54 at hour and 0.54 at hour 48 resting after operation All the patients were hemodynamically stable, without any respiratory failures during the studied time Chapter STUDY SUBJECTS AND RESEARCH METHODS 2.1 Study subjects - Studied subjects were the patients with upper abdominal open surgeries performed in the General Surgery Department of K hospital from April 2012 to April 2014 - Inclusion criterias: + Planned surgery under endotracheal intubation anesthesia Analgesic drugs were administered through epidural space + Age ≥ 18 years old + ASA I, II + Controlled respiratory, endocrinology disorders Normal kidney, liver and coagulation profiles + Patients were able to and effectively cooperate to use PCEA + Patients are in alert state, able to control the EA devices + No contraindication for epidural analgesia - Exclusion criterias: + Inserting a thoracic epidural catheter is not possible + Severe surgical or anesthesic complications + Early re-operated due to surgical complications + Incompletely data collected, patients refuse continuing PCEA, or refuse the postoperative tests for air-flow and artery blood gas + Post operative unstable mental state + Ineligible to remove the intubation in recovery room, need respiratory support + Liver and kidney failures 2.2 Research methods 2.2.1 Study design This study is a single blind, comparative, prospective, random clinical trial 2.2.2 Sample size - Sample size n1 = n2 = n3 = 50 - Study arms: + Arm (L-C): Used levobupivacain 0,125% - clonidin µg/ml for postoperative pain by PCEA + Arm (L-F): Used levobupivacain 0,125% - fentanyl µg/ml for postoperative pain by PCEA + Arm (L-S): Used levobupivacain 0,125% - sufentanil µg/ml for postoperative pain by PCEA 2.2.3 Study procedures - Necessary equipments - Pre-operative evaluation: air-flow test and artery blood gas test - Catheterization and anesthesia  Inserting the catherter to epidural space and ensure the catheter head is between T7, T8 epidurally  Performing the anethesic process as per protocol for three arms  Criterias for intubation removal: + Alert, well responded to verbal orders + Self breath, positive cough reflex + Abdomen-chest combined breath, without participation of adjuvant respiratory muscles + Respiratory rate < 25 bre/min, Vt > ml/kg + SpO2> 95% (room air) + TOF ≥ 0,9 + No hypothermia (< 36o C), hemodynamically stable - Carrying out postoperative pain control and postoperative monitoring  Creterias for PCEA + Alert + Stable vital signs + Able to self evaluate the pain score, using pain scale * If VAS < then re-evaluated after 15 mins * If VAS > then started the postoperative pain control measures This was time H0 in the study  Starting dose Injecting the drugs via epidural catheter with levobupivacain 0.25% (with adrenalin 1/200.000) for three arms, with the injection volumes were calculated as follow: Chiều cao (cm) - 100 Injection volume = 10 After the induction dose, the level of skin sensory inhibition was measured by cold test or prick test Dermatomes were therefore identified accordingly depending on the analgesic effect of the drugs - PCEA + The drug cocktail for each study arms were as follows : * Arm (L-C) used the combination of levobupivacain 0,125% + clonidin 2µg/ml * Arm (L-F): used the combination of levobupivacain 0,125% + fentanyl 2µg/ml * Arm (L-S): used the combination of levobupivacain 0,125% + sufentanyl 1µg/ml + PCA parameter set-up: * Bolus dose: ml * Lockout interval: 10 minutes * Background infusion rate : ml/h * Total drug in hour: 12 ml During the studied time, if patient was still in unbearable pain after three bolus doses, a « pain rescue » dose of ml of combined analgesics L-C, L-F or L-S correspoding to the research arms, was injected into the epidural space, to attain the VAS score < All the set up PCA parameters remained unchanged + Catheter was removed after 72 hours of PCEA - Artery blood was obtained for blood gas testing - Patients were instructed to blow the peak flow meter for air-flow test - Monitored time points 2.2.4 Main evaluating parameters Study objective 1: - Catheter inserting point, level of pain sensory inhibition - Onset time of pain control - VAS score at rest and percentage of Oates scale reduction compared between research groups - VAS score when coughing, while ambulating and percentage of Oates scale