Thesis full.pdf

A COMPARATIVE STUDY OF 0.1% ROPIVACAINE WITH FENTANYL

VERSUS 0.125% BUPIVACAINE WITH FENTANYL

AS CONTINUOUS EPIDURAL INFUSION IN LABOUR ANALGESIA

DISSERTATION SUBMITTED TO THE

NATIONAL BOARD OF EXAMINATIONS

NEW DELHI

IN THE PARTIAL FULFILLMENT OF THE REQUIREMENT FOR THE

DEGREE OF DIPLOMATE OF NATIONAL BOARD [ANAESTHESIOLOGY]

SUBMITTED BY

DR. JAYAPRAKASH . K

Reg No. 101- 41132-111-100523

JANUARY 2011 – DECEMBER 2013

DEPARTMENT OF ANAESTHESIOLOGY

G. KUPPUSWAMY NAIDU MEMORIAL HOSPITAL

COIMBATORE – 641 037

i

BONAFIDE CERTIFICATE

This is to certify that the dissertation “A COMPARATIVE STUDY OF 0.1%

ROPIVACAINE WITH FENTANYL VERSUS 0.125% BUPIVACAINE WITH

FENTANYL AS CONTINUOUS EPIDURAL INFUSION IN LABOUR ANALGESIA

” is a bonafide work of Dr. JAYAPRAKASH K (Reg No. 101-41132-111-100523), done

under direct guidance and supervision of Dr. RAJANI SUNDAR M.D., D.A during the

academic period 2011-2013 in partial fulfillment of National Board of Examination rules

and regulations for the award of Diplomate of National Board in Anaesthesiology.

DR. RAMKUMAR RAGUPATHY, M.S., MCH DR. RAJANI SUNDAR, M.D., D.A.,

DEAN CHIEF ANAESTHESIOLOGIST

GKNM HOSPITAL, COIMBATORE DEPARTMENT OF ANAESTHESIA

GKNM HOSPITAL, COIMBATORE.

ii

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation entitled “A COMPARATIVE STUDY OF

0.1% ROPIVACAINE WITH FENTANYL VERSUS 0.125% BUPIVACAINE WITH

FENTANYL AS CONTINUOUS EPIDURAL INFUSION IN LABOUR ANALGESIA”

is a bonafide and genuine research work carried out by me under the guidance of

Dr Rajani Sundar, M.D,D.A. Head of the department, Department of Anesthesiology,

G.Kuppusamy Naidu Memorial Hospital, Coimbatore.

Date:

Place:

Dr.Jayaprakash K

Postgraduate in Anaesthesiology

G.Kuppusamy Naidu Memorial Hospital

Coimbatore

iii

Acknowledgement:

I would like to thank Dr.Ramkumar Raghupathy M.S,MCH. Dean, G.K.N.M

hospital for permitting to do this study in our institution.

I would like to express my deep sense of gratitude to Dr.RAJANI

SUNDAR,M.D,D.A., Head of the Department, Anaesthesiology,for having suggested

this topic and providing constant guidance, encouragement and personal attention

during the study, without which this work would not hae been completed

successfully.

I am grateful to all our consultants Dr.Soundravalli M.D,D.A Dr.Palaniappan

M.D,D.A, Dr.Anandhi Arul M.D,D.A,DNB, Dr.Sai Gopalakrishnan D.A,DNB,

Dr.Sathyamurthy D.A,DNB and Dr.Muthukumar DNB for their valuable guidance

throughout the course of my study.

I would like to thank the Consultants and residents of the Department of Obststrics

and Gynaecology for their unwavering support for this study.

I am extremely thankful to the staff nurses of our labour theatre who helped me a lot

during this study.

I would like to thank my fellow post-graduates for their help during the course of this

study.

I thank Dr.Saleendran for his valuable help in completing the statistical analysis and

timely attention in compiling this manuscript.

I would finally thank my mother Mrs.Vasanthi and my wife Dr.Surya for supporting

me through all my endeavours.

Last but not the least, a special thanks to the patients who participated in this study.

Dr.Jayaprakash.K

iv

List of Abbreviations

ACOG - American Congress of Obstetricians and Gynecologists

ASA - American Society of Anesthesiologists

BP - Blood pressure

CaN - Cord around the neck

cm - Centimetre

CNS - Central nervous system

CVS - Cardio-Vascular syatem

EEG - Electroencephalogram

FD - Fetal distress

FP- Failure to progress

Ft-obs - Fetal tachypnea for observation

GDM - Gestational diabetes mellitus

h/hr - Hour

HR - Heart rate

IV - Intravenous

Kg - Kilogram

LOR - Loss of resistance

mcg/µg - Microgram

v

MF- Failure of maternal bearing down

mg - Milligram

ml - Millilitre

ML- Meconium stained liquor

mm - Millimetre

Numb - Numbness

PCEA - Patient controlled epidural analgesia

PIH - Pregnancy induced hypertension

RR - respiratory rate

Rx - Treatment

SpO2 - oxygen saturation

Temp - temperature

VAS - Visual Analog scale

VNRS - Verbal numerical rating scale

vi

Abstract:

Topic:

A comparative study of 0.1% ropivacaine with fentanyl versus 0.125%

bupivacaine with fentanyl as continuous epidural infusion in labour analgesia

Background and objectives:

Ropivacaine has been found to be equally efficacious as bupivacaine in

labour epidural analgesia. In our study we compared the analgesic efficacy, motor

blocking property and the effect on various labour outcomes of ropivacaine with

bupivacaine when used as a continuous epidural infusion during labour.

Methodology:

Seventy ASA I&II parturients with singleton pregnancies who presented in

active labour with cervical dilatation of 3-5cm were studied in a prospective,

randomized control manner. Patients were randomized into Group A(ropivacaine)-

35 patients and Group B(bupivacaine)- 35 patients.

Epidural analgesia was performed with a 18G Tuohy needle and a 20G

epidural catheter was placed in the best interlumbar space between L1 and L4.

Various parameters(heart rate, blood pressure, respiratory rate, oxygen saturation,

pain score) and complications if any were recorded every 15 minutes in the 1st hour,

every 30 minutes in the 2nd hour and every hour later on.

All data were collected and statistical analysis performed using SPSS

statistical package, version 17 for windows.

Results:

vii

There was no significant difference in the hemodynamics, pain relief, motor

block, mode of delivery, duration of labour and complications between ropivacaine

and bupivacaine.

Conclusion:

From this study it can be concluded that though ropivacaine is less potent

than bupivacaine, ropivacaine is as efficacaious as bupivacaine in the

concentrations used in our study.

viii

LIST OF TABLES

S.No TABLES PAGE NO.

1 PAIN IN LABOUR – PATHWAYS AND MECHANISMS 8

2 TECHNIQUES OF LABOUR ANALGESIA 15

3 INDICATION FOR EPIDURAL ANALGESIA 32

4 CONTRAINDICATIONS FOR EPIDURAL

ANALGESIA

32

5 IMMEDIATE COMPLICATIONS OF EPIDURAL

ANALGESIA

33

6 STUDY DRUGS PROTOCOL 91

7 NUMBER OF PATIENTS AT EACH TIME POINT IN

BOTH GROUPS

98

8 COMPARISON OF HEART RATE 98

9 COMPARISON OF MEAN SYSTOLIC BLOOD

PRESSURE

99

10 COMPARISON OF MEAN DIASTOLIC BLOOD

PRESSURE

99

11 COMPARISON OF MEAN RESPIRATORY RATE 100

12 COMPARISON OF MEAN PAIN SCORES(VNRS) 101

13 COMPARISON OF BOLUS REQUIREMENT 101

14 COMPARISON OF MEAN DURATION OF LABOUR 102

ix

List of Figures

S.NO Figures PAGE NO.

1. LABOUR PAIN DURING DIFFERENT STAGES OF LABOUR

7

2. EFFECTS OF LABOUR PAIN 13

3. LABOUR PAIN PATHWAYS & REGIONAL BLOCKS USED

20

4. TECHNIQUE OF LABOUR EPIDURAL ANALGESIA 31

5. STRUCTURE OF ROPIVACAINE 42

6. DOSAGE RECOMMENDATIONS FOR ROPIVACAINE IN ADULTS AND CHILDREN

47

7. STRUCTURE OF BUPIVACAINE 49

8. STRUCTURE OF FENTANYL 62

9. EPIDURAL OPIOIDS 63

10. EPIDURAL TRAY AND EPIDURAL SET 89

11. MEAN AGE AND WEIGHT BY GROUP 95

12. GRAVIDA DISTRIBUTION 95

13. PARITY DISTRIBUTION 95

14. ASA STATUS DISTRIBUTION 96

15. LEVEL OF EPIDURAL PLACEMENT DISTRIBUTION BY GROUP

97

16. MODE OF DELIVERY BETWEEN ROPIVACAINE AND BUPIVACAINE

102

17. NEONATAL OUTCOME BETWEEN ROPIVACAINE AND BUPIVACAINE

103

x

Table of Contents

S.No Contents Page no.

1. BONAFIDE CERTIFICATE i

2. DECLARATION BY THE CANDIDATE ii

3. ACKNOWLEDGEMENT iii

4. LIST OF ABBREVIATIONS iv

5. ABSTRACT vi

6. LIST OF TABLES viii

7. LIST OF FIGURES ix

8. INTRODUCTION 1

9. AIMS AND OBJECTIVES 6

10. LABOUR PAIN 7

11. LABOUR ANALGESIA 15

12. ASSESSMENT OF PAIN 24

13. LABOUR EPIDURAL ANALGESIA 25

14. PHARMACOLOGY OF ROPIVACAINE 42

15. PHARMACOLOGY OF BUPIVACAINE 49

16. PHARMACOLOGY OF FENTANYL 62

17. REVIEW OF LITERATURE 66

18. MATERIALS & METHODS 87

19. RESULTS & OBSERVATION 94

20. DISCUSSION 105

21. SUMMARY 112

22. CONCLUSION 114

23. BIBLIOGRAPHY 115

24. APPENDIX – I 125

25. APPENDIX – II – THESIS PROFORMA 126

26. APPENDIX – III – MASTER CHART 130

1

Introduction

Labour is a word that signifies one of the most happiest as well as one

of the most painful moments in a woman's life. If not dealt with properly, it can

lead to unpleasant experiences and mental agony. Labour is a highly complex

and personal process for every woman. Not every woman wants or needs

analgesic intervention for delivery. Every parturient should be educated

prenatally about labour and various modalities available for helping her. The

decision to receive any form of pain relief should be the patient's informed

decision.

The ASA & ACOG have said that

"Labor causes severe pain for many women. There is no other

circumstance where it is considered acceptable for an individual to

experience untreated severe pain, amenable to safe intervention, while

under a physician's care. In the absence of a medical contraindication,

maternal request is a sufficient medical indication for pain relief during

labor. Pain management should be provided whenever medically

indicated."1

Pain relief during labour has always been associated with religious &

cultural taboos, myths & controversies.

Pain free labour was denied to women because of the misinterpretation

of the biblical scripture

"In sorrow though shall bring forth children"

2

This lead clergymen of those bygone eras to insist that suffering in

labour was consistent with divine intent, since it was god's punishment to Eve

for disobeying his word.

This situation began to change in mid 1850's when few concerned

physicians became sympathetic to this agonising plight of women.

The first documented incident of pain relief during labour in USA was

for Fanny Longfellow in1847 with ether.2 The second woman to become

famous was Emma Darwin, wife of the eminent naturalist Charles Darwin who

was administered chloroform during labour. But the third incident influenced

the history of labour analgesia in a profound way. It was the administration of

chloroform to Queen Victoria by Dr.John Snow for her 8th confinement to

deliver Prince Leopold on April 7,1853.2 This made pain relief in labour

famous as well as more acceptable, since it had a royal patronage.

Advances in the field of labour analgesia have tread a long journey

from the days of ether and chloroform in 1847 to the present day practice of

comprehensive program of labour pain management using evidence based

medicine.

From 1840s to 1960s, different methods of pain relief were tried. This

included inhalational agents, systemic agents[opioids, ketamine, Twilight

sleep(morphine + scoploamine)], local blocks.

Most would agree that the ideal analgesic would be safe for the mother

and newborn, would have minimal effects on the progress of labor, and would

provide flexibility in changing conditions. Additionally, the ideal technique

would provide long-lasting, consistent analgesia titrated to individual

3

parturient’s needs, with minimal or no risk, no undesirable maternal or fetal

side effects, and with minimal physician input and cost.

There are various modalities available now commonly. It includes both

pharmacologic and non - pharmacological methods.

Non - pharmacological methods include psychoprohylaxis, hypnosis,

TENS( transcutaneous electrical nerve stimulation), biofeedback, and

acupuncture. Though they provide some form of pain relief, usually it is not

adequate and patients need additional form of pain relief. These methods

usually are unreliable and not consistent in the pain relief they provide.

Pharmacological methods include inhalational agents(entonox,

sevoflurane), systemic opioids (morphine, fentanyl, remifentanyl as PCEA).

Both these agents produce analgesia but not in a continuous and effective

manner. They also have systemic side effects on both the mother and fetus.

They may also interfere with the progress of labour.

Pharmacological methods also include regional anaesthesia. This in

turn comprises both regional blocks and central neuraxial blocks. Though

regional blocks give good pain relief they are associated with technical

difficulties as well. Paracervical plexus blocks are no longer used because of

their association with a relatively high fetal bradycardia. Pudendal nerve

blocks are mostly useful only in second stage of labour.

Central neuraxial blocks were introduced in labour in 1950. Pioneering

research in this field has lead to great development in the safe and effective

practice of neuraxial techniques. Modern neuraxial labour analgesia reflects a

4

shift in obstetrical anesthesia, thinking away from a simple focus on pain relief

and towards a focus on the overall quality of analgesia.3

Central neuraxial analgesia is the most versatile method of labour

analgesia and the gold standard technique for pain control in obstetrics that is

currently available. The satisfaction of birth experience is greater with

neuraxial techniques.4

Central neuraxial analgesia includes both subarachnoid as well as

epidural block

Among these epidural blockade comes close to being the ideal

analgesic technique in labour.4 It has the advantage of being able to provide

continuous analgesia for an unpredictable period of time and to convert

analgesia to anaesthesia if an operative intervention becomes necessary.

Epidural injection of a local anaesthetic combined with an opioid

provides a more rapid onset of analgesia with little motor blockade. The pain

relief starts sooner and also lasts longer than either drug alone. It allows both

the drugs to be used in lower concentration, thereby reducing the risk of local

anaesthetic systemic toxicity as well as opioid side effects.5,6,7

Bupivacaine and Ropivacaine are widely used to provide efficient

epidural analgesia in labour. The value of bupivacaine is limited by the risks of

motor blockade(associated with maternal dissatisfaction and increased

instrumental deliveries) and cardiac toxicity. Ropivacaine has the advantage

of more sensory motor differential blockade as well as decreased risk of

systemic toxicity. There have been conflicting comparisons of ropivacaine and

bupivacaine for labour analgesia.8,9,10 Some studies have suggested that

5

ropivacaine produces less motor block than bupivacaine while others found

the drugs to be indistinguishable. Dilute solutions of epidural local anesthetics

combined with opioids may be used to minimize unwanted motor block.

