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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES TRAN HOAI NAM RESEARCH ON THE EFFICACY OF PATIENT CONTROLLED THORACIC EPIDURAL ANAL[.]
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES TRAN HOAI NAM RESEARCH ON THE EFFICACY OF PATIENTCONTROLLED THORACIC EPIDURAL ANALGESIA WITH ROPIVACAINE COMBINED WITH FENTANYL AFTER LAPAROTOMY Speciality: Anesthesiologist-rescusitation Code: 62.72.01.22 ABSTRACT OF MEDICAL PH.D THESIS Hanoi – 2022 THE THESIS WAS DONE AT: 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES Supervisor: Ph.D Hoang Van Chuong Ass Prof Ph.D Nguyen Minh Ly Reviewer: This thesis will be presented at Institute Council at 108 Institute of Clinical Medical and Pharmaceutical Sciences Day Month Year The thesis can be found at: National Library of Vietnam Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences Central Institute for Medical Science Information and Technology INTRODUCTION Open abdominal surgery is one kind of surgery that causes pain and affects the functioning of the organ systems The early postoperative recovery care program is increasingly being applied in clinical practices, where postoperative pain relief plays a key role There are many analgesia measures to relieve postoperative pain, of which epidural analgesia is considered the standard for open abdominal surgery (colorectal surgery, hepatectomy, extra-colic abdominal surgery, etc) Patient-Controlled Epidural Analgesia (PCEA) optimizes pain relief while minimizing adverse effects PCEA provides better analgesia, and less sympathetic and motor blockade resulting in greater patient satisfaction than continuous epidural infusion (CEI) analgesia Ropivacaine, which is an isomer of bupivacaine, has similar analgesic efficacy but is less toxic In particular, the outstanding advantage of ropivacaine compared with bupivacaine is less inhibition of movement leading to a shortened postoperative recovery time Using ropivacaine at different concentrations can lead to different analgesic effects In the world, individual studies often use ropivacaine at concentrations of 0.1%, 0.125%, 0.15%, and 0.2% in combination with fentanyl, but there is no consensus on what concentration of ropivacaine is optimal for analgesia after laparotomy In the world, individual studies had often used ropivacaine at concentrations of 0.1%, 0.125%, 0.15%, and 0.2% in combination with fentanyl, but there is no consensus on which ropivacaine concentration is optimal for thoracic epidural analgesia after laparotomy There have been no research projects on the effectiveness of using ropivacaine at different concentrations when combined with fentanyl for PCEA-based on thoracic epidural analgesia after laparotomy in Vietnam Therefore, the thesis: "Research on the efficacy of patient-controlled thoracic epidural analgesia with ropivacaine combined with fentanyl after laparotomy" has been conducted for two following purposes: To compare the effectiveness of patient-controlled thoracic epidural analgesia with ropivacaine concentration of 0.1%; 0.125%; 0.2% plus fentanyl μg/ml after laparotomy To Evaluate the effects on circulation, respiration, and some adverse effects of patient-controlled thoracic epidural analgesia with ropivacaine concentration of 0.1%; 0.125%; 0.2% plus fentanyl μg/ml after laparotomy Chapter OVERVIEW 1.1 Pain after open abdominal surgery 1.1.1 Outline of pain after surgery Postoperative pain is a pain sensation due to surgical intervention, that appears after surgery The level of pain depends on the type of surgery, the surgical technique, and the patient's tolerance level Pain after surgery is divided into categories: acute pain and chronic pain 1.1.2 Mechanism of pain after open abdominal surgery Open abdominal surgery is usually a major surgery, causing damage to many tissues and organizations Therefore, abdominal surgery can cause moderate to severe pain Abdominal surgery has two sources of pain: pain originating from the abdominal wall and pain originating from intra-abdominal viscera 1.1.3 Effect of pain after open abdominal surgery 1.2 Methods of pain relief after open abdominal surgery 1.3 Postoperative epidural analgesia 1.3.1 