Rajiv Gandhi University of Health Sciences s128

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA

SYNOPSIS OF DISSERTATION

“A COMPARATIVE STUDY OF LEVOBUPIVACAINE 0.5% AND BUPIVACAINE 0.5% IN EPIDURAL ANAESTHESIA IN ELECTIVE LOWER LIMB SURGERIES IN ADULTS”

Submitted by

Dr.MANISHA MOHAN SHIVAMOGGI

POST GRADUATE STUDENT IN

ANAESTHESIOLOGY

DEPARTMENT OF ANAESTHESIOLOGY AND CRITICAL CARE

Kempegowda Institute of Medical Sciences,

Bangalore 560004.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE,

KARNATAKA

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE
AND ADDRESS / Dr.MANISHA MOHAN SHIVAMOGGI
POST GRADUATE STUDENT (M.D.)
DEPARTMENT OF ANESTHESIOLOGY AND CRITICAL CARE
O-142, SECTOR-1 HMT OFFICERS’ COLONY, JALAHALLI, BANGALORE-560013
2. / NAME OF THE INSTITUTION /

KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES, BANGALORE 560004.

3. / COURSE OF STUDY AND SUBJECT /

M.D. IN ANAESTHESIOLOGY

4. / DATE OF ADMISSION TO THE COURSE / 30TH AUGUST 2013
5. / TITLE OF THE TOPIC / “A COMPARATIVE STUDY OF LEVOBUPIVACAINE 0.5% AND BUPIVACAINE 0.5% IN EPIDURAL ANAESTHESIA IN ELECTIVE LOWER LIMB SURGERIES IN ADULTS.”
6. / BRIEF RESUME OF THE INTENDED WORK
6.1  NEED FOR THE STUDY
6.2 REVIEW OF LITERATURE
6.3 OBJECTIVES OF THE STUDY / Enclosed
Enclosed
Enclosed
7 / MATERIALS AND METHODS
7.1  SOURCE OF DATA
7.2 METHOD OF COLLECTION OF DATA
7.3 DOES THE STUDY REQUIRE ANY INVESTIGATIONS OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS? IF SO PLEASE DESCRIBE BRIEFLY.
7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3? /