We undertook this study to see whether ropivacaine offers any

significant advantage over bupivacaine in our institutional practice in regards

to obstetrical outcome and whether a changeover from bupivacaine to

ropivacaine was warranted. This study compares the efficacy of Ropivacaine

and Bupivacaine in regards to pain relief, motor block, labour characteristics.

6

AIMS & OBJECTIVES:

Aim:

The aim of the study was to compare the efficacy of ropivacaine with

fentanyl and bupivacaine with fentanyl as continuous infusion in labour

epidural analgesia.

Objectives:

The current study was designed to compare the efficacy of ropivacaine

with fentanyl and bupivacaine with fentanyl as continuous infusion in labour

epidural analgesia with respect to

Pain relief

Motor block

Duration of labour

Mode of delivery

- Vaginal - Spontaneous / Assisted

- Cesarean section

Neonatal outcome - APGAR score, NICU admission

7

PHYSIOLOGY OF LABOUR PAIN

Labour11- Series of events that take place in the genital organs in an effort to

expel the viable products of conception out of the uterus through the vagina.

Traditionally the labour process is sub-divided into three stages:

1st Stage- Onset of true labour to complete dilatation of the cervix uteri to

about 10 cm.

2nd Stage - From the complete dilatation of the cervix to delivery of the fetus.

3rd Stage - From the delivery of the fetus to expulsion of the placenta.

The total time of labour averages 13 to 14 hours in primigravida and 8

to 9 hours in multigravida women11.

An ‘ideal’ method of analgesia for delivery should therefore abolish the

pain without interfering with the uterine kinetics which are necessary for the

expulsion of the fetus.

Figure-1 - Labour Pain during different stages of Labour

(Copied from Regional Anaesthesia and Analgesia for Labour and delivery; N Engl J Med 2003;348: pg 321)

8

TABLE-1 - Pain in Labour: Pathways and Mechanism (Crawford)12

Site of

Origin

Mechanism Pathway Site of Pain

Uterus and

Cervix

Distortion,

stretching tearing

of fibres

(i)Afferents

accompany

sympathetic

pathway to T10, T11,

T12 and L1

(ii)Dorsal rami T10 –

L1 referred to

cutaneous branches

of posterior divisions

Upper abdomen

and groin

Mid – back

Peri-uterine

tissues,

Lumbosacral

region

Pressure often in

association with

fetal malposition or

platypelloid pelvis

Lumbosacral plexus

L5,S1 (Pelvic

splanchnic nerves)

Lowback, thigh

Bladder,

urethra

rectum

Pressure by

presenting part

S2,3,4 Referred to

Perineum and

sacral area

Vagina Distension, tearing Somatic S2,3,4 Not referred

Perineum Distention, tearing Pudendal N. S2,3,4

Genitofemoral N.L1,2

Ilioinguinal N. L1

Posterior cutaneous

Nerve of thigh, S2,3

Not referred

9

Pain pathways and mechanisms13,14

The description of peripheral pain pathway proposed by Cleland in

193315 was modified by Bonica14 and is fundamental to any consideration of

obstetric analgesia.

Pain in first stage of labour:

Intrinsic mechanism: During the first stage of labour, the pain is caused by:

1. Pressure on the nerve ending between the muscle fibres of the uterine

body and the fundus.

2. Contraction of the ischemic myometrium and the cervix, consequent to

the expulsion of blood from the uterus during contractions.

3. Inflammatory changes in the uterine muscle.

4. Contraction of the cervix and the lower uterine segment consequent to

the fear induced hyperactivity of the sympathetic nervous system.

Uterine contractions cause stretching, tearing and distortion and

possible ischemia of the uterine tissues, while simultaneous dilatation of the

cervix and stretching of the lower uterine segment is occurring. The pain

experienced by the mother is very variable and bears no constant relation with

the dilatation of cervix. These painful stimuli are transmitted by Aδ and C

fibres which accompany sympathetic pathways through the pelvic plexus,

inferior, middle and superior hypogastric plexus and the lumbar sympathetic

chain. The white rami of spinal nerves T11 and T12 are involved, but as labour

progresses T10 and L1 are recruited.

10

Pain pathways in second stage:

Intrinsic mechanism: Pain in the second stage of labour is mainly due to the

progressively increasing pressure of the presenting part causing:

1. Traction on the pelvic parietal peritoneum.

2. Stretching and tension of the bladder, urethra and rectum

3. Stretching and tension of ligaments and muscle of the pelvic cavity and

4. Abnormal pressure on one or more roots of the lumbosacral plexus.

Pain in the second stage is caused by distension of the pelvic

structures and peritoneum following the descent of the presenting part, in

addition to the pain of uterine contractions, although, once cervical dilatation

is complete, the pain induced by uterine contractions is much less intense.

The uterine pain produced by stretching or by pressure exerted in intra pelvic

structures including peritoneum, bladder, urethra and rectum is referred to

sacral segments. Pressure on the roots of lumbosacral plexus may manifest

itself as pain felt low in the back or in the thighs. Pain produced by stretching

of the peritoneum is transmitted by pudendal nerve (S2,3,4) and in part by the

posterior cutaneous nerve of thigh (S2,3), the genitofemoral nerve (L1,2) and

the ilioinguinal nerve (L1).

Central processing of pain:

The Aδ and C fibres conduct pain sensations from the uterus and the

spinal cord. The pain of parturition is mainly a visceral pain and therefore is

conducted in the Aδ and C fibres to the spinal cord. These fibres make

11

contact with lamina I, II and V. The convergence of cutaneous and visceral

fibres in lamina V is believed to form the basis of referred pain in labour.

From the spinal cord, the pain signals are transmitted to the brain via

the spinothalamic tract, which is divided into lateral and medical system. The

lateral system projects into the somatosensory cortex and brings about higher

responses such as fear, anxiety and also helps to initiate an appropriate

course of action. The medial system (slow conducting) project to the reticular

formation, periaqueductal grey matter, the hypothalamus and the limbic

system and is responsible for primitive responses to pain, which includes the

neuroendocrine response and hyperventilation.

Applied Clinical Aspects13:

During the latent phase of the first stage, the pain is felt as an ache or

a moderate cramp and is limited to the T11 and T12 dermatomes. As labour

progresses to the active phase, where the uterine contractions become more

intense, the pain in T11 and T12 dermatomes becomes sharp and cramping

and spreads to the adjacent T10 and L1 dermatomes.

The distribution of T10, T11, T12 and L1 dermatomes in the back overlies

the lower three lumbar vertebrae and the upper half of the sacrum. An

epidural block limited to these four segments produces relief of the low back

pain.

In the late 1st stage and in the early 2nd stage the pain is felt most

sharply in the perineum, in the lower part of the sacrum, anus and in the

thighs. Aching burning or cramping discomfort may appear. By blocking the

lower lumbar and upper sacral segments analgesia can be guaranteed.

12

Complete block of the sacral segments need only be performed when perineal

pain becomes worrisome and by this stage, the block of thoracolumbar

segments will hopefully be decaying to such an extent that abdominal muscle

strength will be adequate to permit voluntary expulsive efforts by the mother.

Effects of neural blockade on parturition13:

The effect of spinal innervation on uterine activity are complex and

depend on neural, hormonal and hemodynamic factor.

Previously it was believed that the motor activity of the uterus was

dependant on the sympathetic output through the lower seven thoracic

segments and that uterine activity would be impaired by blockade upto the

fifth thoracic segment. However subsequent work showed that the uterus is

independent of motor innervation and that uterine activity was more

dependant on humoral factors.

Normal progress in the 2nd stage of unstimulated labour is mainly

dependant on the strong expulsive efforts by the diaphragm on the abdominal

muscles, combined with tone of the pelvic diaphragm through which the

descending part of the fetus rotates. Premature loss of tone in the extrauterine

muscles will modify or delay the progress through poor expulsive efforts or

failure to rotate.

Labour may slow down further if the perineum is anaesthetized too

early in labour due to abolition of ‘Ferguson’s reflex’. The afferents of this

reflex come from receptors of the cervix and the vagina and pass centrally to

stimulate oxytocin secretion from posterior pituitary. However this deficit can

be readily overcome by exogenous oxytocin infusions.

13

In slow, incoordinate labour, analgesia relaxes the patient and the weak

irregular contractions of a high basal tone develop into low pressure, regular,

powerful uterine contractions.

In summary, the epidural blockade appears to have no direct

depressant effect on the uterine contractility besides inhibition of the oxytocin

release due to abolition of the Ferguson reflex. However indirectly, the neural

blockade may result in hypotension, reducing the myometrial perfusion

causing the contractility to fade. Besides, if early blockade of sacral segments

is prevented, the incidence of instrumental deliveries could be curtailed.

Figure – 2 - Effects of Labour pain

(Copied from Epidural Analgesia for Labor and Delivery; N Engl J Med

2010;362:1505)

14

Physiological effects of pain13

When pain of parturition is not adequately treated, several maternal

and fetal sequelae ensue because of the widespread maternal sympathetic

activation. This leads to various hormonal and metabolic disturbances in the

mother. These responses may be classified into cortical, suprasegmental and

segmental effects.

Cortical:

Pain will lead to fear, anxiety and increased skeletal muscle activity.

Suprasegmental:

Hyperventilation causes shift of maternal oxygen dissociation curve to

the left leading to foetal hypoxemia. Hyperventilation followed by

hypoventilation during the interval between uterine contractions leads to

transient apnea in mother. Maternal hypoventilation combined with a decrease

in uterine blood flow caused by catecholamines may lead to fetal hypoxemia.

Increased catecholamine production, hypertension, tachycardia,

increased lactic acid and free fatty acid production, hyperglycemia, increased

oxygen consumption, decreased uterine blood flow, impaired uterine

contractions, increased production of corticosteroids, beta-endorphins etc. are

the other suprasegmental effects.

Segmental:

Increased sympathetic tone produces decreased gastrointestinal

motility, delayed gastric emptying, ileus, nausea and vomiting.

15

LABOUR ANALGESIA

Table-2 - TECHNIQUES OF LABOUR ANALGESIA

Non-Pharmacologic

methods

Pharmacological

methods

Regional

Anaesthetic

techniques

Continuous support

in labour

Touch and massage

TENS

Intradermal

injections

Water bath

Upright posture

Acupuncture/Acupre

-ssure

Hypnosis

Intravenous

Opioids-

Pethidine,

Fentanyl,

Morphine,Remife

ntanyl,

Butorphanol,

Pentazocine

Ketamine

Tramadol

Benzodiazepines

Neuraxial

techniques

Continuous

lumbar

epidural

Combined

spinal

epidural

analgesia

Subarachnoid

block

Continuous

spinal

analgesia

Inhalational

Entonox

Sevoflurane

Alternative regional

techniques

Paracervical

block

Pudendal

block

Lumbar

sympathetic

block

Perineal

infiltration

16

Attempts to minimize the pain of labour non-pharmacologically first

began in the early 20th century. Natural childbirth was pioneered by Grantly,

Dick, Read in 1932. He suggested that the pain of childbirth was brought

about by fear and tension and recommended passive muscle relaxation to

reduce the pain17.

Psychoprophylaxis is a technique which involves educating the

mother about the functioning of her body and the physiology of labour. It

originated in Russia and later popularized in France by Lamez18. Other

techniques involve simple emotional support from the patient’s partner or

another labour companion, touch and massage, the application of hot or cold

compresses and hydrotherapy.

Some techniques require fairly extensive preparation and antenatal

training. These include Biofeedback, Acupuncture, Hypnosis and

Transcutaneous electrical nerve stimulation (TENS). TENS involves the

application of a variable electrical stimulus to the skin at the site of pain and is

based upon the gate theory of pain control36. Studies have shown there to be

great or considerable relief of labour pain in 20-24% of mothers with about

60% having slight relief.

The advantages of all these techniques include quick discontinuation,

noninvasiveness and lack of any demonstrable ill effect on the fetus.

17

Systemic drugs13:

All drugs given systemically will cross the placenta to some extent.

Drugs which may reach the fetus in large amount are those with higher lipid

solubilities and low degrees of ionization20.

Pethidine is the most commonly used opiate in obstetric practice. It is

a synthetic opioid and the usual dose is 50 mg intramuscularly. Intramuscular

pethidine 100mg or 150mg was deemed satisfactory by only 22.4% of women

in first stage of labour and in 47.7% it gave no relief at all. Nausea and

vomiting occur in 50% of patients and exerts both immediate and long term

effects on fetus.

Morphine is a powerful opiate with a longer duration of analgesic

action compared to pethidine. It benefits from the ability to allay anxiety but

frequently causes nausea and vomiting and is apotent depressor of neonatal

respiration.

Benzodiazepines are used for maternal sedation. Diazepam has an

active metabolite, desmethyldiazepam which has a very long half life. Fetal

side effects include hypotonicity, decreased activity, respiratory depression

and decreased response to metabolic stress21. Lorazepam is relatively long

acting but has no active metabolites. It provides good anterograde amnesia,

which may not however be desirable during the birth experience.

Pentazocine is a partial agonist analgesic, and when used in multiple

doses, produces fewer low Apgar scores in babies as compared to

pethidine22. In addition the fetal heart rate is not so affected by pentazocine as

18

it is with pethidine. The chief drawback of pentazocine is unpleasant

hallucinogenic side effects and the limited pain relief that it can produce.

Ketamine has been used to produce analgesia during labour, doses in

the range of 0.25mg/kg reportedly produce effective analgesia without any

adverse effect on uterine blood flow, uterine activity or neonatal status23,24.

Remifentanil is a potent short-acting μ-opioid receptor agonist which is

rapidly metabolised in the mother and fetus. It has been used in PCA(patient

controlled analgesia) successfully with a setting of 20-40 µg bolus with a lock-

out interval of 2-3 minutes. The side effects associated are sedation,

respiratory depression and other opioid related effects. Remifentanil PCA for

labor analgesia is an important advance in the obstetric anesthesia

armamentarium, especially for parturients who do not want neuraxial

analgesia or when its use is contraindicated.25,26,27

Inhalational agents:

Until 1983 when the central midwives board withdrew approval for the

use of trichloroethylene by unsupervised midwives, there were 3 agents

available for use Nitrous oxide, trichloroethylene and methoxyflurance.

Trichloroethylene commonly causes nausea and vomiting and its

sweet smell may be unpleasant. Its use in labour is now uncommon.

Analgesia produced by Methoxyflurance persists into the period after

inhalation ceases. Nausea and vomiting are uncommon and although

inorganic fluoride concentrations are increased in both mother and infant, the

19

risk of renal damage seems negligible as long as inhalation is restricted to low

concentrations for limited periods.

Nitrous oxide was first used as an obstetric analgesic by Klikowitsch

in 1881. It became widely used with the introduction of the Minnitl apparatus

(1934) which delivered a mixture of nitrous oxide in air. In the early 1960’s the

currently available 50:50 prepared mixture of nitrous oxide and oxygen

(entonox) was described by Tunstall(1961). Entonox is employed as aself

administered intermittent inhalation which if used in the correct manner can

produce acceptable levels of analgesia. The effectiveness of entonox in

preventing the pain of labour is of approximately the same order as pethidine.