Distribution and absorption of local anesthetics in the epidural space 1.3.2 Patient-controlled epidural analgesia 1.3.3 PCEA setting - Loading dose (initial dose): Current PCA machines are all set to this parameter, this is the amount of anesthetic with a certain volume pumped into the epidural space compartment when starting the process of self-control pain relief, to bring the patient's VAS score back to normal value < - Bolus dose (demand dose): The required dose is the amount of drug injected into the epidural space by the PCA when the patient presses the autopilot button - Lockout interval: Lockout time is the minimum period allowed between two successful presses of the button for pain relief The lockout period is designed to prevent overdose due to intentional or accidental patient repeatedly pressing the PCA button - Dose limit: The PCA device allows the selection of the total volume of anesthetic injected into the epidural space over a 1hour or 4-hour period for the additional purpose of ensuring patient safety Once the patient has received a sufficient volume of local anesthetic into the epidural space within the set time, even if the PCA button is pressed, the machine will not deliver additional anesthetic - Background infusion rate: also known as continuous infusion dose, the parameter is set or not set at the discretion of the user and remains unchanged whether the patient presses the control button or not 1.3.4 Factors affecting the effectiveness of epidural analgesia 1.4 Pharmacology of drugs used in epidural 1.5 Studies on patient-controlled epidural analgesia in abdominal surgery with ropivacaine 1.5.1 Epidural analgesia ropivacaine in combination with other drugs Research of Perotti L (2015) compared the analgesic effect of levobupivacaine 0.125% + sufentanil 0.75 μg/mL and ropivacaine 0.2% + sufentanil 0.75 μg/mL at the rate of mL/h in 48h The results showed no significant difference between the two combinations in terms of analgesia, but the ropivacaine mixture was able to reach maximum plasma concentrations faster than the levobupivacaine mixture The research of Markantonis, S L (2016) evaluated the pain relief of ropivacaine 0.75% through the ICP and continuous incision infiltration combined with morphine to prevent postoperative pain The results showed that ropivacaine levels were maintained more stable and had better analgesic effects in the route of epidural analgesia than continuous wound infiltration 1.5.2 Epidural analgesia with ropivacaine and fentanyl Studies using ropivacaine alone for 24 to 72 hours have shown that a large proportion (up to 50%) of patients required additional analgesics or were withdrawn from the research because they did not provide the required analgesia This makes sense because the phased elimination is faster with ropivacaine than with bupivacaine; however when combined with fentanyl (2 to μg/mL), 0.2% ropivacaine provided similar analgesic qualities to bupivacaine (0.1% to 0.2%) 1.5.3 Epidural analgesia with different concentrations of ropivacaine A comparison of the effects of drugs used for epidural analgesia has been reported previously with the efficacy of a combination of ropivacaine and fentanyl Shen-Chih Wang compared three different concentrations of ropivacaine solution (0.1%, 0.15%, 0.2%) in combination with μg/ml fentanyl for PCEA in patients undergoing upper abdominal surgery However, there was no difference between the three groups in terms of total consumption In group 1, VAS scores during activity and cough 12 h after surgery were significantly higher than in the other two groups (p < 0.05) Four patients in group had a loss of temperature sensation The overall incidence of adverse events is less than 40% Therefore, ropivacaine 0.1% and 0.15% combined with fentanyl are preferred to limit unwanted effects Research by Shruti Shrikant Patil performed in 2018 compared the effects of ropivacaine 0.125% plus fentanyl μg/ml with levobupivacaine 0.125% plus fentanyl μg/ml to reduce pain after major abdominal surgery in 60 patients were randomized to either 0.125% levobupivacaine fentanyl μg/ml (Group B) or 0.125% ropivacaine to fentanyl μg/ml (Group R) After monitoring within 24 hours after surgery, the