Enclosed

Enclosed

Yes
Yes
8. / LIST OF REFERENCES / Enclosed
9. / SIGNATURE OF THE CANDIDATE /
10. / REMARKS OF THE GUIDE / This study will compare the efficacy and safety of the new drug, levobupivacaine 0.5% and bupivacaine 0.5% when used epidurally in elective lower limb surgeries.
11 / NAME AND DESIGNATION OF:
11.1 GUIDE / Dr. N.S. SHREESHA M.D., D.A.
ASSISTANT PROFESSOR,
DEPARTMENT OF ANESTHESIOLOGY AND CRITICAL CARE
KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
BANGALORE 560004.
11.2 SIGNATURE OF THE GUIDE
11.3 HEAD OF DEPARTMENT / Dr. CHAYA. S. D.A., M.D.
PROFESSOR AND HEAD OF DEPARTMENT,
DEPARTMENT OF ANESTHESIOLOGY AND CRITICAL CARE
KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
BANGALORE 560004.
11.4 SIGNATURE
12. / 12.1 REMARKS OF THE PRINCIPAL
12.2 SIGNATURE
6. / BRIEF RESUME OF THE INTENDED WORK;
6.1 NEED FOR THE STUDY:
·  Epidural anaesthesia is one of the most common regional anaesthetic technique which has the following advantages:
a.  It provides effective surgical anaesthesia
b.  It can meet the extended duration of surgical needs.
c.  It provides segmental block. Hence reduces the incidence of adverse haemodynamic changes as a result of sympathetic blockade comparable to related regional techniques.
d.  It provides post operative analgesia1
e.  Advantages over spinal anaesthesia being able to provide anaesthesia for prolonged surgeries and better hemodynamic stability.
f.  Advantages over general anaesthesia being avoidance of intubation and extubation responses and chance to provide continuous postoperative analgesia2.
·  Different local anaesthetics are used for epidural anaesthesia namely lignocaine, bupivacaine, ropivacaine and now levobupivacaine.
·  Bupivacaine has been widely used as a local anesthetic because of its long duration of action and beneficial ratio of sensory to motor block when used for epidural anaesthesia. However, it has the disadvantage of being more cardiotoxic than other amide local anaesthetics3.
·  Levobupivacaine, an S (-) enantiomer of bupivacaine, is a long acting local anaesthetic shown to have an advantage of being less cardiotoxic and less neurotoxic. Levobupivacaine has been shown to have less of a negative inotropic effect and at intravenous doses >75 mg, shown to produce less prolongation of the QTc interval than bupivacaine.4.
·  Hence, there is an attempt to compare levobupivacaine 0.5% with bupivacaine 0.5% in epidural anaesthesia in elective lower limb surgeries.
6.2 REVIEW OF LITERATURE:
Epidural anaesthesia is a neuraxial technique where the drug is deposited in the epidural space. First approach to epidural space was caudal approach reported by Sicard and Catheline in 1901. In 1921, Fiedel Pages reported his work with lumbar epidural anaesthesia5. The introduction of Tuohy needle for epidural in 1949 increased the popularity of lumbar epidural block.
Many local anaesthetics like lignocaine, bupivacaine, ropivacaine and levobupivacaine are commonly used by epidural route. Nowadays, levobupivacaine is becoming increasingly popular because of its less cardiotoxic effects.
·  Fesih KARA, Hüsnü KÜRŞAD et al in 2013 conducted a study on a total of 70 ASA 1 and 2 patients aged between 30 and 70 years who underwent elective hip and lower extremity operations. The patients who received bupivacaine were assigned to Group B(n=35) and those who received levobupivacaine to Group L(n=35). In this study, they concluded that Levobupivacaine could be a good alternative to bupivacaine in patients administered epidural anesthesia in elective hip and lower extremity operations in terms of hemodynamic parameters, quality of anesthesia and analgesia, patient and surgeon satisfaction and complications6.
·  Gristwood RW in 2002, in his journal titled ‘Cardiac and CNS toxicity of levobupivacaine: strengths of evidence for advantage over bupivacaine’, concluded that Levobupivacaine was found to cause smaller changes in indices of cardiac contractility and the QTc interval of the electrocardiogram and also to have less depressant effect on the electroencephalogram. Assuming that levobupivacaine has the same local anaesthetic potency as bupivacaine, then, all things being equal, it was found that it is difficult to argue that levobupivacaine should not displace bupivacaine as the long-acting local anaesthetic of choice7.
·  Cheng CR,Su TH et al in 2002 conducted a prospective, controlled, double-blinded study in 45 ASA class 1 and 2 Taiwanese obstetric patients undergoing elective Caesarean Section under extradural anesthesia. Patients were randomized to receive either 25 ml of 0.5% bupivacaine or 0.5% levobupivacaine in a double-blinded fashion. They concluded that levobupivacaine had the efficacy and safety profile equivalent to bupivacaine in epidural anaesthesia for Caesarean section8.
·  Koch T,Fichtner A,et al in 2002 conducted a randomized, single blind phase IIIb study on 88 patients undergoing hip surgeries. They were randomly assigned to 3 different treatment groups each receiving either levobupivacaine 0.5%, bupivacaine 0.5% or ropivacaine 0.75%. In this study, they concluded that the efficacy of epidural levobupivacaine for hip surgery and postoperative analgesia is equivalent and shows a comparable clinical profile to bupivacaine and 50-60% higher concentrated ropivacaine9.
·  Stefania Leone, Simone Di Cianni et al in a review titled ‘Pharmacology, toxicology and clinical use of new long acting local anaesthetics, ropivacaine and levobupivacaine’ showed the evidence that both ropivacaine and levobupivacaine have been developed to offer a safer alternative to bupivacaine, having the desirable blocking properties of bupivacaine with a greater margin of safety due to their reduced toxic potential. They found that it resulted in not only higher plasma concentrations and doses before signs of systemic toxicity occur, but also in no cardiovascular toxicity or only minimal signs of cardiac effects after CNS toxicity occurs. In conclusion, the reduced toxic potential of both levobupivacaine and ropivacaine should be carefully considered when choosing the local anesthetic for regional anaesthesia techniques requiring large volumes and infusion rates, such as for epidural anesthesia/analgesia, peripheral nerve blocks, and local infiltration10.
·  Foster RH et al in 2000 concluded that levobupivacaine had a lower risk of cardiovascular and CNS toxicity than bupivacaine. It has been showed that levobupivacaine has less of a negative inotropic effect and at intravenous doses >75 mg, produced less prolongation of the QTc interval than bupivacaine. Fewer changes indicative of CNS depression on EEG were evident with levobupivacaine4.
·  Hazel Bardsley et al in 1998 conducted a randomized crossover study on 14 healthy male volunteers in which each volunteer received both levobupivacaine and bupivacaine intravenously on two separate occasions with a washout period of at least 1 week in between the treatments. In this study they concluded that following i.v. administration levobupivacaine produces significantly less effects on cardiovascular function than does rac-bupivacaine. In particular the negative inotropic effect for levobupivacaine was less than that for rac-bupivacaine as indicated by changes in stroke index, acceleration index and ejection fraction11.
·  Dilek B.Surav et al in 2011 conducted a study on 40 adult patients with an ASA 1-3 undergoing transurethral endoscopic surgery. They were randomly divided into 2 groups of 20 each to receive either isobaric levobupivacaine 0.5% or isobaric levobupivacaine 0.75% for epidural anaesthesia. In this study they concluded that 10 ml of 0.5% levobupivacaine plus 5 ml of 0.9% saline is a suitable solution for use in epidural anaesthesia because it produces a block clinically comparable to that of 10 ml of 0.75% levobupivacaine plus 5 ml of 0.9% saline for transurethral resection of prostate surgery12.
6.3 OBJECTIVES OF THE STUDY:
To compare the efficacy of levobupivacaine 0.5% and bupivacaine 0.5% in epidural anaesthesia in elective lower limb surgeries in adults, regarding:
1.  Onset, duration and maximum dermatomal level of sensory blockade
2.  Onset , duration and intensity of motor blockade
3.  Duration of analgesia
4.  Haemodynamic changes