This has been stated by Beazley et al (1967) as 23% total success but 40%

total failure. It should be possible for 82% of mother to obtain substantial

benefit from inhalational analgesia when properly managed by the midwife.

Isoflurane, a volatile anesthetic agent has been used in a 0.75%

concentration in oxygen (Mc Leonetal 1985) where it produced good

analgesia but with a higher degree of drowsiness. More recently it has been

used in a 0.2% concentration in entonox (Wee et al 1993) where it produced

superior analgesia to entonox alone with no increase in drowsiness.

Sevoflurane, a volatile anaesthetic agent, because of its short onset

and offset of action, appears to be a best suited inhalational agent for labour

analgesia. It is used in the concentration of 0.8% with oxygen. It can provide

useful pain relief during the first stage of labour, and to a greater extent than

Entonox. Although greater sedative effects were experienced with

sevoflurane, it was preferred to Entonox(Yeo ST 2007).28.

20

Figure- 3 - Pathways of labour pain illustrating the nerve pathways

responsible for pain in various stages of labour and the types of blocks that

can block nerve impulse transmission through these pathways to alleviate

labour pain

(Copied from Regional Anaesthesia and Analgesia for Labour and delivery; N

Engl J Med 2003;348: pg 320)

Peripheral nerve blockade:

Paracervial block can be of value in the first stage of labour. It

provides successful analgesia in approximately 80% of mothers (Belfrage and

Floberg 1983). However in the first few minutes after initiating a block a high

incidence of fetal bradycardia associated with a falling pH and oxygen tension

have been seen (Baxi et al 1979). It has been suggested that the block should

be administered in well spaced stages in order to minimize these effects (Van

21

Dorsten at al 1981). This complication has led to a marked diminution of its

use worldwide, although its success and simplicity might justify

reinvestigation.

Pudendal nerve block is almost always used to facilitate operative

vaginal delivery and is usually performed by the obstetrician. Local infiltration

of the perineum may be necessary as one study showed that bilateral

pudendal nerve block was not totally effective in nearly 50% of cases.

Central neuraxial blockade:

Lumbar epidural block

Lumbar epidural is currently the gold standard for pain relief in

obstetrics. Epidural analgesia provides the most effective form of pain relief

devised so far for labour and delivery3,29. The establishment of an epidural

service requires committed individuals and the precence of an anaethetist in

the labour ward, as well as equipment and staff education.

Corning has been credited with being the first to use epidural analgesia

in 1885. For many years caudal rather than lumbar epidural blockade was the

preferred method of obstetrics and postoperative pain relief. The use of

Tuohy’s needle in 1949 and the use of continuous catheter technique in both

caudal and lumbar epidural played a major part in enabling improvement in

epidural neural blockade.

Early 1970s saw an increased understanding of the segmental

blockade and its advantages with minimal local anesthetic dosage, thus

reducing the toxicity.

22

Caudal extradural block

Caudal extradural block is useful in the late first stage and second

stage of labour. It provides good relaxation of the perineal muscles. Problems

include a relatively high forceps rate, attributed to abnormalities of rotation of

the fetal head due to relaxation of the pelvic floor.

Intrathecal block

Single shot spinal have limited utility in early labour and are more

useful in the second stage of labour. It is an easier block than epidural

blockade and provides good relaxation for the pelvic musculature.

Disadvantages citied include post dural puncture headaches. However its

incidence is low with the use of fine pencil point (26 or 27G) needles.

Combined spinal epidural (CSE)

Since the introduction of this technique in the early 1980’s it has gained

increasing popularity for analgesia in labour and delivery. Because CSE has

a higher ambulatory potential it has been called the walking epidural. The

advantages are rapid and excellent pain relief, lower drug usage, and can be

used in advanced labour and in very demanding and uncooperative patients.

Requirements of a satisfactory analgesic technique in labour are as

follows (after Bromage)30

1) Safety

2) Effective analgesia throughout painful periods of labour.

3) No depressant effect on the maternal respiratory or cardiovascular

system.

23

4) No depressant effects on the progress of labour.

5) No depressant effects on the baby before or after delivery.

6) No unpleasant maternal side effects.

7) High technical success rate.

24

ASSESSEMENT OF ACUTE PAIN16

Pain is a uniquely personal symptom with no reliable objective signs,

so we have to accept an individual’s “self-report” of the severity of the pain

they are experiencing. A variety of “self-reporting” pain severity scoring

systems are used for adults; they correlate well and are generally reliable. It is

important that patients understand the method used, what us being assessed,

and why, and that the same method continues to be used to ensure reliability

and avoid confusion.

Categorical rating scales (CRS)

Frequently used to assess postoperative pain because it is a widely

applicable verbal method that can employ different descriptors of pain, e.g. No

pain, mild pain, moderate pain, severe pain.

Visual analog scale (VAS)

Employs a 10-cm draw line with the left anchor point descriptor labeled

“no pain’’ and the right-sided equivalent labeled “worst possible pain”. It

requires patients to mark their current pain severity on the continuum. The

VAS score is the measured distance from the “no pain” point to the pain

estimate.

Verbal numerical rating scale (VNRS)

Asks patient to estimate their pain severity as a number,”0” being no

pain and “10”being the worst possible pain. VNRS is easy to use, has better

responsiveness and better compliance.31Studies have shown NRS and VAS

have similar sensitivity.32 Beilin(2003)33 found NRS useful in the parturient

patients. Hence in this study we decided to use VNRS as the pain scoring

system.

25

Labour Epidural Analgesia

Of all the various modalities of pain relief available, Neuraxial labor

analgesia(most commonly epidural or combined spinal-epidural) is the most

effective method of pain relief during childbirth, and the only method that

provides complete analgesia without maternal or fetal sedation.3 Recent

Cochrane review on epidural analgesia has also come to the same

conclusion. Though CSEA is growing by leaps and bounds and offers effective

analgesia, we have limited our study to Continuous Epidural Analgesia.

26

ANATOMY OF EPIDURAL SPACE

Definition13

Epdidural Space is a potential space within the bony cavity of the

spinal canal outside the dural sac. It extends from foramen magnum to

coccyx communicating laterally with paravertebral space through the

intervertebral formina.

Boundaries35

Superiorly -The foramen magnum where the periosteal and spinal

layers of dura fuse together.

Inferiorly - The Sacrococygeal ligament.

Anteriorly - The posterior longitudinal ligament covering the posterior

aspect of the vertebral bodies and the intervertebral disc.

Posteriorly - Ligamentum flavum and the periosteum of the laminae.

Laterally - The pedicles of the spinal column and the intervertebral

foramina containing their neural elements.

Contents of the epidural space

The epidural space contains nerve roots that traverse it from foramina

to peripheral location, fat, areolar tissue, lymphatics and blood vessels, which

include the well organized Batson venous plexus.36

27

Epidural Veins

The epidural venous plexus is a valveless system, well known as

Batson venous plexus37. The veins form a network that run in four main trunks

along the space. They communicate with venous rings at each vertebral level,

with the basivertebral veins on the posterior aspect of each vertebral body

and with the ascending and deep cervical, intercostals, iliolumbar and lateral

sacral veins. They connect the pelvic veins below with the intracranial veins

above, so that air or other local anaesthetic solution injected into one of them

may ascend straight to the brain31.

Chronically increased intra-abdominal pressure or obstruction of the

inferior vena cava (as in late trimester of pregnancy or in the presence of

large intra abdominal tumour) can distend the epidural venous plexus, with

important implications for epidural anaesthesia.

Arterial Supply

Arteries enter the epidural space at each intervertebral foramen and

supply adjacent vertebra, ligaments and spinal cord. These arteries are from

the vertebral, deep cervical, ascending cervical, intercostal and lumbar and

iliolumbar arteries. They anastamose with their neighbors above and below,

cross the midline and lie chiefly in the lateral parts of the epidural space.

Fat and Areolar Tissue13

The epidural space is always said to contain fat, but since dural sac

virtually fills the bony spinal canal, this usually amounts to no more than a thin

transparent film of areolar tissue.

28

Nerve Roots13

31 pairs of spinal nerves with their dural cuffs traverse the space on

their way to the intervertebral foramina, the lower ones traveling at an

increasingly oblique angle.

Epidural Space in Pregnancy

The epidural space in parturients is at a distance of about 4-5cm from

the skin. The distance from the postero-medial border of ligamentum flavum

to the duramater is greatest in the second lumbar interspace ranging between

4mm to 8mm. Hence an epidural needle interested by the midline approach

should enter the space as close to the midline as possible to maximize the

distance between the ligamentum flavum and the dura38.

Hormonal changes affect vertebral ligamentous structure and may

make the ligamentum flavum feel softer39. Pregnant patients do not flex their

lumbar spine optimally, which may narrow the interspinous spaces and move

the line between interiliac crests [Tuffier’s line] more cephalad35.

Pregnancy induced widening of the pelvis may result in a head down

tilt of the spine in the lateral position potentially affecting the spread of

drugs40. Parturients may have presacral edema, making landmark

identification more difficult.

Epidural Volume13,36

The epidural veins are veins of the vertebral venous plexus, which form

an alternative pathway by which blood can reach the heart from the lower

extremity. This is of special Importance in pregnancy for compensating for the

obstruction to the inferior vena cava. In consequence, the epidural veins are

29

dilated and engorged. Since the total volume of the epidural space is fixed,

the engorged veins act as a space – occupying lesion to reduce the volume of

the extravascular portion of the space. Hence the local anaesthetic solution

injected in the epidural space will spread more extensively, reducing the dose

requirement of lumbar epidural analgesia in pregnancy. Also puncture of

engorged veins by an epidural catheter tip is more common during pregnancy.

Epidural Pressure13

In non-pregnant subjects the pressure in the lumbar epidural space is

normally 1 cm H2O. In early labour, between contractions, pressure in the

lateral position averages 1.63 cm H2O and rises to between 4-10 cm H2O by

the end of the first stage. Assuming the supine position will increase epidural

space pressure by upto 50% and this is proportional to the degree of inferior

vena caval obstruction. Uterine displacement will moderate the rise

prouduced in this position41.

Clinical Significance

The pressure in the epidural space is positive during labour. So

methods of identifying the space that depend on negative pressure should not

be used.

During uterine contraction the reflex increase in abdominal muscle tone

and the sudden efflux of blood from the contraction myometrium into the

venous system contribute to a further rise in epidural space pressure from 2-

8cm H2O, even in lateral position. Adequate epidural pain relief minimizes the

pressure rise produced during contraction13.

30

Reasons for decrease in local anesthetic doses are:

1. Decrease in epidural space volume

2. Increased lordosis

3. Progesterone effect

4. Sensitivity to local anesthetic agent

5. During uterine contraction epidural space pressure increases

Taken together these changes may contribute to the observation that

pregnancy increases the extent of epidural block produced by a given dose of

drugs.42,43

Site of Action13

When a solution of a local anaesthetic is injected into the epidural

space, it may exert its effects.

1. On the nerve roots in the epidural space

2. On the nerves in the paravertebral spaces after they have shed their

dural sheaths

3. On the nerve roots in the subarachnoid space after inward diffusion of

drug across the dura

31

Sensitivity of Local Anaesthetic Agents

Nerves from pregnant animals (including humans) appear more

susceptible to local anaesthetic blockade. In rats44,45 and humans42,46,

pregnancy enhances the effect of central and peripheral local anaesthetics.

However, pregnancy does not enhance isolated spinal nerve root axon

susceptibility to bupivacaine47. Proposed mechanisms of enhanced neural

blockade during pregnancy include hormone related changes in the action of

spinal cord neurotransmitters, potentiation of the analgesic effect of

endogenous analgesic systems, increased permeability of the neural sheath

and other pharmacodynamic or pharmacokinetic difference between pregnant

and non-pregnant women48. Even during early pregnancy, the spread of

epidural local anaesthetic blockade is increased42, a phenomenon explained

by altered sensitivity to local anaesthetic as opposed to gross changes in

spinal column anatomy.

Figure-4

Technique of Labour

Epidural Analgesia

(Copied from Regional

Anaesthesia and

Analgesia for Labour

and delivery; N Engl J

Med 2003;348:pg 320)

32

INDICATIONS AND CONTRAINDICATIONS FOR EPIDURAL ANALGESIA

Indications16:

Maternal Fetal

1. Painful Labour

2. Incoordinate uterine action

3. Pregnancy induced hypertension

4. Cardiac diseases

5. Premature Labour

6. Multiple Births

7. Diabetes Mellitus

8. Asthma and respiratory diseases

9. Neurovascular diseases

10. Prolonged labour

1. Prematurity

2. Breech presentation

3. Multiple gestation

Contraindications16

Absolute Relative

1. Patient refusal

2. Local sepsis

3. Severe anemia

4. Coagulopathy

5. Hypovolemia

6. Fixed cardiac output state

7. Inability to cooperate

1. Pre-existing neurological

disease

2. Severe deformity of spine

Table-4 Contraindications for epidural analgesia

Table-3-Indications for epidural analgesia

33

ADVERSE MATERNAL AND FETAL EFFECTS OF EPIDURAL

ANALGESIA13

Maternal

Immediate

During Insertion – needle or catheter

Penetrate blood vessel, duramater,

neural tissue, broken catheter

Due to Injection

Subarachnoid

Intravascular

Adverse reaction to local anesthetic

Neural blockade

Hypotension

Motor block

Bladder dysfunction

Horners syndrome

Shivering

Inadequate analgesia Total failure

Partial failure

Progress of labour Prolonged labour

Increased instrumental deliveries

Delayed

a) Neurological - Epidural abscess

Epidural Hematoma

Chemical meningitis

Damage to nerve roots by needle

Ischemia of cords

Table-5 – Immediate complications of epidural analgesia

34

b) Headache - Post dural puncture

c) Soreness at the site of needle entry

d) Broken cannula tip retention

Fetal

Immediate

a) Direct effect of local anesthetic

b) Indirect effect – Changes in uterine blood flow, Maternal hypoxia,

Changes in progress and outcome of labour

Delayed

a) Neurobehavioral Changes

PROBLEMS ASSOCIATED WITH EPIDURAL ANALGESIA

Hypotension:

It is a relatively common complication that can be easily prevented by

preloading the patient with ringer lactate solution (10-15ml/kg) and avoiding

aortocaval compression. Treatment includes more fluids, oxygen, and

ephedrine 3-6 mg IV in incremental doses49.

Dural puncture and post dural puncture headache:

The reported incidence of inadvertent dural puncture varies from 0.2-

7%49. Though a rare complication, it has disturbing sequelae of post dural

puncture headache. Its incidence in obstetrics remains about 1-5% even with

35

very small-bore spinal needle and optimized tip. PDPH has a major impact on

morbidity and on the patient’s satisfaction50.

The maintenance of high intake of fluids either orally or intravenously

has been suggested as a means of alleviating the symptoms of PDPH

(Kaikinen. S. Kaukinen 1981). Caffeine is commonly recommended for the

treatment of PDPH because of its cerebral vasoconstrictor properties.