reduction compared between research groups - Need of using PCEA and need of using the “rescue dose” + Number of Demand (D) and number of Actual (A), rate of A/D (%) + Number of “rescue dose”, the average time length from starting the PCEA to the first “rescue dose” - Amount of consumed analgesic and adjuvant drugs: + Volume of the induction analgesics + Comparing the amount of levobupivacain used in three groups, on day 1, day 2, day and total amount for days + Amount of adjuvant drug used in three groups - Time points when patients were able to sit up and pass gas - Patient satisfaction with pain control in three groups Study objective 2: - Impact on respiratory functions: + Changes of respiratory rate + Changes of SpO2 + Changes of peak flow (PEF) at 24 hours, 48 hours and 72 hours + Changes of artery blood gases at 24 hour and 48 hours: Blood oxygen (SaO2, PaO2, PaO2/FiO2), alkaline-acid balance (PaCO2, pH, HCO3, BE, AaDO2, a/AO2) - Impact of circulatory functions: heart beat frequency, blood pressure - Other adverse effects: + Sedation + Nausea and vomit + ischuria + Pruritus + Motor block + Catheterization related complications (epidural bleeding, epidural rupture, catherter dislocation and infection) 2.2.5 Other parameters - Studied population characteristics - Anesthesia and surgery: + Time length of anaesthesia and operation + Features of the skin cut : type and the length of skin cut, distance from the epigastrium to the proximal end of the skin cut - Respiratory function test 2.2.6 Criterias and definition used in the study 2.2.7 Data management - Data was collected and analyzed by SPSS 16.0 software - Data was presented by : + Quantitative paramaters: X ± SD + Qualitative parameters: n (%) - Comparation of differences: • Quantitative paramaters: One sample T test was used to compare two means in one group, T-student test to compare two independent means, and ANOVA test to compare more than two means P value of < 0,05 was considered statistically significant • Qualitative parameters: χ2 was used to test using 2x2 table, Fisher exact test was used when a single n was smaller than 2.2.8 Research ethics 2.2.9 Study algorimth Chapter STUDY RESULTS 3.1 Studied population charecteristics Patient charecteristics was presented in table 3.1, table 3.2, table 3.3, table 3.4, table 3.5, table 3.6 and table 3.7 There were not statistically differences among studied groups of patient 3.2 Parameters to evaluate the pain control efficacy Table 3.8: Volume of induction doses and inhibited dematomes 11 - Number of demand in group LF was significantly lower than of groups LC and LS, p < 0,01 - Rate of actual/demand (A/D) in group LF was significantly lower than of groups LC and LS, p < 0,01 Table 3.14: Number of patients require, and did not require, the “pain rescue doses“ - There were 18 patients in group LF need one rescue dose (36.0%) In group LC, 19 (38.0%) patients need one rescue dose and (14%) patients need two rescue doses In group LS, 21 (42.0 %) patients need one rescue dose and (8.0%) patients need two rescue doses All the rescue doses were used within the first 24 hour postoperative - The mean of rescue doses in groups LF was significantly lower than in groups LC and LS, p* < 0,05 Table 3.15: Time to the first rescue dose - Time to the first rescue dose was shortest in group LS and longest in groups LF The differences of time to the first rescue doses of the † three groups were significant statistically, p*, < 0,05 Chart 3.5 Kaplan - Meier curve of the time to the first “pain rescue” dose of the three groups 12 Table 3.16: Amount of levobupivacain used Group Total amount (mg) 0-24h min-max 24-48h min-max 48-72h min-max Group LC (n=50) X ± SD Group LF (n=50) X ± SD Group LS (n=50) X ± SD 154,58±13,96 132,50-187,50 126,15±9,65 105,0-150,0 98,95±9,82 72,5-117,5 133,40±9,62* 115,0-155,0 103,75±9,64* 77,5-122,5 75,5±4,13* 67,5-122,5 0-72h min-max 379,68±20,86 336,25-427,50 312,65±17,50* 263,75-345,00 150,78±12,21 127,5-187,5 126,35±8,15 110,0-147,5 98,25±9,56 72,5-117,5 375,38±14,75 340,00410,00 5,27±0,29 4,34±0,24 5,21±0,20 < 0,05 < 0,05 < 0,05 Mean dose (mg/h) p” p < 0,001 < 0,001 < 0,001 < 0,001 < 0,001 - Mean amount of levobupivacain used were highest in the first day and lowest in the third day postoperative (p” < 0,05) - Group LF required the lowest total