parameters and VAS scores in the two groups were similar, the pain suppression level was higher than in group B, but not statistically significant Shruti concluded, that at a concentration of 0.125% and in combination with fentanyl μg/ml, both ropivacaine and bupivacaine were safe and effective for postoperative analgesia Chapter SUBJECTS AND METHODS 2.1 Researching subjects Patients were indicated to open laparotomy in 103 Military Hospital between April/2015 and July/2017 2.1.1 Selection criteria for researching subjects - The patient is over 18 years old and agrees to receive the method of epidural analgesia - Normal mental status, know how to use PCA device - Classification ASA I, II, III - Patients who agree to participate in the research 2.1.2 Exclusion criteria - Patients with liver failure, and kidney failure - Patients with contraindications to analgesia: + Have heart failure, blood clotting disorder + Allergy to ropivacaine, fentanyl + There is an infection in the needle puncture site + There are deformities and diseases of the spine 2.1.3 Criteria for taking out of the research - Unable to place the epidural catheter - Surgical or anesthesia complications lead to stopping using PCEA - The patient did not agree to continue participating in the research 2.2 Research methodology 2.2.1 Research design - Methods: prospective, clinical intervention, randomized, comparative 2.2.2 Sample size and sample selection - Research sample size: the sample size was calculated based on the formula for calculating sample size for multiple groups’ mean comparisons (ANOVA): (𝒁𝜶 + 𝒁𝜷 )𝟐 𝒏 = 𝟐 𝟐 (𝟏) 𝑬𝑺 In particular: n: minimum sample size for the research Type I error (α) is 0.05, then the confidence Zα/2 is 1.96 Type II error (β) is 0.05, then the confidence level Zβ is 1.645 ES: the influence coefficient, calculated by the formula: ̅ )𝟐 𝒁𝒌𝒋=𝟏 (𝝁𝒋 − 𝝁 𝑬𝑺 (𝒆𝒇𝒇𝒆𝒄𝒕 𝒔𝒊𝒛𝒆) = √ (𝟐) 𝒌𝝈𝟐 In particular: µj is the individual mean for each group, and μ is the group average 𝝈𝟐 is the sum of squares of the standard deviations in the groups k is the number of groups in the research, where k = From the research results of Anita Kulkarni (2018), the research of Patil SS (2018), and that of Madhuri Sharma (2019), rounding to divide equally among groups required a total of at least 105 subjects (minimum 35 subjects per group) 2.3 Drugs and research facilities 2.4 Conducting research 2.4.1 Prepare the patient Preoperative examination - Patients were examined one day before surgery, and selected patients who met the criteria for inclusion in the research group - Explain to the patient the method of anesthesia and the method of pain relief after surgery will be carried out Educate patients on how to use the PCA, pain metrics, and how to rate satisfaction based on the quality of pain relief and side effects - Preoperative blood gas test (patient breathes with air) Use pre-anesthesia In the operating room - Monitor: Heart rate, systolic blood pressure, diastolic blood pressure, mean blood pressure, lead DII electrocardiogram, respiratory rate, and capillary oxygen saturation (SpO2) through the monitor - Breathing oxygen through the nose, flow rate 3l/min - Insert peripheral line with 18G needle, crystalloid infusion 10ml/kg Insertion of a bladder-urethral catheter (performed after anesthesia) 2.4.2 Perform the technique of placing the catheter into the thoracic epidural cavity 2.4.3 Mix a mixture of anesthetics to relieve pain after surgery Prepare a solution of ropivacaine 0.1%/ 0.125%/ 0.2% + fentanyl (2 μg/ml) a Principle of drug preparation: sterile b Prepare: - Dispensers: anesthesiologists, and anesthesiologists have washed their hands, wore sterile gowns, and put on surgical gloves - Means: 01 syringes of 50 ml with a small head, 01 needles for taking medicine, 01 infusion line, 01 forks - Medicines: ropivacaine 0.2%/20ml; ropivacaine 0.5 %/10ml; 06 ampoules of fentanyl 0.1 mg; 01 bottle of 0.9% NaCl c How to prepare the anesthetic solution - Ropivacaine solution concentration 0.1% + fentanyl 2μg/ml: use a 50ml syringe to aspirate 150ml of 0.2% ropivacaine solution (7.5 ampoules of 0.2%/20ml ropivacaine), together with 06 tubes of fentanlyl ,1 mg/2ml was added to a bottle containing 138 ml