Camann et al51 evaluated the use of caffeine for the treatment of PDPH and

found ab Improvement in 18 of the 20 patients. Epidural blood patch remains

the gold, standard treatment for PDPH with success rate of greater than 90%

and a low complication rate52.

Total spinal block

Total spinal block with rapidly developing hypotension,

unconsciousness, and respiratory paralysis may occur if the drug us

accidentally injected intrathecally. However this complication can be avoided

by a cautious approach and using test dose before the injection of the drug.

Since a smaller dose is used in selective epidural block, recovery will be more

rapid.

Blood tap:

The epidural venous plexus distortion present during pregnancy further

increases during uterine contractions. As a result, upto 10% of obstetric

epidural needle insertion amy involve a bloody tap and catheterization of

epidural vein may occur in upto 9% of cases (Verniquet 1980). Repositioning

the catheter in an adjacent space in the event of bloody tap can prevent

intravenous injection of the local anesthetic49.

36

Backache:

The incidence of backache after epidural anaesthesia has varied from

15-45%. However similar rates of 10.5 – 40% have been reported following

vaginal delivery without epidural block (Grovel L.H, Moir D.D, Mc Arthur) and

therefore other causes of backache need to the explored. Ronbuttler53 in his

study has found that back pain following epidural anaesthesia is common but

persistent back pain is much less common and a previous history of backache

increases the likelihood of postpartum backache following epidural

anaesthesia.

Shivering:

Incidence of shivering, in parturients receiving epidural analgesia

ranges from 20-50%(Webb 1981) with an incidence of 22% in parturients

without epidural analgesia. Thus an epidural vasodilatation cannot be wholly

responsible and other mechanisms such as maternal immunoglobulin

response to amniotic fluid or fetal cells has been suggested.

Urinary retention:

When the epidural block affects the sacral segments the mother may

not be aware of full bladder which may impede the progress of labour. Thus

the mother should be encouraged to void regularly and If required intermittent

catheterization should be done49.

Non fatal neurological complications:

Recent survey indicates that the incidence of non-fatal neurological

complication various from 1 in 7000 to 1 in 14,000(Scott D.B.) of which

37

commonest was single nerve neuropathy. In most cases the problem resolved

spontaneously but recovery may take several months49.

THE ADVANTAGES OF OBSTETRIC EPIDURAL ANALGESIA:

In obstetric units where successful epidural service is established,

almost any medical or obstetric complication may be regarded as an

indication for regional analgesia. This is largely because it may be desirable to

avoid both the stress of painful labour and the risk of general anaesthesia

should operative delivery be necessary.

Pain relief:

It is a single most important indication for epidural analgesia, which not

only provides physiological benefits to both mother and fetus but also makes

a parturient more comfortable, less fatigued and therefore more cooperative.

Hypertension:

Pregnancy induced hypertension is the commonest obstetric indication

for epidural analgesia. Epidural blockade is of little value in the absence of

pain,but in labour it has generally been found to control hypertension

successfully and better than hydralazine and magnesium sulphate (Neri et al

1986). Epidural analgesia prevents the sympathoadrenal over activity that is

characteristic of preeclampsia54, produces favorable hemodynamic changes

(Newsome et al 1986) and a consistent improvement in intervillous blood

flow55. Early work also showed how the complete analgesia could minimize

the chance of seizures (Moir et al 1972). Moreover, general anaesthesia that

is particularly risky in the presence of laryngeal edema can be avoided. There

38

can be little doubt however of its value in preeclampsia provided the catheter

is inserted before the onset of any coagulopathy.

Cardiac disease:

These patients have a propensity towards decompensation during

labour. Epidural pain relief can minimize the adverse effect of increased

cardiac output due to pain or anxiety.

Pulmonary disease:

Epidural analgesia is of benefit in pulmonary disease because it avoids

hyperventilation associated with painful contraction.

Trial of labour:

Review of labour in several 100 women with previous caesarean

sections suggest that epidural anaesthesia in no way masks the danger of

scar dehiscence or rupture (Carlsson et al 1980, Uppington 1983). The pain

from the scar and pain from the uterine contractions are felt at the same site

and the scar is most likely to be stressed during a contraction. Epidural local

anaesthetic more readily blocks the pain of uterine contraction (which is

conducted by AD fibres) than pathological pain, (predominantly C fibre

stimulation) so that it may aid in the diagnosis of scar dehiscence.

Rowbottom56 in his study found that the pain of uterine rupture was relieved

by bupivacaine 0.375% 6ml but not masked by the addition of fentanyl 25mcg

to bupivacaine 0.25% 6ml. The same phenomenon has been observed with

placental abruption in which epidural blockade does not abolish the pain

(Paterson 1979). Analgesia given early in these patients may reduce maternal

39

exhaustion and subsequently be converted to epidural anaesthesia in case a

caesarean section is warranted.

Conversion to obstetric anaesthesia:

If an epidural catheter is already insitu, in the event of fetal distress or

any need of caesarean section; it can easily be converted to anesthesia by

simply altering the dose of the drug, and the position of the patient, thus,

saving time and effort.

Preterm labour and twin pregnancy:

Osbourne et al suggested that the use of epidural analgesia in preterm

labour did improve the outcome for baby. Labour is less stressful and delivery

is less traumatic. Epidural analgesia was associated with reduced neonatal

mortality rate among low birth weight babies (David and Roren 1976).

Likewise the outlook in twin pregnancy particularly for the second twin is

improved (Crawford 1987).

Benefit in incoordinate uterine action:

By decreasing the catecholamine secretion associated with labour

pain, epidural block can improve uterine contractility and rhythmicity and is

especially indicated in cases of incoordinate uterine action.

Fetal indications:

Preterm fetus, Breech Presentation & Multiple pregnancy-

In these conditions an epidural block allows a more controlled delivery

because of relaxed pelvic floor muscles and a decreased urge to push.

40

Decreased blood loss:

It is evidenced following vaginal delivery under epidural block as

compared to delivery without epidural block (Bound A.G., Minor D.D). This

can be explained by the epidural induced peripheral vasodilatation that leads

to venous pooling and thus decreased cardiac output. Also, since the pelvic

viscera receive their vasomotor innervation (motor efferent) from T5 to T10,

which is above the level of epidural blockade (only T11 to L1 segment is

blocked in selective epidural) the baroreceptor response can produce

compensatory vasoconstriction of the pelvic viscera via the unblocked T5 to

T10 a segment and thus, lead to diminution of bleeding49.

Modes of epidural:

The epidural is usually initiated with a loading dose of either local

anaesthetic or local anaesthetic with opioids. Following this there are different

types of maintenance regimes. They are

1.Intermittent boluses – The patients are given intermittent boluses when

their pain increases. The maternal satisfaction is good & quality of analgesia

is good. But there may be peaks and valleys in pain relief. There is greater

chance of risk of hypotension, local anaesthetic toxicity and motor block.

2.Continuous infusion – The patients are on a background infusion of

local anaesthetic and opioids and breakthrough pain is treated with top-up

boluses. The maternal satisfaction, quality of analgesia is good. The analgesia

is also continuous without the peaks and troughs. The amount of drug

utilization may be high. The risk of hypotension, motor block is intermediate.

41

3.PCEA(patient controlled epidural analgesia) – Here the patient

controls her own medications. The PCEA can be given as demand only or

with continuous infusion The bolus, lock-out interval, maximum dose per hour

are set with or without a basal infusion. The maternal satisfaction is the

highest in this group, since it gives the pain control in the hands of patient

itself. The quality of analgesia is good, the drug utilization minimal. The risk of

local anaesthetic toxicity, hyotension and motor blockade is minimal. Demand

only PCEA has an increased incidence of breakthrough pain and higher pain

scores.

42

ROPIVACAINE

It is a new, long-acting local amide anesthetic with similarities in

structure, pharmacology and pharmacokinetics to that of bupivacaine.

Ropivacaine is a pure (S-isomer) enantiomer.

STRUCTURAL FORMULA

MECHANISM OF ACTION 57,58

Ropivacaine reversibly interferes with the entry of sodium into the

nerve cell membranes, leading to decreased membrane permeability to

sodium and raises the threshold for electrical excitability. It blocks the

generation and the conduction of nerve impulses, presumably by increasing

the threshold for electrical excitation in the nerve, by slowing the propagation

of the nerve impulse, and by reducing the rate of rise of the action potential.

The order of blockade affecting the nerve fibres is: autonomic, sensory and

motor; and the effect disappears in the reverse order. Clinically the order of

loss of sensation is: pain, temperature, touch, proprioception and skeletal

muscle tone. Repeated activation by a train of depolarizing pulses increases

the inhibitory effects of ropivacaine and produces a hyperpolarizing shift.

Figure – 5 - Structure of Ropivacaine

43

PHYSIOCHEMICAL PROPERTIES

It is chemically described as S-(-)-1-propyl-2',6'-pipecoloxylidide

hydrochloride monohydrate. The drug substance is a white crystalline powder,

with a molecular formula of C17H26N2O·HCl·H2O and molecular weight of

328.89. The pKa of ropivacaine is approximately the same as bupivacaine

(8.1) However, ropivacaine has an intermediate degree of lipid solubility

compared to bupivacaine and mepivacaine. The specific gravity of

ropivacaine solution ranges from 1.002 to 1.005 at 25°C.

PHARMACOKINETICS 58

ABSORPTION

The systemic concentration of ropivacaine is dependent on the total

dose and concentration of drug administered, the route of administration, the

patient's hemodynamic/circulatory condition, and the vascularity of the

administration site. From the epidural space, ropivacaine shows complete and

biphasic absorption. The half-lives of the 2 phases, (mean ± SD) are 14 ± 7

minutes and 4.2 ± 0.9 h, respectively. The slow absorption is the rate limiting

factor in the elimination of ropivacaine which explains why the terminal half-

life is longer after epidural than after intravenous administration. Ropivacaine

shows dose proportionality up to the highest intravenous dose studied, 80 mg,

corresponding to a mean ± SD peak plasma concentration of 1.9 ± 0.3 µg/mL

DISTRIBUTION

After intravascular infusion, ropivacaine has a steady state volume of

distribution of 41 ± 7 litres. Ropivacaine is 94% protein bound, mainly to α1-

44

acid glycoprotein. An increase in total plasma concentrations during

continuous epidural infusion has been observed, related to a postoperative

increase of α1-acid glycoprotein. Variations in unbound, i.e.,pharmacologically

active concentrations have been less than in total plasma concentration.

Ropivacaine readily crosses the placenta and equilibrium in regard to

unbound concentration will be rapidly reached.

METABOLISM

Ropivacaine is extensively metabolized in the liver, predominantly by

aromatic hydroxylation mediated by cytochrome P450 (CYP)1A2 to 3-hydroxy

Ropivacaine and by N-dealkylation by CYP3A4 to 2',6'-pipecoloxylidide

(PPX).After a single IV dose, approximately 37% of the total dose is excreted

in the urine as both free and conjugated 3-hydroxy ropivacaine. Low

concentrations of 3-hydroxy ropivacaine have been found in the plasma.

Urinary excretion of the 4-hydroxy ropivacaine, and both the 3-hydroxy N-de-

alkylated (3-OH-PPX) and 4-hydroxy N-de-alkylated (4-OH-PPX) metabolites

account for less than 3% of the dose. An additional metabolite, 2-hydroxy-

methyl-ropivacaine has been identified but not quantified in the urine.

The N-de-alkylated metabolite of ropivacaine (PPX) and 3-OH-

ropivacaine are the major metabolites excreted in the urine during epidural

infusion. Total PPX concentration in the plasma was about half as that of total

ropivacaine; however, mean unbound concentrations of PPX was about 7 to 9

times higher than that of unbound ropivacaine following continuous epidural

infusion up to 72 hours. Unbound PPX, 3-hydroxy and 4-hydroxy ropivacaine,

45

have a pharmacological activity in animal models less than that of

ropivacaine.

There is no evidence of in vivo racemization in urine of ropivacaine.

ELIMINATION

The kidney is the main excretory organ for most local anesthetic

metabolites. In total, 86% of the ropivacaine dose is excreted in the urine after

intravenous administration of which only 1% relates to unchanged drug.

Ropivacaine has a mean ± SD total plasma clearance of 387 ± 107 mL/min,

an unbound plasma clearance of 7.2 ± 1.6 L/min, and a renal clearance of 1

mL/min.

The mean ± SD terminal half-life is 1.8 ± 0.7 h after intravascular

administration and 4.2 ± 1.0 h after epidural administration.

DIFFERENTIAL CONDUCTION BLOCK

With low concentrations of local anaesthetic, selective blockade of pre -

ganglionic sympathetic nervous system B fibres occur. Slightly higher

concentrations interrupt conduction in small C fibres and small and medium

sized Aδ fibres with loss of pain and temperature sensation.

PHARMACODYNAMICS

Systemic absorption of ropivacaine can produce effects on the central

nervous and cardiovascular systems. At blood concentrations achieved with

therapeutic doses, changes in cardiac conduction, excitability, refractoriness,

contractility, and peripheral vascular resistance have been reported. Toxic

blood concentrations depress cardiac conduction and excitability, which may

46

lead to atrioventricular block, ventricular arrhythmias and to cardiac

arrest,sometimes resulting in fatalities. In addition, myocardial contractility is

depressed and peripheral vasodilation occurs, leading to decreased cardiac

output and arterial blood pressure. Animal studies have demonstrated that the

cardiac toxicity of ropivacaine is less than bupivacaine as ropivacaine causes

significantly less depression of cardiac contractility (QRS widening).59

Following systemic absorption, ropivacaine can produce central

nervous system stimulation, depression or both. Apparent central stimulation

is usually manifested as restlessness, tremors, shivering, progressing to

convulsions, followed by depression and coma, progressing ultimately to

respiratory arrest. However, ropivacaine may have a primary depressant

effect on the medulla and on higher centers. The depressed stage may occur

without a prior excited stage.

DOSAGE AND ADMINISTRATION

The rapid injection of a large volume of ropivacaine solution should be

avoided and fractional (incremental) doses should always be used. The

smallest dose and concentration required to produce the desired result should

be administered.

The dose of ropivacaine administered varies with the anesthetic

procedure, the area to be anesthetized, the vascularity of the tissues, the

number of neuronal segments to be blocked, the depth of anaesthesia and

degree of muscle relaxation required, the duration of anaesthesia desired,

individual tolerance, and the physical condition of the patient. Patients in poor

general condition due to aging or other compromising factors such as partial

47

or complete heart conduction block, advanced liver disease or severe renal

dysfunction require special attention although regional anaesthesia is

frequently indicated in these patients. To reduce the risk of potentially serious

adverse reactions, attempts should be made to optimize the patient's

condition before major blocks are performed, and the dosage should be

adjusted accordingly.

Figure-6 - Dosage

recommendations for

ropivacaine in adults and

children

(Copied from Ropivacaine:

A review of its

pharmacology and clinical

use; Indian J Anaesth.