dose of levobupivacain for post operative pain control, p* < 0,001 Table 3.17: Amount of adjuvant drugs of Fentanyl, Clonidin Sufentanil used in thr three groups The mean amounts of clonidin, fentanyl, sufentanil were highest in the first day and lowest in the third day after surgery (p” < 0,05) Table 3.18: Level of patient satisfaction - At hour 72, the parcentages of patient with full satisfaction were 88%, 84% and 76% respectively in groups LF, LS and LC - The differences of patient satisfaction levels were not statistically significant Table 3.19: Time to first sit-up and gas-passing Time to the fisrt sit-up and gas passing was shortest in group LF, with statistically significant difference to other two groups, p* < 0,05 13 3.3 Parameters to assess adverse effects, including the impact on the respiratory and circulatory systems Table 3.20: Heart rate (beats/min2) Heart rate in the LS group was significantly lower than in the other two groups, recorded at times of H4, H6, H8, H16, p¥ † < 0,01 Table 3.21 and table 3.22: Systolic and diastolic blood pressures (mmHg), over time - Systolic BP and diastolic BP in LC and LS groups were lower than in LF group The differences were statistically significant at H2, H4, H6, H8, H16, p* < 0,05 Table 3.23: Sedative level, measured by Ramsay scale - During the analgesia, sedative levels of the three groups were in normal ranges At times of H8 and H36 the sedative in LF group was better than in LS and LC groups, p* < 0,05 Table 3.24: Respiratory rate (breath/min) - After the analgesic induction, respiratory rates of the three groups were all decreased comparing with the time H0 (p” < 0,05) - Respiratory rate of groups LS was lower than in groups LF and LC at times H2, H4, H6, H8, H16, p¥,† < 0,05 Table 3.25: SpO2 change over time (%) - SpO2 in the three groups were similar and in clinically acceptable ranges Table 3.26: PEF index (L/s) Group Time point Pre-operation H24 H48 H72 p” Group LC (n=50) Group LF (n=50) Group LS (n=50) X ± SD X ± SD X ± SD 6,70 ± 1,90 4,25 ± 1,20 4,22 ± 1,20 4,69 ± 1,33 < 0,05 6,45 ± 1,84 5,18 ± 1,48* 5,32 ± 1,52* 5,86 ± 1,67* < 0,05 6,93 ± 1,73 4,36 ± 1,09 4,53 ± 1,13 4,75 ± 1,19 < 0,05 P > 0,05 < 0,001 < 0,001 < 0,001 - The peak flow indexes were similar in the three groups at preoperation On day one after surgery, the peak flow sharply decreased in all three groups and then recovered on day and day 3, p'' < 0,05 Peak flow in LF groups decreased less and better recovered than in the remaining groups, p* < 0,01 14 Table 3.27: Changes of blood oxygen - SaO2 index tended to remain unchanged in the three groups - The indexes of PaO2 and PaO2/FiO2 decreased after 24 hours and continued to decrease after 48 hours The indexes in LF group had decreased less comparing to other groups, p* < 0,05 Chart 3.12 Change of blood PaO2 Table 3.28: Changes in blood gases and alkaline-acid balance - Patients tended to have postoperative metabolic alkalosis comparing to pre-operative, especially at day after surgery The differences in HCO3- and BE at day postoperative were statistically significant, p < 0,05 - PaCO2 values were not significantly different among groups over time, p > 0,05 Table 3.29: Changes of the indexes related to ventilation disorder Group Index AaD O2 (mm Hg) a/AO2 (%) p” Preoperation H24 H48 Preoperation H24 H48 LC Group (n=50) X ± SD 16,73±2,52 LF Group (n=50) X ± SD 17,07±4,25 LS Group (n=50) X ± SD 17,81±4,94 > 0,05 24,23±9,09 27,46±8,25 84,2±2,0 19,81±7,79* 22,20±7,64* 83,8±4,4 23,80±11,71 25,37±8,00 83,2±5,1 < 0,05 < 0,01 > 0,05 77,7±7,7 73,9±7,4 < 0,05 82,0±7,3* 77,8±6,6* < 0,05 78,5±9,3 74,8±6,42 < 0,05 < 0,05 < 0,05 P 15 - Index of AaDO2 in the LF group increased less than in LS and LC groups, p* < 0,05 - Index of a/AO2 in LF group decreased less than in LS and LC, p* < 0,05 Table 3.30: Adverse effects - Adverse effects of pruritus and ischuria were similar among the three groups - Rates of neausia and vomiting in the LS group were higher than in the other two groups - There was no events of epidural rupture, catheter dislocation to epidural space, epidural bleeding and insertion site infections in all three groups There was no patients with limb motor blocks during the study Chapter DISCUSSION 4.1 Study population characteristics The features of age, sex, height, weight, pulmonary