of 0.9% NaCl to obtain 300 ml of a mixture of local anesthetic ropivacaine 0.1% + fentanyl 2μg/ml - Ropivacaine solution concentration 0.125% + fentanyl 2μg/ml: use a 50ml syringe to aspirate 75ml of 0.5% ropivacaine solution (7.5 ampoules of 0.5%/10ml ropivacaine), together with 06 tubes of 0.1 fentanlyl mg into a bottle containing 213 ml of 0.9% NaCl, obtained 300 ml of a mixture of local anesthetic ropivacaine 0.125% + fentanyl 2μg/ml - Ropivacaine solution concentration 0.2% + fentanyl 2μg/ml: use a 50ml syringe to aspirate 120ml of 0.5% ropivacaine solution (12 ampoules of 0.5%/10ml ropivacaine), together with 06 tubes of 0.1 fentanlyl mg/2ml into a bottle containing 168ml of 0.9% NaCl, 300ml of a mixture of local anesthetic ropivacaine 0.2% + fentanyl 2μg/ml was obtained 2.4.4 Anesthesia 2.4.5 Post-operative pain relief The patient was discharged from the operating room when Aldrete score = 10 after times 10 minutes apart, satisfactory spontaneous breathing, SpO2≥95%, and VAS 0.05) Table 3.18 Distribution of patient satisfaction In groups, the only group I had patients with average satisfaction levels, accounting for 17.1% Group II and GroupIII have 100% of patients feel satisfied and very satisfied with the PCEA analgesia method The difference was statistically significant between group I and the other groups (p0.05) 3.3 Indicators to evaluate the effects on circulation and respiration Table 3.19 Change in mean heart rate at time points Chart 3.5 Graph of heart rate change at time points - After being injected with a local anesthetic, the heart rate at all times decreased compared to the heart rate at the time of H0, the difference was statistically significant (p0.05) - There was no patient with a heart rate < 60 beats/min Table 3.20 Change in mean SBP at time points Chart 3.6 Change in mean SBP at time points - The mean SBP at the time from H0.25 to H72 was lower than the mean SBP at the time of H0 in all three groups, the difference was statistically significant (p0.05) Table 3.21 Change in average DBP at time points (*: p0.05) Table 3.25 Results SaO2 - At all times, the SaO2 index changed little in all three groups And this change is not statistically significant (p>0.05) - However, the SaO2 index at the time of surgery decreased compared to the time before surgery, with statistical significance (p0.05) Table 3.28 Adverse effects - Nausea and headache occurred in all groups with a small number, the difference between groups was not statistically significant (p>0.05) - No other undesirable effects such as low blood pressure, chills, itching, inhibition of movement, 16 CHAPTER DISCUSSION 4.1 General features General characteristics of the groups in terms of gender, age, weight, height, BMI, ASA degree, comorbidities, diseases requiring surgery, length and location of incision as well as surgery time, transit time, and the time to sit up was not statistically significant The local anesthetic needle puncture site and the depth of the catheter in the MI compartment were consistent with recommendations for analgesia for laparotomy 4.2 Effective pain relief after surgery Initial dose injection volume in the epidural space Table 3.9 shows the results of the average volume of the starting dose injected into the epidural space for groups: 5.66 (group I), 5.82 (group II), and 5.55 (group III), respectively the difference is not statistically significant This result is consistent with the recommendation of Visser W et al (2008) when the authors said that enough inhibition for each segment of the spinal cord requires 11.5 ml of local anesthetic Calculation of the volume of the starting dose is based on age and height With age, the myocardial space narrows due to degeneration of the spinal system, the proliferation of fibrous tissue, narrowing of the foramen, and fibrosis of the arterial system, leading to an increased risk of spreading local anesthetic Between the ages of 10 and 20, the volume of local anesthetic can be as high as 1.6 ml per segment, while at the age of 80, this volume can be as low as 0.8 ml Number of segments inhibited and time of onset of analgesia A single dose of drug injected into the epidural space but varying in volume and concentration may