2011 Mar;55(2):pg107)

48

SIDE EFFECTS:

INCIDENCE (≥5%)

For the indications of epidural administration in surgery, cesarean

section, postoperative pain management, peripheral nerve block, and local

infiltration,, the following treatment-emergent adverse events were reported

with an incidence of ≥5% in all clinical studies(N=3988):hypotension (37.0%),

nausea(24.8%), vomiting(11.6%), bradycardia(9.3%),fever(9.2%), pain(8.0%),

postoperative complications(7.1%), anemia(6.1%), paraesthesia(5.6%),

headache(5.1%), pruritus (5.1%), and back pain (5.0%).

INCIDENCE (1-5%)

Urinary retention, dizziness, rigors, hypertension, tachycardia, anxiety,

oliguria, hypoesthesia,chest pain, hypokalemia, dyspnea, cramps, and urinary

tract infection.

PRECAUTIONS:

Ropivacaine should be used in patients receiving CYP1A2(involved in

metabolizing Ropivacaine to 3-hydroxy Ropivacaine,a major metabolite)

inhibitors like fluvoxamine and enoxacin,since this may lead to an increased

plasma concentration of Ropivacaine.

49

BUPIVACAINE

It was synthesized by O.F Ekenstan in 1957. It is the first long acting

amino-amide local anaesthetic agent. It was introduced in clinical practice by

Widman in 1963. It is chemically designated as 2-piperidinecarboxamide, 1-

butyl-N-(2, 6- dimethylphenyl)-, monohydrochloride,monohydrate and has the

following structure

MECHANISM OF ACTION

Bupivacaine reversibly interferes with the entry of sodium into the

nerve cell membranes leading to decreased membrane permeability to

sodium and raises the threshold for electrical excitability.60 It blocks the

generation and the conduction of nerve impulses presumably by increasing

the threshold for electrical excitation in the nerve, by slowing the propagation

of the nerve impulse, and by reducing the rate of rise of the action potential.

Binding affinities of local anesthetics to sodium channels are stereo specific

and depend on the conformational state of the sodium channel.61 Sodium

channels exist in activated (open), inactivated (closed) and resting (closed)

states during various phases of the action potential. Bupivacaine selectively

binds to sodium channels in the inactivated closed state, thereby stabilizing

these channels and preventing their change to rested closed and activated

Figure-7- Structure of bupivacaine

50

open states in response to nerve stimulus. It binds to specific sites located on

the inner position of the sodium channels and obstructs the external openings

and maintains them in the inactivated closed state, which is not permeable to

sodium, so that the conduction of nerve impulses does not occur. On repeated

application of depolarization, partially depressed sodium ion current (tonic

inhibition) is further reduced leading to phasic inhibition called use dependent

block. The sole use of local anesthetic is less common than the use of local

anesthetic-opioid combination because of a significant failure rate (regression

of sensory block and inadequate analgesia) and relatively high incidence of

hypotension. In general, the progression of Anaesthesia is related to the

diameter, myelination and conduction velocity of affected nerve fibers.

Clinically, the order of loss of nerve function is as follows: (1) pain, (2)

temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

PHYSIOCHEMICAL PROPERTIES

Bupivacaine Hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-

dimethylphenyl)-,monohydrochloride, monohydrate, a white crystalline powder

that is freely soluble in 95 percent ethanol, soluble in water, and slightly

soluble in chloroform or acetone. The pKa of bupivacaine is 8.1. However,

bupivacaine possesses a greater degree of lipid solubility and is protein

bound to a greater extent than lidocaine.

It is 95% protein bound. It is a chiral drug having a left(S) or right (R)

configuration. It is available for clinical use as racemic mixtures of the

enantiomers. It is 4 times more potent than lidocaine.

51

The dural permeability and the movement of local anaesthetic through

the sodium channel of the nerve membrane is claimed to be more dependent

on the molecular weight. The molecular weight of bupivacaine is 288: most

other local anesthetics are of smaller molecular weights.

High lipid solubility promotes diffusion through membranes, thereby

speeding the onset of action and also increasing the potency and duration of

effect. Higher the aqueous lipid solubility coefficient (343 for bupivacaine),

more rapid is the entry into the lipid membrane and longer is the duration of

action.

DIFFERENTIAL CONDUCTION BLOCK

With low concentrations of local anaesthetic, selective blockade of pre-

ganglionic sympathetic nervous system B fibres occur. Slightly higher

concentrations interrupts conduction in small C fibres and small and medium

sized A fibres with loss of pain and temperature sensation.

PHARMACOKINETICS

ABSORPTION

The rate of systemic absorption of local anesthetics is dependent upon

the total dose and concentration of drug administered, the route of

administration, the vascularity of the administration site, and the presence or

absence of epinephrine in the anesthetic solution. A dilute concentration of

epinephrine (1:200,000 or 5 mg/mL) usually reduces the rate of absorption

and peak plasma concentration of bupivacaine, permitting the use of

52

moderately larger total doses and sometimes prolonging the duration of

action.

The onset of action with bupivacaine is rapid and anaesthesia is long-

lasting. The duration of Anaesthesia is significantly longer with bupivacaine

than with any other commonly used local anesthetic. It has also been noted

that there is a period of analgesia that persists after the return of sensation,

during which time the need for potent analgesics is reduced.

DISTRIBUTION

Local anesthetics are bound to plasma proteins in varying degrees.

Generally, the lower the plasma concentration of drug, the higher the

percentage of drug bound to plasma proteins. Local anesthetics appear to

cross the placenta by passive diffusion. The rate and degree of diffusion is

governed by: (1) the degree of plasma protein binding, (2) the degree of

ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local

anesthetics appear to be inversely related to the degree of plasma protein

binding, because only the free, unbound drug is available for placental

transfer. Bupivacaine, with a high protein binding capacity (95%), has a low

fetal/maternal ratio (0.2-0.4). First pass pulmonary extraction is dose

dependent.62

The extent of placental transfer is also determined by the degree of

ionization and lipid solubility of the drug. Lipid soluble, non-ionized drugs

readily enter the fetal blood from the maternal circulation.

53

Depending upon the route of administration, local anesthetics are

distributed to some extent to all body tissues, with high concentrations found

in highly perfused organs such as the liver, lungs, heart and brain.

Pharmacokinetic studies on the plasma profile of bupivacaine after

direct intravenous injection suggest a three-compartment open model. The

first compartment is represented by the rapid intravascular distribution of the

drug. The second compartment represents the equilibration of the drug

throughout the highly perfused organs such as the brain, myocardium, lungs,

kidneys, and liver. The third compartment represents an equilibration of the

drug with poorly perfused tissues, such as muscle and fat. The elimination of

drug from tissue depends largely upon the ability of binding sites in the

circulation to carry it to the liver where it is metabolized.

After injection of bupivacaine for caudal, epidural or peripheral nerve

block in man, peak levels of bupivacaine in the blood are reached in 30 to 45

minutes, followed by a decline to insignificant levels during the next 3 to 6

hours.

Various pharmacokinetic parameters of the local anesthetics can be

significantly altered by the presence of hepatic or renal disease, addition of

epinephrine, factors affecting urinary pH, renal blood flow, the route of drug

administration, and the age of the patient. The half-life of bupivacaine in

adults is 2.7 hours and in neonates 8.1 hours.

In clinical studies, elderly patients reached the maximal spread of

analgesia and maximal motor blockade more rapidly than younger patients.

Elderly patients also exhibited higher peak plasma concentrations following

54

administration of this product. The total plasma clearance was decreased in

these patients.

METABOLISM

Amide-type local anesthetics such as bupivacaine are metabolized

primarily in the liver via conjugation with glucuronic acid. Patients with hepatic

disease, especially those with severe hepatic disease, may be more

susceptible to the potential toxicities of the amide-type local anesthetics. The

major metabolite of bupivacaine is N-desbutyl bupivacaine.63 The clearance

rate is 0.47 litres/min.

EXCRETION

The kidney is the main excretory organ for most local anesthetics

(bupivacaine) and their metabolites. Urinary excretion is affected by renal

perfusion and factors affecting urinary pH.

Only 5% of bupivacaine is excreted unchanged in the urine. The

elimination half-life is 210 minutes. In infants and elderly the half life is

prolonged.

When administered in recommended doses and concentrations,

bupivacaine does not ordinarily produce irritation or tissue damage and does

not cause methemoglobinemia.

PHARMACODYNAMICS

Systemic absorption of local anesthetics (bupivacaine) can produce

effects on the central nervous and cardiovascular systems. At blood

concentrations achieved with therapeutic doses, changes in cardiac

55

conduction, excitability, refractoriness, contractility, and peripheral vascular

resistance have been reported. Toxic blood concentrations depress cardiac

conduction and excitability, which may lead to atrioventricular block,

ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities.

In addition, myocardial contractility is depressed and peripheral vasodilation

occurs, leading to decreased cardiac output and arterial blood pressure.

Following systemic absorption, local anesthetics (bupivacaine) can

produce central nervous system stimulation, depression or both. Apparent

central stimulation is usually manifested as restlessness, tremors, shivering,

progressing to convulsions followed by depression and coma ultimately

laeding to respiratory arrest. However, the local anesthetics have a primary

depressant effect on the medulla and on higher centers. The depressed stage

may occur without a prior excited stage.

DOSAGE AND ADMINISTRATION

The rapid injection of a large volume of bupivacaine solution should be

avoided and fractional (incremental) doses should always be used. The

smallest dose and concentration required to produce the desired result should

be administered.

The dose of any local anesthetic administered varies with the

anesthetic procedure, the area to be anesthetized, the vascularity of the

tissues, the number of neuronal segments to be blocked, the depth of

anaesthesia and degree of muscle relaxation required, the duration of

anaesthesia desired, individual tolerance, and the physical condition of the

patient. Patients in poor general condition due to aging or other compromising

56

factors such as partial or complete heart conduction block, advanced liver

disease or severe renal dysfunction require special attention although regional

anaesthesia is frequently indicated in these patients. To reduce the risk of

potentially serious adverse reactions, attempts should be made to optimize

the patient's condition before major blocks are performed, and the dosage

should be adjusted accordingly.

In recommended doses, bupivacaine hydrochloride produces complete

sensory block, but the effect on motor function differs among the three

concentrations.

0.25%—when used for caudal, epidural, or peripheral nerve block, produces

incomplete motor block. Should be used for operations in which muscle

relaxation is not important, or when another means of providing muscle

relaxation is used concurrently. Onset of action may be slower than with the

0.5% or 0.75% solutions.

0.5%—provides motor blockade for caudal, epidural, or nerve block, but

muscle relaxation may be inadequate for operations in which complete

muscle relaxation is essential.

0.75%—produces complete motor block. Most useful for epidural block in

abdominal operations requiring complete muscle relaxation, and for

retrobulbar anaesthesia. Not for obstetrical anaesthesia.

The duration of anaesthesia with bupivacaine is such that for most

indications, a single dose is sufficient.

57

Maximum dosage limit must be individualized in each case after

evaluating the size and physical status of the patient, as well as the usual rate

of systemic absorption from a particular injection site. Most experience to date

is with single doses of bupivacaine up to 225 mg with epinephrine 1:200,000

and 175 mg without epinephrine; more or less drug may be used depending

on individualization of each case.

These doses may be repeated up to once every three hours. In clinical

studies to date, total daily doses up to 400 mg have been reported. Until

further experience is gained, this dose should not be exceeded in 24 hours.

The duration of anesthetic effect may be prolonged by the addition of

epinephrine.

These dosages should be reduced for young, elderly or debilitated

patients.

Bupivacaine is contraindicated for obstetrical paracervical blocks, and

is not recommended for intravenous regional anaesthesia (Bier Block).

Use in Epidural Anaesthesia

During epidural administration of bupivacaine, 0.5% and 0.75%

solutions should be administered in incremental doses of 3 mL to 5 mL with

sufficient time between doses to detect toxic manifestations of unintentional

intravascular or intrathecal injection. In obstetrics, only the 0.5% and 0.25%

concentrations should be used; incremental doses of 3 mL to 5 mL of the

0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are

recommended. Repeat doses should be preceded by a test dose containing

epinephrine if not contraindicated. Use only the single dose ampoules and

58

single dose vials for caudal or epidural Anaesthesia; the multiple dose vials

contain a preservative and therefore should not be used for these procedures

FACTORS INFLUENCING ANAESTHETIC ACTIVITY

ADDITION OF VASOCONSTRICTOR: The duration of action of bupivacaine

is proportional to the time the drug is in contact with the nerve fibres. The

addition of vasoconstrictor like epinephrine will prolong the duration of action

of drug. However the effect of prolonging the duration of action by adding

epinephrine is less than that observed with lidocaine which is attributed to its

high lipid solubility.

DOSAGE OF THE DRUG: Increase in dose of bupivacaine either by larger

volume or more concentrated solution results in more profound depth,

prolonged duration and faster onset of block.

SITE OF INJECTION: Rapid onset and shorter duration occur with intrathecal

or subcutaneous infiltration of bupivacaine.

CARBONATION AND pH ADJUSTMENT: An increase in the pH of the drug

increases the amount of drug in the unionized for resulting in faster onset of

conduction blockade. Carbon dioxide raises the threshold for impulse firing by

changing the extent of channel inactivation at rest.

LIPOSOMAL LOCAL ANAESTHETICS: Large unilamellar vesicles that

exhibit a pH gradient can efficiently encapsulate bupivacaine and

subsequently provide a sustained release system that greatly increases the

duration of neural blockade when compared with plain local anaesthetic

solutions.64

59

SIDE EFFECTS

1. Allergic reactions

2. Systemic toxicity

ALLERGIC REACTIONS: They are less than 1% and are immunologically

mediated.65 The occurrence of rash, utricaria and laryngeal edema with or

without hypotension and bronchospasm during intradermal testing is highly

suggestive of allergic reactions.

SYSTEMIC TOXICITY:

Bupivacaine toxicity occurs due to excess plasma concentration of the

drug. The magnitude of systemic absorption depends on the dose

administered into the tissue, vascularity at the injection site, presence of

epinephrine in the solution. CNS manifestations occur with plasma

concentrations of 4.5-5.5mcg/ml.66 The features are numbness of tongue and

circumoral tissues, restlessness, vertigo, tinnitus, difficulty in focusing, slurred

speech, skeletal muscle twitching of face and extremities and convulsions.

The treatment comprises oxygenation, ventilation and intravenous midazolam.

In the 1980’s reports indicated that bupivacaine possessed a relatively

high potency for cardiotoxicity. Accidental IV injection of bupivacaine results in

precipitious hypotension, cardiac dysrhythmias and atrioventricular heart

block.67 It is found that due to rapid saturation of the protein binding sites,

significant mass of unbound drug is available for diffusion into the conducting

system of heart. Cardio toxicity occurs at a plasma concentration of 8-

10mcg/ml.68

60

The threshold for cardiac toxicity produced by bupivacaine may be

decreased in patients on antidysrhythmic drugs and medications which

depress impulse propagation (beta blockers,digitalis and calcium channel

blockers).69 In the presence of propanolol, cardio toxic effects occur at 2-

3mcg/ml of plasma concentration. Epinephrine and Phenylephrine also

increases bupivacaine toxicity.

