Luan an tom tat anh

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENSE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES ------ TRAN DUC THO EFFECTIVENESS OF LEVOBUPIVACAIN COMBINED WI

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: Anesthesia Reanimation

Code: 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:

1 The National Library

2 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

1 Research objectives

- To compare the efficacy of postoperative pain control of levobupivacain 0,125% in combination with sufentanil 1 ug/ml or with fentanyl 2 ug/ml or with clonidine 2 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 1 ug/ml or with fentanyl 2 ug/ml or

with clonidine 2 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

3 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

4 Structure of the research report

- The thesis report was 142 pages long, including 2 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, 2 pages of conclusion and 1 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 1 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 3 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 1 µg/ml and gained satisfactory pain control results, with mean VAS scores of 1.54 at hour 1 and 0.54 at hour 48 resting after operation All the patients were hemodynamically stable, without any respiratory failures during the studied time

Chapter 2 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

+ 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

- 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 > 5 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 < 4 then re-evaluated after 15 mins

* If VAS > 4 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:

Injection volume = Chiều cao (cm) - 10010

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 1 (L-C) used the combination of levobupivacain 0,125% + clonidin 2µg/ml

* Arm 2 (L-F): used the combination of levobupivacain 0,125% + fentanyl 2µg/ml

* Arm 3 (L-S): used the combination of levobupivacain 0,125% + sufentanyl 1µg/ml

+ PCA parameter set-up:

* Bolus dose: 2 ml

* Lockout interval: 10 minutes

* Background infusion rate : 2 ml/h

* Total drug in 1 hour: 12 ml

During the studied time, if patient was still in unbearable pain after three bolus doses, a « pain rescue » dose of 5 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 < 4 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 3 and total amount for 3 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:

+ 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 :

< 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 3 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 3 studied groups of patient

3.2 Parameters to evaluate the pain control efficacy

Table 3.8: Volume of induction doses and inhibited dematomes

- The mean volume of levobupivacain 0,25% (with adrenalin 1/200000) injected into the epidural space was 6,11 ± 0,62 ml, lowest was 4,7 ml, highest was 7,5 ml

- Mean number of inhibited dermatomes was 6,75 ± 1,02, ranging from 5 to 8 dermatomes

- Onset time of pain control were not statistically different among three groups, p > 0,05

Table 3.9: Changes of postoperative pain at rest by visual analog scale

Chart 3.2 Changes of postoperative pain at rest of the three groups, by

VAS score

Table 3.10: Levels of pain control: good, fairly good, average and bad,

according to Oates scale

- At 1 hour postoperative, 100%, 96% and 94% of patients in groups LF, LC anf LS, respectively, achieved fairly good or good level

of pain control

- 100% patients in LF group achieved good level of pain control (VAS ≤ 2) at 4 hour postoperative Similar level of pain control achieved at 8 hour postoperative in LC and LS groups

Table 3.11: Changes of postoperative pain, when coughing and while

Chart 3.3 Changes of postoperative pain, when coughing and while

ambulating, by VAS score

Table 3.12: Levels of pain control, when coughing and while

ambulating: good, fairly good, average and bad, according to Oates scale

- In the LF group, 100% of the patient achieved the fairly good or above level (VAS ≤ 3), when coughing, after 8 hours postoperative For the LC and LS groups, the required time was after 16 hours

Table 3.13: Number of D (demand) and number of A (actual)

Variables

Group LC (n=50)

Groups LF (n=50)

Group LS (n=50)

- 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 7 (14%) patients need two rescue doses In group LS, 21 (42.0 %) patients need one rescue dose and 4 (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