have different levels of response A large volume of a low-concentration anesthetic solution will cause multiple myelosuppression but less sensory and motor inhibition Sympathetic nerve fibers have the smallest diameter and are most susceptible to inhibition, even with low concentrations of local anesthetic, and the degree of the sympathetic blockade is related to the number of segments inhibited With epidural catheters, the dose can be increased gradually and this is important to prevent high sympathetic nerve block from causing excessive hypotension 17 The number of segments inhibited The research results in Table 3.10 show that the average number of segments due to analgesia by ropivacaine combined with fentanyl is 6.4 ± 0.8 with the group I, 6.5 ± 1.3 with group II and 6.6 ± 1.1 with group III This result is similar to Tran Duc Tho's research in 2017 with an average inhibitory segment of 6.7 segments To achieve the effect of inhibiting myeloid segment, - 1.5 ml of EPIDURAL SPACE injectable cytoplasm is required Onset time of the analgesic effect The results from table 3.10 also showed that there was no significant difference between the research groups in terms of time to onset of analgesic effect (p>0.05) On average, the local anesthetic onset of analgesia was 8.8 ± 1.9 in group I and 8.9 ± 2.0 in groups II and III This result is equivalent to the research of Tran Duc Tho (2017) with an average of 8.8 minutes in the LC and LF groups [19] Chhetty when using a single dose of 15ml ropivacaine 0.125% to relieve pain in labor in over 40 women with 0.125% ropivacaine, the results ranged from 5-14 minutes to VAS score < [40] In our research, the time to onset of analgesic effect in all three groups was in the range of 7-14 minutes, equivalent to the Chhetty research despite the difference in concentrations used The amount of medicine used by the thoracic intramuscular route to relieve pain after surgery The total dose of ropivacaine From Table 3.11, we found that the mean total dose of ropivacaine gradually increased in groups I, II, and III, respectively (p0.05) Thus, the combination with fentanyl is an important factor in reducing the dose of local anesthetics while ensuring effective pain relief Choice of ropivacaine concentration Senard (2004) compared ropivacaine 0.1% with levobupivacaine 0.1% for pain relief after abdominal surgery and found no difference in analgesic efficacy as well as undesirable effects between the two groups 18 In 2001, Puozeratte Y et al compared the effects of ropivacaine 0.125% in combination with sufentanil and ropivacaine 0.2% on patient-controlled ICP with a bolus dose setting of 2–3 mL and a baseline rate of 3-5 mL/h The author found that the total dose of ropivacaine 0.125% combined with sufentanil was 0.2% lower than that of the ropivacaine group while still ensuring effective pain relief and few unwanted effects Whiteside (2004) studied 40 patients who were randomly divided into two groups after surgery for gynecological cancer and received analgesia with ropivacaine 0.1% and 0.2% The author found that the analgesic effect, as well as the adverse effect between the two groups, were the same, although the difference in the total dose of ropivacaine was statistically significant (p 0.05) This result is similar to the research of Shantiraj G (2018) showing that the analgesic mixture with ropivacaine started to achieve the expected effect at hour postoperatively This research also showed that the use of a mixture of ropivacaine and fentanyl had a better analgesic effect than ropivacaine alone (p < 0.001) VAS score during exercise ... 0.125% plus fentanyl μg/ml to reduce pain after major abdominal surgery in 60 patients were randomized to either 0.125% levobupivacaine fentanyl μg/ml (Group B) or 0.125% ropivacaine to fentanyl. .. ropivacaine 0.1% + fentanyl 2μg/ml - Ropivacaine solution concentration 0.125% + fentanyl 2μg/ml: use a 50ml syringe to aspirate 75ml of 0.5% ropivacaine solution (7.5 ampoules of 0.5%/10ml ropivacaine),... ropivacaine 0.125% + fentanyl 2μg/ml - Ropivacaine solution concentration 0.2% + fentanyl 2μg/ml: use a 50ml syringe to aspirate 120ml of 0.5% ropivacaine solution (12 ampoules of 0.5%/10ml ropivacaine),