function at preoperation, natures of sugery and types of surgery were not significantly different among the three groups It is therefore confirmed the homogeneity of the studied populations The needle insertion sites of the three groups were T7-T10, aiming for the catherter head was placed in the epirual spaces of T7 and T8 which is considered proper for upper abdominal surgeries The mean volume of induction analgesics of the three groups was 6,11 ± 0,62 ml, ranging from 4,7 ml to 7,5 ml The mean number of inhibited dematomes was 6,75 ± 1,02 This was similar to Visser’s study in which 1-1,5 ml of analgesic drugs used epidurally for one dermatome to be inhibited In Vietnam, according to Ton Duc Lang, each 1,5 ml of analgesic can inhibit one dematome The mean onset time of pain control after the induction dose to VAS < in all three groups 9,03 ± 1,93 minutes This similar onset time was also observed in the study by Nguyen Van Quy (9,0 ± 1,2 minutes) 16 4.2 Concentration selection Selecting the optimal concentration of analgesic and adjuvant drugs was based on the equilibrium between pain control effect and adverse effects According to Murdoch, when levobupivacain was used at concentration of > 0,15%, motor block and postural hypotension were more frequently occurred It was recommended to use levobupivacain at the concentrations of 0,0625 % to % In this study we used levobupivacain 0,125 %, because it was evidenced in published literature that with this concentration, sensing function was blocked but motor funtion was not According to Liu Spencer, fentanyl when used as an adjuvant, concentrations of 2-5 µg/m was considered proper Studies by Berti, Ozalp, Arip Yegin, Nguyễn Văn Quỳ and Nguyễn Tiến Đức used fentanyl µg/ml in combination with analgesics in epidural pain control and achieved satisfactory results, with less adverse effects and no respiratory failure Sufentanil was usually used epidurally with concentration of 0,5 – µg/ml According to Singh V high concentration of sufentanil would not only improve pain control efficacy but also increase risk of over sedation Studies by De Cosmo, Laveaux, Mourisse, Smet I., Snijdelaar all confirmed that sufentanil µg/ml in combination with analgesics in epidural approach would obtain optimal balance of pain control and advers effects Doses of clonidine when used in combination with epidural analgesics, was recommended to be less than 20 µg/h in order to reduce sedation and postural hypotension Essam A indicated that the pain control efficacy was similar with levobupivacain 0,125% in combination with either fentanyl µg/ml or clonidine µg/ml 17 4.3 Pain control efficacy 4.3.1 Comparation of pain control efficacy between groups The mean VAS postoperative scores at rest of the three the studies by Tekelioglu U I., De Cosmo and Essam A Mahran Our study showed that VAS score of groups LF was lower than of groups LC and LS, at all time points, significantly p < 0,05 From the time H4, 100% of the patients in group LF obtained the good level of pain control at rest (VAS ≤ 2) Similar results were obtained in groups LC ans LS from H8 time point During the study, the VAS scores of groups LC and LS were similar in the first 36 hours (p † > 0,05) From hour 48 to 72, the VAS score of group LS was significantly lower than of the group LC, with p† < 0,05 It was likely that sufentanil which is dissolvable in lipid had been effective in combination with levobupivacain 0,125% and brought better effect in pain control compared with clonidine 4.3.2 Pain control when coughing and while ambulating Levels of postoperative ambulating were measured by coughing, deep inhaling, knee inwarding and thigh inwarding in bed After 24 hours of operation, if pain was well controlled, then patients would be able to sit up, stand up, walk slowly around bed One hundred percent of the patient in the groups LF, LC and LS achieved VAS ≤ After analgesic induction the mean VAS scores (table 3.1.1) in the three groups were lower than at time H0 (p'' < 0,05) In the first 48 hours after surgery, the VAS score of group LF was always lower than that of groups LC and LS (p < 0,05), from hour 48 to 72, the VAS scores were not different among the three groups p > 0,05 Althought the VAS scores of LC and LS groups were higher than the LF group, they were still in good clinical