MATERIALS AND METHODS:
7.1 SOURCE OF DATA:
The study will be conducted in the Department of Anesthesiology and Critical Care, KIMS hospital, Bangalore from December 2013 to July 2015.
SAMPLE SIZE: 60. Two groups of 30 patients in each group.
SAMPLING METHOD: Random sampling
STUDY DESIGN: Comparative Randomized study
STATISTICALANALYSIS: Student’s t-test
7.2 METHOD OF COLLECTION OF DATA
·  A prospective, randomized controlled study will be conducted on 60 patients of ASA grade 1 and 2 aged between 18 to 60 years of either sex posted for elective lower limb surgeries in the Department of Anaesthesiology and Critical Care, at KIMS hospital, Bangalore.
INCLUSION CRITERIA:
·  Age group of 18 to 60 years of either sex
·  ASA grades 1 and 2
·  Patients posted for elective lower limb surgeries
·  Height 150- 180cm
·  Weight 50-80 kg
EXCLUSION CRITERIA:
·  Patient refusal for regional anaesthesia
·  Patients having allergy to local anaesthetics
·  Pregnancy and lactation
·  Patients with morbid obesity
·  Patients having
(a)local infection
(b)severe hypovolaemia
(c)bleeding diathesis and coagulopathy
(d)uncontrolled hypertension and diabetes mellitus
(e)neurological disorders
(f)raised intracranial tension and deformities of spine
(g)hepatic diseases.
·  The study population is divided into two groups of 30 patients in each group:
1.  Group L (n=30) -12ml of levobupivacaine 0.5% epidurally.
2.  Group B (n=30) -12ml of bupivacaine 0.5% epidurally.
PROCEDURE OF THE STUDY
·  Preoperative assessment will be done for each patient and written informed consent is taken. Patients will be allowed for a period of absolute fasting of atleast 8 hours.
·  Intravenous line will be secured with 18G cannula in upper limb. Patient will be monitored using automated multiparameter monitor. Basal vital parameters like heart rate, blood pressure, respiratory rate and SPO2 will be noted.
·  Patient will be placed in lateral position. Epidural space identified with loss of resistance to air technique at L2-L3/L3-L4 level using 18G Tuohy’s needle. An epidural catheter will be advanced in cephalad direction into epidural space for 3cm and fixed. Test dose of 3ml of 2% lignocaine with adrenaline 1:200000 will be given after negative aspiration for CSF and blood. This is to exclude the presence of needle in epidural vein or subarachnoid space. After confirming the correct position of the catheter, patient will be turned to supine position. Five minutes after the test dose, when there was no evidence of intravascular or subarachnoid injection, 12ml of study drug will be given at a rate of 1ml/3sec through the catheter.
·  Intraoperatively, the following parameters will be monitored :
o  Onset and degree of sensory block
o  Onset and degree of motor blockade – using Modified Bromage scale
o  Duration of analgesia –The time interval between the onset of pain relief and the first requirement of supplementary analgesia will be noted.
o  Haemodynamic changes- heart rate, blood pressure, mean arterial pressure and respiratory rate
·  All the above parameters will be recorded every minute for the first 5 minutes, every 5 minutes till the end of 1hour and then every 15 minutes till the end of surgery.
·  Intra operative and post operative complications if any – such as nausea, vomiting, hypotension, bradycardia, respiratory depression will be looked for, recorded and treated accordingly.
·  After the surgery, patients will be referred to the post anaesthesia care unit where they will remain until there is complete recovery of sensory and motor blockade. Postoperatively, vital parameters will be recorded every 15 minutes. Duration of analgesia, sensory and motor blockade, any adverse events like nausea, vomiting, shivering etc will be noted. Study concludes when the patient first complains of pain after the administration of the drug under study epidurally.
·  Continuous epidural infusion will be given as 5ml of bupivacaine 0.125% with 1µg of fentanyl in each ml of local anaesthetic for the next 72 hours.
Definitions:
Onset of sensory blockade: It is the time taken from the completion of the injection of study drug till the patient does not feel the pin prick at L1 level.