Dissociation of highly lipid soluble bupivacaine from sodium channel

receptor site is slow causing persistent depressant effect on Vmax and cardio

toxicity.70Patients with cardiac depression or cardiac arrest due to bupivacaine

toxicity will be difficult to resuscitate. R-enantiomer of bupivacaine is more

toxic than the S-enantiomer. Tachycardia can enhance frequency dependent

blockade of cardiac channels by bupivacaine leading to cardiac toxicity.71

Cardiac arrest caused by bupivacaine is very difficult to treat and

reverse.

Bretylium 20 mg/kg IV reverses bupivacaine induced cardiac

depression and increase the threshold for ventricular tachycardia but since

the world's natural supply of bretylium is nearly exhausted, and the drug is no

longer available it has been deleted from the Advanced Cardiovascular Life

Support (ACLS) algorithm.72 On intravascular infusion of encapsulated

bupivacaine in multilamellar liposome, the nervous and cardiac toxicity of

bupivacaine was found to be reduced.73 Intralipid or commonly available IV

lipid emulsion can be effective in treating severe cardiac toxicity secondary to

local anaesthetic over dosage. Human cases have been reported with

successful use of Intralipid in the treatment of cardiac toxicity.74,75

61

NEUROTOXICITY

Spinal anaesthesia with 0.5% bupivacaine is associated with a lower

incidence of transient radicular irritation compared to lidocaine.76

USES

Bupivacaine is used for local infiltration, epidural anaesthesia and

analgesia, spinal anaesthesia and all peripheral nerve blocks.

RECENT ADVANCES

Apart from sodium channel blockade, non-sodium channel action also

plays an important beneficial role by local anesthetics in subtle modulation on

neutrophil function. They selectively inhibit priming without affecting activation

of neutrophils and prevent hyper-sensitization causing tissue damage. This

effect occurs at much lower concentration than those required for sodium

channel blockade. This is mediated by local anaesthetic interactions with G

protein signaling.77

CONTRAINDICATIONS

Presence of hypersensitivity to local anesthetics of the amide type or

other components of bupivacaine solutions. Other conditions are presence of

inflammation and or sepsis near the proposed site of injection, severe shock,

heart block and for intravenous regional anaesthesia(IVRA).

62

FENTANYL

It is a phenyl piperidine derivative, synthetic opiod agonist which is 75-

125 times more potent than morphine.78

STRUCTURAL FORMULA

MECHANISM OF ACTION

Opioids act as agonists at stereo specific opioid receptors at

presynaptic and postsynaptic sites in the central nervous system (principally

brainstem and spinal cord) and outside the central nervous system in

peripheral tissues.79,80

Analgesia that follows epidural placement of opioid reflects diffusion of

the drug across the dura to gain access to mu opioid receptors in the

substantia gelatinosa of the spinal cord as well as systemic absorption to

produce effects similar to those that would follow IV administration of opioid.

The principal effect of opioid receptors activation is a decrease in

neurotransmission.81,82 This occurs largely by presynaptic inhibition of

neurotransmitter (acetylcholine, dopamine, nor epinephrine, substance P)

release, although postsynaptic inhibition of evoked activity might also occur.

Figure-8-Structure of Fentanyl

63

PHYSIOCHEMICAL PROPERTIES

The pKa is 8.4. At physiological pH, it is in non-ionized form. The

octanol/H2O partition coefficient is 955. High lipid solubility results in rapid

onset of action. It is 84% protein bound. The effect-site equilibration time

between blood and brain is 6.4 minutes.

Figure – 9 – Epidural Opioids

When a drug is administered epidurally, it can reach the spinal cord by diffusion through the meninges. The most important barrier to meningeal permeability is the arachnoid mater; meningeal permeability is determined primarily by the drug’s lipid solubility. In the spinal cord, equilibrium of the nonionized hydrophilic drug (blue circles) and the ionized hydrophilic drug (red triangles) at the site of the spinal opioid receptor (purple receptors) is shown, as well as nonspecific lipid-binding sites (green receptors). Diffusion into the epidural space and into epidural veins is the major route of clearance, as illustrated in the left portion of the image.

Copied from Eltzschig HK, Lieberman ES, Camann WR. Regional

anesthesia and analgesia for labor and delivery. N Engl J Med. 2003 Jan

23;348(4):319-32.

64

PHARMACOKINETICS

On administration, it undergoes rapid redistribution to inactive tissue

sites such as fat and skeletal muscles.83 The lungs exert a significant first

pass effect and transiently take up approximately 75% of the injected dose.84

The t1/2 α is 1-2.5 minutes and t1/2 β is 10-30 minutes. The volume of

distribution is 335 litres. It is primarily metabolized in liver by N-dealkylation

and hydroxylation providing nor-fentanyl. The metabolite is excreted by

kidneys and can be detected in urine upto 48 hours. Animal studies suggest

that nor-fentanyl has less analgesic potency than fentanyl.85 The elimination

half-life is 3.1-6.6 hours. The elimination half time is longer than morphine due

to greater lipid solubility and larger volume of distribution. The clearance rate

is 1530 ml / minute. Context sensitive half time after 4 hours of infusion is 260

minutes.

PHARMACODYNAMICS

Central nervous system: It reduces the MAC of isoflurane upto 80%86,

produces ceiling effect with increased dosage hence little effect on EEG. It

also decreases CMRO2 and intracranial pressure, increases muscle tone and

causes muscle rigidity.

Cardiovascular system: It reduces the heart rate due to stimulation of the

central vagal nucleus and reduction of sympathetic tone thus decreasing the

hemodynamic response to laryngoscopy and endotracheal intubation.

Respiratory system: It depresses the upper airway, tracheal and lower

respiratory tract reflexes,eliminates or blunts somatic and autonomic response

65

to tracheal intubation and causes dose dependent depression of ventilatory

response to CO2.

Endocrine effects: Modifies humoral response to surgery, prevents increase

in blood glucose, plasma catecholamine, antidiuretic hormone, renin,

aldosterone, cortisol and growth hormone concentrations.

Gastrointestinal system: It causes relaxation of the lower esophageal

sphincter and delays gastric emptying. It increases biliary duct pressure and

causes spasm of sphincter of Oddi. Stimulation of Chemoreceptor trigger

zone in area postrema of medulla leads to nausea and vomiting.

Renal system: There are no significant effects

DOSAGE AND ADMINISTRATION

INTRAVENOUS DRUG DELIVERY: Fentanyl 1-2 µg/kg provides analgesia. In

doses 2-20µg/kg, it blunts the pressor response to laryngoscopy and surgical

stimulation along with inhalational agents. Used in total intravenous

anaesthesia with loading dose 4-20µg/kg and maintainenance infusion rate of

2-10µg/kg/hr or additional boluses of 25-100µg.

EPIDURAL DELIVERY: Fentanyl is used in the dose of 50-100µg for

initiation of epidural analgesia. For maintenance a dose 1-4µg/ml is

used.87,From previous studies a dose of 2µg/ml is the commonly used dose

which provides the best pain relief with minimal side effects. The addition of

fentanyl decreases the MLAC(minimum local anaesthetic concentration) of

local anaesthetics. They act synergistically with the local anaesthetics in

epidural space.88

66

REVIEW OF LITERATURE:

Stienstra et al(1995)89 did a prospective randomized study in 76 full

term parturients to compare the effects of continuous epidural infusion of

ropivacaine 0.25% with bupivacaine 0.25% on pain relief and motor block

during labor, and on the neonate.Group I & group II received 10 ml of 0.25%

bupivacaine and 0.25% ropivacaine respectively. Then they were started on

an epidural infusion of the same drug at 6-12 ml/h. Top-up boluses of 6-10ml

were given as and when required. They found that the onset of pain relief

(verbal scale), contraction pain (visual analog scale), intensity of motor

block(modified Bromage scale), and duration of motor block were not

statistically different between the groups. However the ropivacaine group had

a higher proportion of neonates with neurologic and adaptive capacity

score(NACS) >35 than the bupivacaine group 2 hours after delivery. They

concluded that ropivacaine 0.25% and bupivacaine 0.25% are equally

effective for epidural pain relief during labor.

McCrae AF(1995)90 compared ropivacaine and bupivacaine in labor

epidural analgesia regarding pain relief in a prospective randomized

controlled trial. Epidural analgesia was initiated with 10ml of 0.5%

ropivacaine. When a top-up was requested, 0.25% ropivacaine or 0.25%

bupivacaine 10 ml was given (the same drug as the main dose). The study

ended when a second top-up was requested or delivery of the baby occurred.

The only significant difference between the groups was a shorter onset of pain

relief after the main dose of bupivacaine. There were no significant differences

n duration, onset of pain relief after top-up, quality of analgesia, spread of

67

sensory block and motor block between the groups. Cardiovascular changes

and neonatal outcome were also similar in the two groups.

Eddleston JM et al(1996)91 compared 0.25% ropivacaine and 0.25%

bupivacaine in a total of 104 parturients for extradural analgesia in labour. The

women in the bupivacaine group required more top-up doses to maintain

analgesia (median 3.0 vs 2.0) (P < 0.05). The onset of sensory block, quality

of analgesia, ultimate level of maximum sensory block and maternal

satisfaction were similar in both groups. The incidence, intensity and duration

of motor block were slightly but not significantly less in the ropivacaine group.

The ropivacaine group had a higher incidence of spontaneous vaginal delivery

(70.59% vs 52.00%). There was no significant difference in neonatal outcome

as assessed by Apgar scores, umbilical acid-base status and neurological and

adaptive capacity score at 2 and 24 h after delivery. They concluded that

ropivacaine and bupivacaine in a concentration of 0.25% produced

comparable analgesia for pain relief of labour with no detectable adverse

effect on the neonate.

Benhamou et al.(1997)92 did a prospective randomized on 133

parturients for identifying the optimum infusion rate of 0.2% ropivacaine as

continuous infusion. Four groups received a fixed rate 0.2% ropivacaine of

4/6/8/10 ml/h and additional bolus doses as and when necessary. Contraction

pain, quality of analgesia, sensory block, motor block and neonatal Apgar

scores were assessed. There were no significant differences between groups

in terms of analgesia, motor block, obstetrical or neonatal outcome. However

the 4 ml/h group required more boluses and the 10ml/h group received a

significantly higher dose of ropivacaine compared to 6ml/h. They concluded

68

that 0.2% ropivacaine was effective and well tolerated when given as a

continuous extradural infusion at 6-8 ml/h and may be used as the sole

analgesic during labour.

Cascio et al.(1997)93 compared four different rates of 0.2%

ropivacaine in continuous labour epidural analgesia in 128 parturients as a

prospective randomized study.After a bolus of 5 ml of 0.2% ropivacaine, a

continuous infusion was started at 4, 6, 8, or 10 mL/hour. Rescue analgesia

was provided with 5-mL "top-up" injections as and when necessary. Pain relief

was assessed by using a visual analog pain scale (VAPS) and motor block

was assessed by using a modified Bromage scale. They found that all

infusion regimens effectively decreased VAPS, and most patients in all groups

had minimal or no motor block at the end of the first stage of labor. Mean total

number of the top-up injections required per patient were 3, 2, 1.5, and 1.4,

respectively, in the 4, 6, 8, and 10-mL/hour groups (P < .05, 4 mL/hour vs. all

other groups). Despite receiving more total bolus dosages, the 4-mL/hour

group had less motor block in the lower extremities (P < .05). Apgar scores

and neurological adaptive capacity scores were similar for all groups.Thay

finally concluded that a rate of 6 mL/hour may be the lowest effective rate that

provides the best combination of pain relief, motor block, and rebolusing.

Owen et al.(1998)10 did a prospective double blind randomized

controlled trial on 51 labouring ASA I and II parturients.Their aim was to

compare the effects of 0.125% ropivacaine with 0.125% bupivacaine in

laboring patients using patient-controlled epidural analgesia (PCEA). Basal

infusion rates of 6 ml/h were supplemented with patient-controlled boluses of

5 ml, available every 10 min with a 30-ml/h limit. For inadequate analgesia,

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10-ml boluses of study solution was administered until patient comfort was

achieved. There were no significant differences in verbal pain scores, amount

of local anesthetics used, sensory levels, motor blockade, labor duration,

mode of delivery, side effects, or patient satisfaction. They concluded that

0.125% ropivacaine and bupivacaine were clinically indistinguishable and are

both highly effective for labor analgesia using PCEA.

Yaakov Beilin et al(1999)94 did a prospective, randomized, double-

blinded study to determine the lowest concentration of ropivacaine that offers

pain relief for the initiation of labor epidural analgesia. Group I received 0.2%

ropivacaine, Group II received 0.15% ropivacaine, Group III received 0.1%

ropivacaine. Initially 13 ml was given in each group. Fifteen minutes later, the

adequacy of analgesia was assessed. If the patient reported that her degree

of analgesia was not adequate, an additional 5 mL of the study medication

was given, the degree of pain relief was reassessed 15 min later and the

study was concluded. They found that in Group I 26 of 28(93%),in Group II 18

of 28(64%),in Group III 4 of 12(33%) had adequate analgesia.They found that

0.2% ropivacaine offers significant analgesia more often than 0.15% or 0.1%

ropivacaine. They concluded that if ropivacaine is selected as the sole local

anaesthetic for the initiation of labor epidural analgesia, the minimal

concentration should be 0.2%.

Gautier et al.(1999)95 did a prospective randomized double blinded

study in 90 patients to evaluate the benefits of the administration of

intermittent bolus doses of 0.125% ropivacaine compared with 0.125%

bupivacaine after addition of sufentanil for analgesia during labor. The 90

patients were assigned randomly to receive 10 ml of 0.125% bupivacaine,

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plus 7.5 µg sufentanil or 10ml of 0.125% ropivacaine, plus 7.5 µg sufentanil.

The duration of analgesia, visual analogue scores for pain, motor blockade

(using a six‐point modified Bromage scale), patient satisfaction scores,

nausea, pruritus, heart rate, and blood pressure were recorded. There were

no significant differences in analgesia onset time, number of patients requiring

reboluses, total infusion volume, VAS pain scores, duration of 2nd stage of

labour or mode of delivery. However the ropivacaine group had lower

incidence of motor block after the 3rd injection. They concluded that 0.125%

ropivacaine with sufentanil affords reliable analgesia with minimal motor

blockade.

Meister et al (2000)96 compared 0.125% Ropivacaine with 2µg/ml

Fentanyl and 0.125% Bupivacaine with 2µg/ml Fentanyl for epidural Labour

Analgesia. They chose 50 laboring women and randomized them to receive

either 0.125% Ropivacaine with Fentanyl 2µg/ml or 0.125% Bupivacaine with

Fentanyl 2µg/ml by using patient controlled epidural analgesia (PCEA)

technique. They found no differences in verbal pain scores; local anesthetic

used patient satisfaction or side effects between the groups. However the

Ropivacaine/Fentanyl group developed significantly less motor block than

Bupivacaine/Fentanyl group. They concluded that although

Ropivacaine/Fentanyl group developed less significantly less motor blockade

whether these results are applicable to anesthesia practices which do not use

PCEA remained to be determined.