range After 16 hours of analgesia, 100% of patients in LC and LS groups achieved complete pain control or mild pain while ambulating (VAS ≤ 3), confirming the effectiveness of drug combination and PCEA set-up Studies by De Cosmo et al in postoperative analgesia with levobupivacain 0,125% + sufentanil µg/ml in thoracic surgeries found 18 that the mean VAS score while ambulating in the first 48 hours were 1,7 to2,7 points Smet I., when compared pain control efficacy by PCEA between groups of levobupivacain 0,125% + sufentanil µg/ml and ropivacain 0,165% + sufentanil µg/ml in orthopedic surgeries, found that the pain control effectiveness was similar between the two groups The mean VAS score of levobupivacain 0,125% + sufentanil µg/ml group when coughing at hour 48 was less than It is therefore concluded that the drugs in the LF group were the most effective combination comparing to other two groups 4.3.3 Assessment of PCEA Number of demand (D) and rate of Actual (A/D) For the first 72 hours, the mean number of demand in group LF (57,8 ± 6,8 times) was significantly lower than group LS (94,0 ± 5,4 times) and group LC (99,0 ± 9,8 times), with p* < 0,001 However, the rate of successful demand (A/D rate) in group LF (89,9 ± 3,0 %) was significantly higher than in groups LS (81,7 ± 6,1 %) and LC (79,0 ± 1,0%) Comparing rates among groups showed that the A/D rate was highest in group LF, lowering in group LS and group LC, with p*,† 0,05 (table 3.18) 4.3.5 Time to recovery Time to the first sit-up (table 3.19) in group LC was 19,5 ± 3,2 (hours), in group LF was 17,8 ± 2,2 (hours) and in group LS was 19,1 ± 3,3 (hours) with p* < 0,05 Time to the first gas-passing was 38,3 ± 6,7 (hours) in group LF, significantly shorter than in groups LC (41,6 ± 6,9) and LS (41,1 ± 5,4), with p* < 0,05 (table 3.19) Being able to sit up and pass gas would reduce the abdominal bloating, enable the patients to reduce the risk of respiratory failure and facilitate the wound healing process Patients, therefore would be more ambulatory and reduce the time of postoperation recovery 4.4 Adverse effects 4.4.1 Sedation and effects on circulatory system 4.4.1.1 Changes in heart rate Heart rates of all three groups were decreased compared with the H0 time, accompanied with the decreases in VAS scores at rest and when coughing Pain was, therefore, the factor that contributed to the increased heart rate by stimulating the sympathetic system Heart rate of the group LS was significantly lower compared with other two groups at H4, H6, H8, H16, (with p† < 0,01 and p¥ < 0,001) However, there was no patients with heart rate less than 50 b/min that required atropine, as a result of sympathetic system inhibition All three groups had heart rates in the safe ranges 20 4.4.1.2 Change of blood pressure Systolic and diastolic BPs of the three groups were slightly decreased after the analgesics induction Blood pressures of groups LC and LS were more decreased than in group LF at times from H2 to H16, as a result of using more analgesics in the first day which increased the sympathetic inhibition that caused BP decreases However, BP in all three groups were in the safe limits 4.4.1.3 Changes in level of sedation As presented in the table 3.23, sedation scores of the three groups after the analgesia were higher comparing to that of time H0 (p 0,05 4.4.5.4 Limbs motor block There was no patient in any studied groups had symptoms of motor block during our studied timeframe 4.4.5.5 Complications of epidural catheterization There was no patient in any studied groups had complications of epidural injuries, nervous demages, epidural emboli or abces or nervous system toxicity CONCLUSIONS The study was to compare the PCEA pain control efficacy of three combinations of levobupivacain 0,125% with clonidine 2µg/ml, or fentanyl 2µg/ml or sufentanil 1µg/ml in 150 patients with upper abdominal surgeries, in the (K) National Cancer Hospital from 4/2012 to 4/2014 Belows are the conclusions from our reseach: 23 Pain control efficacy The patient controlled epidural analgesia (PCEA) using either combinations of LF, LS, LC achieved expected pain control outcomes and full satisfaction from patients (LF: 88%; LS: 84%; LC: 76%) However, the pain control efficacy in LF was significantly higher compared with other two groups of LC and LS (p