Time for maximum sensory blockade: It is defined as the time from the completion of the injection of the study drug to the maximum sensory blockade attained.
Onset of motor blockade: It is taken from the completion of the injection of study drug till the patient develops modified Bromage scale grade 1 motor blockade.
Time for maximum motor blockade: It is defined as the time from the completion of the injection of the study drug to the maximum motor blockade attained.
Duration of motor block: It is taken from the time of injection till the patient develops modified Bromage scale grade 0.
Duration of analgesia: It is taken from the time of injection till the patient complains of pain at the site of surgery.
Hypotension is defined as reduction of systolic blood pressure more than 30% below baseline value or blood pressure less than 90mmHg, it will be treated with injection Ephedrine 6mg in bolus doses and increased administration of intravenous fluids .
Bradycardia is defined as heart rate less than 50/minute and will be treated with injection Atropine 0.6mg iv.
MODIFIED BROMAGE SCALE
0  - able to perform a full straight leg raise over the bed for 5sec
1  - unable to perform a leg raise but can flex the leg on knee
2  - unable to flex knee but can flex ankle
3  - unable to flex ankle
4  - unable to move toes
7.3 Does the study require any investigation or intervention to be conducted on patients or other human or animal? If so please describe briefly
No animal experiments conducted.
The following routine investigations will be done in patients after taking written and informed consent:
–  Complete blood count & Blood grouping.
–  Blood sugars, Blood urea & Serum creatinine.
–  Bleeding time and Clotting time.
–  Serum electrolytes (Sodium, Potassium, Chloride).
–  Chest x-ray and ECG.
–  Other investigations deemed to be appropriate for the surgery.
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
Yes
8) LIST OF REFERENCES:
1)Feldman HS, Arthur GR, Covino BG. Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine and lidocaine in the conscious dog. Anaesthesia analgesia 1989;69:794-801.
2)Dr. Leon Visser. Epidural Anaesthesia. 2001;11(13):1-4.
3)Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine Anesthesiology 1979 Oct;51(4);285-7.
4)Foster RH,Markham A. Levobupivacaine: a review of its pharmacology and use as a local anaesthetic. Drugs 2000 Mar;59(3):551-79.
5)Micheal A. Frolich, Donald Caton. Pioneers in epidural needle design. Anaesth Analg 2001 Jun;93(1):215-20.
6) Fesih Kara, Husnu Kursad, Mine Celik, Aysenur Dostbil, Ilker Ince, Ahmet Faruk Giren et al. Comparison of the effects of epidural 0.5% bupivacaine and 0.5% levobupivacaine administration on anesthesia quality, side effect incidence, and analgesia requirement times in hip and lower extremity surgery .Turkey Turk J Med Sci 2013;43:580-585.
7)Gristwood RW. Cardiac and CNS toxicity of levobupivacaine: strengths of evidence for advantage over bupivacaine. Drug Saf 2002;25(3):153-63.
8) Cheng CR, Su TH, Hung YC, Wang PT.A comparative study of the safety and efficacy of 0.5% levobupivacaine and 0.5% bupivacaine for epidural anesthesia in subjects undergoing elective caesarean section. Acta Anaesthesiol Sin 2002 Mar;40(1):13-20.
9)Koch T,Fichtner A,Schwemmer U,Standl T,Volk T,Engelhard K et al. Levobupivacaine for epidural anaesthesia and postoperative analgesia in hip surgery: a multi-center efficacy and safety equivalence study with bupivacaine and ropivacaine. Anaesthesist 2008 May;57(5):475-82.
10)Stefania Leone, Simone Di Cianni, Andrea Casati, Guido Fanelli. Pharmacology, toxicology, and clinical use of new long acting local anesthetics, ropivacaine and levobupivacaine. Acta Biomed 2008 Aug;79:92-105.
11) Hazel Bardsley, Robert Gristwood, Halen Baker, Norma Watson & Walter Nimmo, A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers.Br J Clin Pharmacol 1998;46(3):245–249.
12) Dilek B.Surav, AyseHanci, G. UluferSivrikaya, MetinBektas, Leyla T.Kilinc. The effects of Different Concentrations and Equivalent Volumes of Levobupivacaine in Epidural Anesthesia. ESRA 2011 Apr;72(2):71-78.

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