Campbell et al (2000)97 conducted a prospective randomized double

blinded study to compare the efficacy of 0.08% Bupivacaine and 2µg/ml

Fentanyl or 0.08% Ropivacaine and 2µg/ml Fentanyl to initiate ambulatory

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labour epidural analgesia. 40 nulliparous women in early labour <5cm cervical

dilation received either 20ml of 0.08% Bupivacaine and 2µg/ml Fentanyl (BF)

or 20ml of 0.08% Ropivacaine and 2µg/ml Fentanyl (RF) to initiate epidural

analgesia. They found that 0.08% Ropivacaine and 2µg/ml Fentanyl provided

consistent, effective labour analgesic without causing clinically significant

adverse maternal/fetal effects while concurrently preserving maternal ability to

void urine and ambulate.

Fettes et al (2000)98 conducted a randomized double blinded trial with

40 primigravid patients to compare intermittent bolus vs. continuous

administration of epidural Ropivacaine with Fentanyl for epidural analgesia.

Plain Ropivacaine 0.2%, 15-20 ml was titrated until analgesia and bilateral

sensory block to T10 was produced (Time Zero).Patients were then given

either an infusion of Ropivacaine 2mg/ml with 2µg/ml Fentanyl or hourly

boluses of 10ml of the same solution and on request additional 10ml were

given for analgesia. They found no differences between the two groups in

patient characteristics, obstetric/neonatal outcome, and sensory/motor block.

However the total drug dose used in the intermittent group was lower and

duration of uninterrupted analgesia (time to 1st rescue bolus) was longer. They

concluded that intermittent bolus is a more efficacious mode of analgesia.

Fischer et al(2000)99 conducted a prospective randomized double

blinded trial on 200 parturients to compare the administration of 0.1%

ropivacaine and 0.5 µg/ml sufentanil with that of 0.1% bupivacaine and 0.5

µg/ml sufentanil via patient controlled epidural analgesia route during labor. A

test dose of 5ml study solution was administered, followed by a loading dose

5 min later. PCEA regimen was of 5ml bolus,10 min lockout time.

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Supplementary analgesia was of 5ml of study solution administered through

the PCEA pump by the nurse. The two groups did not differ in VAS, volume of

anesthetic solution used, mode of delivery, or side effects. The ropivacaine

group had significantly less motor block during first stage of labor and the

second stage of labour was shorter. The ropivacaine group patients also

requested more supplemental boluses to achieve analgesia during the second

stage of labor.Maternal satisfaction was greater in the bupivacaine group.

They concluded that 0.1% ropivacaine and 0.5 µg/ml sufentanil produce less

motor block but are clinically less potent than 0.1% bupivacaine and 0.5 µg/ml

sufentanil when given as PCEA infusion.

Helene Finegold et al(2000)100 did a double blind, randomized study

to compare analgesic efficacies of ropivacaine-fentanyl and bupivacaine-

fentanyl infusions for labour epidural analgesia in 100 term nulliparous

women. One group received a bolus of 10ml of 0.25% bupivacaine and

infusion of 0.125% bupivacaine with 2 µg/ml fentanyl. Another group received

10 ml of 0.2% ropivacaine bolus and infusion of 0.1% ropivacaine with 2 µg/ml

fentanyl. The median VAS scores were not different between the groups at

any of the evaluation periods. However, at least 80% of patients in the

ropivacaine group had no demonstrable motor block after the first hour

compared with only 55% of patients given bupivacaine. They concluded that

though bupivacaine and ropivacaine produced satisfactory labour analgesia,

ropivacaine infusion was associated with less motor block throughout the first

stage of labour and at 10 cm dilatation .

Ruban P et al(2000)101 did a prospective randomized controlled trial on

36 nulliparous parturients to study the effect of adding fentanyl 2 µg/ml on

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demand-only PCEA using ropivacaine 0.125% for labour analgesia. All

patients were started on epidural analgesia with 10 ml 0.2% ropivacaine.

Then one group was started on 0.125% ropivacaine and another group on

0.125% ropivacaine with fentanyl 2 µg/ml. PCEA was was programmed to a

demand-only mode with bolus of 5 ml, lockout time of 10 minutes and

maximum volume per hour of 20 ml. Both groups were similar in the ratio of

successful PCEA demand to total number of demands, the satisfaction score

and the maternal-fetal outcome. However the total amount of ropivacaine

used per hour was lower in the group that received fentanyl. They concluded

that the addition of fentanyl had a dose-sparing effect on the requirement of

ropivacaine.

McClellan KJ, Faulds D(2000)102 updated the use of ropivacaine in

regional anaesthesia. Ropivacaine is a long-acting, enantiomerically pure (S-

enantiomer) amide local anaesthetic with a high pKa and low lipid solubility

which blocks nerve fibres involved in pain transmission (A delta and C fibres)

to a greater degree than those controlling motor function (A beta fibres). The

drug was less cardiotoxic than equal concentrations of racemic bupivacaine

but more so than lidocaine (lignocaine) in vitro and had a significantly higher

threshold for CNS toxicity than racemic bupivacaine in healthy volunteers

(mean maximum tolerated unbound arterial plasma concentrations were 0.56

and 0.3 mg/L, respectively). Extensive clinical data have shown that epidural

ropivacaine 0.2% is effective for the initiation and maintenance of labour

analgesia, and provides pain relief after abdominal or orthopedic surgery

especially when given in conjunction with opioids (co administration with

opioids may also allow for lower concentrations of ropivacaine to be used).

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The drug had efficacy generally similar to that of the same dose of

bupivacaine with regard to pain relief but caused less motor blockade at low

concentrations. They concluded that ropivacaine is a well tolerated regional

anaesthetic with an efficacy broadly similar to that of bupivacaine. However, it

may be a preferred option because of its reduced CNS and cardiotoxic

potential and its lower propensity for motor block.

Dresner M, Freeman J, Calow C, Quinn A, Bamber J(2000)103

compared ropivacaine 0.2% with bupivacaine 0.1% with fentanyl for analgesia

during labour. In the bupivacaine group (BUPIV), 101 healthy parturients

received 0.1% bupivacaine with fentanyl 2 µg/ml and 102 women received

0.2% ropivacaine in the ropivacaine group (ROPIV). Both groups received an

initial loading dose of 15 ml, a continuous infusion of 8 ml/hr, and top-ups of

10 ml. Breakthrough pain not responding to a routine top-up was treated with

an 'escape' top-up of 10 ml 0.25% bupivacaine. The two groups were

compared for complete analgesia at 30 min, routine and 'escape' top-up

requirements, midwife assessment of analgesic efficacy, delivery mode,

patient VAS for first and second stage analgesia, overall satisfaction, and

patient assessment of motor blockade. Patients receiving ropivacaine

received fewer routine top-ups and fewer escape top-ups. The ropivacaine

group was more likely to be pain free in the first stage. There were no

significant differences in patients' assessment of motor block or mode of

delivery between the groups. Pain relief and satisfaction scores from

midwives and patients were consistently better in the ropivacaine group, but

did not reach statistical significance.

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Merson N(2001)104 did a comparison of motor block between

ropivacaine and bupivacaine for continuous labor epidural analgesia. 68

healthy term primigravid parturients were randomized to receive an initial

bolus dose of 10 mL of 1 of the following: 0.25% bupivacaine (high

bupivacaine), 0.25% ropivacaine (high ropivacaine), 0.125% bupivacaine (low

bupivacaine), or 0.125% ropivacaine (low ropivacaine) along with 10 µg of

sufentanil added to it. A continuous infusion of a 0.1% study drug infusion with

0.6 µg/ml of sufentanil at a rate of 8 to 14 ml/h was then started .

Supplemental doses of 10 ml of a 0.125% study solution with 10 µg of

sufentanil were given as needed. He observed that a statistically significant

greater percentage of parturients receiving bupivacaine had motor block than

those who received ropivacaine, with a marked decrease in the occurrence of

motor block in the low ropivacaine group. Though the pain relief seemed to be

less satisfactory in the ropivacaine groups, the difference was not statistically

significant. Ropivacaine produced significantly less motor block than

bupivacaine in the 0.25% and the 0.125% loading doses, with the greatest

difference seen in the lower concentration loading dose of ropivacaine.

Chua NP, Sia AT, Ocampo CE(2001)105 compared hourly dose

requirement of ropivacaine 0.125% (group R, n = 16) with bupivacaine

0.125% (group B, n = 16) provided by demand-only (bolus 5 ml, lockout 10

min) in parturient-controlled epidural analgesia during labour. The hourly dose

requirement was comparable although group R had a lower successful to total

demands ratio (p < 0.05). They also found that both groups were clinically

indistinguishable in terms of pain relief and side effects. They concluded that,

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at a concentration of 0.125%, ropivacaine and bupivacaine were equally

effective when self-administered using this patient-controlled regimen.

Fernández-Guisasola J et al.(2001)106 did a prospective randomized

double blinded study on 98 parturients to compare 0.0625% bupivacaine with

fentanyl and 0.1% ropivacaine with fentanyl which were thought to be

equipotent for continuous epidural labor analgesia. Epidural analgesia was

initiated with 8ml of 0.7% lignocaine and 50µg of fentanyl for both the groups.

Continuous epidural infusion of 0.0625% bupivacaine with fentanyl 2 µg/ml or

0.1% ropivacaine with fentanyl 2 µg/ml was started at 15ml/h depending upon

the study group. Top-up boluses of 5ml of study solution was used as and

when required. There were no statistically significant differences in pain

intensity, level of sensory block, degree of motor block, hemodynamic

variables, secondary effects, mode of delivery, neonatal outcome or patient

satisfaction. They concluded that both solutions were equally efficient in

providing highly effective epidural analgesia for labor with minimal motor

block, but the results suggest that bupivacaine may be more potent than

ropivacaine.

H.J.Clement et al (2002)107 did a double blind, randomized,

prospective trial on 140 parturients who requested epidural analgesia to

compare 0.15% ropivacaine plus sufentanil 0.5 µg/ml versus 0.10%

bupivacaine plus sufentanil 0.5 µg/ml. No differences was observed between

the two groups for pain scores, total volume of anaesthetic solution used,

duration of labour, mode of delivery, side‐effects or satisfaction score. They

concluded that 0.1% bupivacaine and 0.15% ropivacaine produce effective

and equivalent analgesia during labour, with similar incidences of motor block.

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Lacassie HJ et al.(2002)108 conducted a study to determine the motor

block MLAC(minimum local anaesthetic concentration) of bupivacaine and

ropivacaine. 60 parturients were enrolled. Each received a 20-mL bolus of

epidural bupivacaine or ropivacaine. The first woman in each group received

0.35%. Up-down sequential allocation was used to determine subsequent

concentrations at a testing interval of 0.025%. Effective motor block was

defined as a Bromage score <4 within 30 min. The up-down sequences were

analyzed by using the Dixon and Massey method and probit regression to

quantify the motor block minimal local analgesic concentration. They found

that motor block MLAC for bupivacaine was 0.326% and for ropivacaine was

0.497%. The ropivacaine/bupivacaine potency ratio was 0.66 and was similar

to the sensory potency ratio for these two drugs.

Owen MD et al.(2000)109 designed this study to evaluate a

concentration near the reported 50% effective dose values for ropivacaine

and bupivacaine in an attempt to detect differences between the drugs during

routine clinical use in labor epidural. This was because studies had shown

that ED50 of Ropivacaine was 60% as potent as Bupivacaine. Fifty-nine

nulliparous women in labor were randomized to receive 0.075% ropivacaine

or bupivacaine, each with fentanyl 2 µg/mL. Epidural analgesia was initiated

with 20 ml of study dolution and PCEA was initiated with the following

settings: 6 mL/h basal rate, 5 mL bolus, 10 min lockout, and 30 mL/h limit.

Breakthrough pain was treated with 10-mL boluses of study solution. They

found that both 0.075% ropivacaine and bupivacaine, with fentanyl, were

equally effective for labor analgesia using the patient-controlled epidural

analgesia technique. There were no statistically significant differences in the

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amount of local anesthetic used, verbal pain scores, sensory levels, motor

blockade, labor duration, mode of delivery, side effects or patient satisfaction.

Lee BB et al.(2002)110 formulated a study to compare 0.1%

ropivacaine with 0.2% ropivacaine and to examine the effect of addition of

fentanyl. 58 nulliparous laboring parturients were enrolled in a prospective

double-blind randomized control study. Epidural analgesia was established

with 0.2% ropivacaine and the patients were then randomized to receive one

of the following epidural infusions at 10 mL/h: 0.2% ropivacaine (group R2, n

= 19), 0.1% ropivacaine (group R1, n = 19), or 0.1% ropivacaine with 2 µg/mL

fentanyl (group RF, n = 20). Supplementary analgesia was provided on

request with 5-mL boluses of 0.2% ropivacaine. All solutions provided

effective analgesia during early labor, with all groups requiring similar

numbers of supplementary top-ups. Visual analog pain scores in groups R2

and RF were equivalent and lower than in group R1 (P =.006). Hypotension

was more frequent in group RF compared with groups R2 and R1 (P =.014).

Patient and midwife satisfaction and obstetric and neonatal outcomes were

similar among groups. Maternal venous plasma concentrations of ropivacaine

were greater in group R2 compared with groups R1 and RF (P =.008), but

umbilical venous concentrations were similar. They concluded that epidural

infusion of 0.1% ropivacaine alone at 10 mL/h provided adequate analgesia in

the first stage of labor. The addition of 2 µg/mL fentanyl to 0.1% ropivacaine

improved analgesia to a quality similar to 0.2% ropivacaine alone.

Asik I, Goktug A, Gulay I, Alkis N, Uysalel A(2002)111 compared

bupivacaine 0.2% and ropivacaine 0.2% combined with fentanyl for the

initiation and maintenance of analgesia during labour and delivery in sixty

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labouring nulliparous women who were randomly allocated to receive either

bupivacaine 0.2% with fentanyl 2 µg/ml (B/F), or ropivacaine 0.2% with

fentanyl 2 µg/ml (R/F). For the initiation of epidural analgesia, 8 mL of the

study solution was administered. Supplemental analgesia was obtained with 4

ml of the study solution according to parturients' needs when their pain was >

or = 4 on a VAS. Analgesia, hourly local anaesthetic use, motor block, patient

satisfaction and side effects between groups were evaluated during labour

and at delivery. No differences in verbal pain scores, hourly local anaesthetic

use or patient satisfaction between groups was observed. However, motor

block was observed in 10 patients in the B/F group whereas only two patients

had motor block in the R/F group (P < 0.05). The incidence of instrumental

delivery was also higher in the B/F group than in the R/F group (P< 0.05).

They concluded that ropivacaine 0.2% combined with fentanyl 2 µg/ml

provided effective analgesia with significantly less motor block and need for

an instrumental delivery than a bupivacaine/fentanyl combination at the same

concentrations during labour and delivery.

Fernandez C et al.(2003)112 compared the analgesic efficacy and

extent of motor block when 0.125% ropivacaine or 0.125% bupivacaine were

given in continuous perfusion through an epidural catheter during labor in 60

ASA I-II women, each carrying a single fetus at full term and in spontaneous

labor. Women in the ropivacaine group (R) (n = 30) received 8 mL of 0.2%

ropivacaine for analgesic induction, followed by a continuous perfusion of 10

mL/h of 0.125%. The bupivacaine group (B) (n = 30) received the same

concentration and infusion rate as group (R).The objective of analgesia was to

achieve a score less than 3 on a visual analog painscale. If analgesia was

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inadequate, a 5 mL bolus of 0.2% ropivacaine or bupivacaine, depending on

group, was administered. The motor block was evaluated on an abbreviated

Bromage scale and hemodynamic stability, fetal status, type of delivery and

the total dose of local anesthetic was also recorded. Analgesia and

haemodynamics were similar in both groups. Group R required a larger

number of additional boluses, although the difference was not statistically

significant. Motor block was observed in 8 patients in group B and 1 in group

R (p < 0.05). Fetal status was similar in both groups. Both drugs were equally

effective for controlling the pain accompanying labor, such that ropivacaine

offered no advantage over bupivacaine in that regard. Ropivacaine's reduced

motor block effect at the doses administered may offer an advantage in some

situations, such as when a walking epidural is provided.

Boselli et al.(2003)113 compared the PCEA administration of 0.15%

ropivacaine plus 0.5 µg/mL of sufentanil with that of 0.1% ropivacaine plus

0.5 µg/mL of sufentanil for labor analgesia. This was done to determine

whether a decreased concentration of ropivacaine could produce equally

effective analgesia. This was done in a prospective double blind randomized

controlled study on 130 parturients. They found that 0.1% Ropivacaine plus

0.5 µg/mL of sufentanil given via patient-controlled epidural anesthesia for

labor analgesia was equally as effective as ropivacaine 0.15% plus 0.5 µg/mL

of sufentanil, with a 30% local anesthetic-sparing effect and a 40% reduction

in cost. However this reduction in ropivacaine concentration was not

associated with a decrease in the incidence of motor block, side effects, or

instrumental deliveries.

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Gogarten W et al.(2004)114 did a multicentric double-blinded

randomized study on 450 women to determine the optimal concentration of

ropivacaine for bolus-only patient-controlled epidural labour analgesia. The 4

groups received bupivacaine 0.125% with sufentanil 0.75 µg/ml, ropivacaine

0.125% or 0.175% with sufentanil 0.75 µg/ml or ropivacaine 0.2%. After an

initial bolus of 10 mL of the study solution, and once visual analogue scores

(VAS) were below 30 mm, patient-controlled epidural analgesia was initiated

with a bolus of 4 mL, a lockout interval of 15 min and without a background

infusion. They observed that Bupivacaine 0.125% and ropivacaine 0.125%

with sufentanil proved equally effective in providing labour analgesia without a

difference in local anaesthetic consumption, motor blockade or mode of

delivery. Ropivacaine 0.175% plus sufentanil enhanced the quality of

analgesia of the initial loading dose, whereas ropivacaine 0.2% without

sufentanil increased the consumption of local anaesthetics and the degree of

motor blockade. They concluded that despite recent studies indicating that

bupivacaine and ropivacaine may not be equipotent, both local anaesthetics

provided equi-effective analgesia at equal doses without a difference in side-

effects.

Atienzar MC et al.(2004)115 did a prospective randomized study on 80

nulliparous parturients in labour to evaluate the efficacy of 0.1% ropivacaine

with fentanyl 2µg/ml in labour epidural analgesia. All patients had epidural

analgesia initiated with 0.2% ropivacaine and fentanyl and were then

randomized to receive either 0.1% ropivacaine with fentanyl 2 µg/ml at 10ml/

h(Group R1, n = 38) or 0.2% ropivacaine with fentanyl 2 µg/ml at 8

ml/h(Group R2, n = 39) as epidural infusions. Supplementary analgesia was

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provided on request with 5ml of 0.2% ropivacaine as an epidural bolus. They

found that there were no significant differences between the groups in visual

analogue pain scores, motor block or sensory block. Side effects, patient

satisfaction, labour outcome and neonatal outcomes were similar in both

groups. However the amount of local anaesthetic used was lower in the 0.1%

ropivacaine plus fentanyl group than in the 0.2% ropivacaine group. They

concluded that 0.1% ropivacaine plus fentanyl provided adequate analgesia

and the level of analgesia was comparable to that provided by 0.2%

ropivacaine with no differences with regard to motor or sensory block.

Neera Sah et al.(2007)116 conducted a prospective randomized double

blinded study in 162 ASA-I and II full term primiparous laboring women to

compare the efficacy of Ropivacaine, Bupivacaine and Levobupivacaine. All

patients received 8ml of local anesthetic + fentanyl (100µg) followed by

infusion of 12 ml/hr of local anesthetic with 2µg/ml of fentanyl. Patients were

allocated to one of the three groups, group 1 received bolus infusion of

Bupivacaine 0.125%, group 2 received bolus and infusion of Levobupivacaine

0.125%, and group 3 received bolus of ropivacaine 0.2% and infusion of

ropivacaine 0.1%. Vital signs, VAS score, sensory and motor block were

recorded every hour. They found no statistically significant difference in pain

(VAS) / motor (Bromage) score among the 3 groups.

Yaakov Beilin et al.(2007)117 studied the effects of mode of delivery of

bupivacaine, ropivacaine and levobupivacaine. They sought to determine if

there was a difference in mode of delivery among parturients who receive

epidural bupivacaine, ropivacaine, or levobupivacaine. Nulliparous women at

term requesting labor analgesia with a cervical dilation of 5 cm were

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randomized to receive epidural bupivacaine, ropivacaine, or levobupivacaine.

Analgesia was initiated with a bolus of 15 mL of 0.0625% of the assigned LA

with fentanyl 2 µg/mL. Analgesia was maintained with an infusion of the same

solution at 10 mL/h. The primary endpoint was the operative delivery rate

(instrumental assisted vaginal delivery plus cesarean delivery). Ninety-eight

women received bupivacaine, 90 ropivacaine, and 34 levobupivacaine (before

it was removed from the US market). There was less motor block in the

levobupivacaine group when compared with the ropivacaine and bupivacaine

groups, P less than 0.05. There was no significant difference in the duration of

the first or second stage of labor, the total dose of LA received per hour of

labor, or neonatal outcome among groups. They concluded that bupivacaine,

ropivacaine, and levobupivacaine all confer adequate labor epidural

analgesia, with no significant influence on mode of delivery, duration of labor,

or neonatal outcome.

Wang Li Zhong et al.(2010)118 conducted a randomized clinical trial in

450 nulliparous parturients to compare Ropivacaine, Bupivacaine and

Levobupivacaine with Sufentanil for PCEA during labour. A concentration of

0.05%, 0.075%, 0.125% or 0.15% of either Ropivacaine (group R),

Bupivacaine (group B) and Levobupivacaine (group L) with Sufentanyl

0.5µg/ml was epidurally administered by PCEA mode. Effective analgesia was

defined as VAS score ≤30mm. The relative median potency for each local

anesthesia was calculated using a probit regression model. They found no

significant difference among groups in the numbers of effective analgesia,

pain scores, hourly local anesthesia concentration used and sensory/motor

blockade. They concluded that by using PCEA lower concentration of

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Ropivacaine, Bupivacaine and Levobupivacaine with Sufentanil produced

similar analgesia and motor blockade. Analgesic efficacy mainly depends on

concentration rather than type of anesthetics.

Sumit Kalra et al.(2010)119 compared the efficacy of low concentration

of Bupivacaine with Fentanyl and Bupivacaine with Sufentanil for epidural

labour analgesia. 50 full term parturients received a initial bolus dose of a

10ml of 0.125% Bupivacaine. The patients were randomly divided into two

groups: Fentanyl group (F) received 0.0625% Bupivacaine + 2.5µg/ml

Fentanyl. Sufentanil group (S) received 0.625% Bupivacaine + 0.25µg/ml

Sufentanil. Verbal analogue pain scores, need of supplementary boluses,

mode of delivery and maternal satisfaction neonatal APGAR scores were

recorded. No significant difference was observed in the 2 groups. They

concluded that both Fentanyl and Sufentanil were equally effective in

providing labour analgesia with hemodynamic stability, maternal satisfaction

without serious maternal / fetal side effects

Ngan Kee WD et al.(2010)120 compared the complete dose response

curves of bupivacaine and ropivacaine through a random allocation-graded

dose-response study of these drugs given epidurally for labor analgesia.

Three hundred laboring nulliparous patients were randomly given epidural

bupivacaine (5, 10, 15, 20, 30, or 40 mg) or ropivacaine (7, 15, 20, 30, 45, or

60 mg) in 20 ml of saline. Visual Analog Scale pain scores were recorded for

30 min. Response was defined by the percentage decrease in pain score from

baseline at 30 min, and dose-response data were analyzed by using nonlinear

regression. The ED50 of ropivacaine was greater than that of bupivacaine

(15.3 mg vs. 11.3 mg, P = 0.0003), but ED90 was similar (40.6 mg vs. 33.4 mg,

85

P = 0.29). The potency ratio at ED50 for ropivacaine:bupivacaine was 0.75.

The curves had similar steepness .They concluded that ropivacaine is less

potent than bupivacaine, but otherwise they have similar dose–response

characteristics. The difference in potency was not statistically significant at

ED90 doses.

Lee HL, Lo LM, Chou CC, Chuah EC(2011)121 did a comparison

between 0.08% ropivacaine and 0.06% levobupivacaine for epidural

analgesia during nulliparous labor in a retrospective study in a single center.

The purpose of the retrospective study was to assess whether a combination

of 0.06% levobupivacaine and fentanyl 2 µg/ml had the same effects as

0.08% ropivacaine and fentanyl 2 µg/ml on the mode of delivery and other

obstetric outcomes when used for epidural analgesia of labor in nulliparous

women. Computer records of 392 Asian nulliparous parturients, who had

presented with spontaneous labor or spontaneous rupture of the membranes,

and had received epidural analgesia, were retrospectively reviewed. Of these,

193 received 0.08% ropivacaine and 199 received 0.06% levobupivacaine.

Fentanyl 2 µg/ml was used in both regimens. There were no significant

differences in the mode of delivery, duration of labor, or neonatal outcome

between the two groups. In the levobupivacaine group, the parturients

required top-up boluses of local anesthetics more frequently and the

incidence of temporary maternal fever and the cost of local anesthetic were

higher. However, the amount of local anesthetic administered during labor

was lower than for the ropivacaine group. 0.06 % levobupivacaine was as

effective as 0.08% ropivacaine,when both were used with fentanyl 2 µg/ml for

labor epidural analgesia of nulliparous women.

86

Materials & Methods

This was a prospective randomized control trial involving 70 parturients

(35 in each group) attending the Dept. of Obsetrics & Gynaecology,

G.Kuppusamy Naidu Memorial Hospital, Coimbatore over a period of 1

year(December 2011-December 2012).Institutional ethics committee and

scientific committee approval was obtained. All patients admitted to the labour

room were counseled regarding labour analgesia. The procedure was

explained to the patient. Informed consent was obtained. Detailed history of

the patient was collected. Routine investigations like blood grouping and

typing, hemoglobin and platelet count were done as per our hospital labour

protocol. Patients fulfilling the inclusion criteria and who gave consent were

then randomly allocated to one of the study groups on the basis of

computerized randomized list.

Inclusion Criteria:

1.Normal singleton pregnancies.

2.Age – 18-35 years

3.ASA status- I & II

4.Patients in active labour with cervical dilatation – 3-5 cm.

Exclusion Criteria:

1.Contraindications to epidural block

2.Pre-term pregnancy

3.Multiple pregnancy

4.Previous cesarean section.

87

Materials needed:

1. 18 G Tuohy needle

2. 20 G epidural catheter

3. 2 cc,5 cc,10 cc sterile syringes

4. Hypodermic needles – 18G & 26G

5. Bowl, Sponge holding forceps, Swabs, Chlorhexidine solution.

6. Sterile gown, Gloves, Cap & Mask

7. Tape for fixing catheter.

8. Local anaesthetic solution – 2% Lignocaine%

9. 2% lignocaine with adrenaline vial, 0.25% Bupivacaine vial, 0.2%

Ropivacaine ampoule, Fentanyl - 100µg.

10. Emergency kit with working laryngoscope, cuffed endotracheal tubes of

appropriate size, airway, suction apparatus with suction catheter,

Inj.Adrenaline, Inj.Atropine, Inj.Thiopentone, Inj.Succinyl choline,

Oxygen cylinder.

11. Monitor for continuous monitoring for Non-invasive blood pressure,

ECG, Respiratory rate, Oxygen saturation.

88

Figure-10 - Epidural tray and epidural set

89

Methodology:

An 18G IV cannula was inserted and patient was started on an infusion

Ringer lactate solution.

The patient was then positioned in Lt. lateral position or sitting position

based on the anaesthetist convenience and her back aligned with the edge of

the bed. Under strict aseptic precautions, the skin over the lower thoracic and

lumbar region was cleaned and area draped. The best interlumbar space

between L1 and L4 was identified and infiltrated with 2% lignocaine.

The skin was pierced with 18G needle in the interlumbar space. The

epidural needle was inserted with bevel facing upward and pushed till it

pierced the interspinous ligament. The stylet was then removed. A 10ml

LOR(Loss Of Resistance) syringe filled with either Air or saline was attached

to the hub of the epidural needle. The needle was then slowly advanced with

pressure exerted on the air/saline column through the plunger of the LOR

syringe. The epidural space was identified with LOR to injection of air or

saline. Careful aspiration was done to make sure that the duramater was not

punctured. If CSF was aspirated, the needle was withdrawn and reintroduced

in a different space. If no CSF was aspirated, the LOR syringe was removed.

The depth of the epidural space was noted. A 20G fine epidural catheter was

threaded through the needle into the epidural space. The epidural needle was

removed. The catheter was positioned so that a length of 5cm of catheter

remained in the epidural space. Careful aspiration of the cathter was again

done to check for CSF or blood.

90

Once the cathter was satisfactorily sited, the puncture site was cleaned

and an occlusion dressing applied over it. A bacterial filter was attached to the

hub of the cathter. A small test dose of local anaesthetic(3ml of 2% Lignocaine

with Adrenaline) was injected via the catheter to rule out intravascular or

intrathecal placement of catheter. If there were no signs of motor block

(intrathecal placement) or tachycardia(intravascular placement) after 5

minutes the patient was turned supine. A bolus dose of the test drug was

given followed by the infusion. The bolus and infusion protocol of each study

group were as follows :

Table-6-Study drugs protocol

Group Bolus Infusion

A 6ml of 0.2%

Ropivacaine

6-8ml/hr of 0.1% Ropivacaine with 2µg/ml

fentanyl

B 6ml of 0.25%

Bupivacaine

6-8ml/hr of 0.125% Bupivacaine with

2µg/ml fentanyl

Breakthrough pain was managed with 6ml of either 0.2% Ropivacaine

or 0.25% Bupivacaine depending on the study group they were involved.

Various maternal parameters were continuously monitored and noted

every 15 minutes in the first hour, every 30 minutes in the second hour and

every hourly thereafter. Continuous fetal heart monitoring was also done.

91

Parameters monitored:

1.Maternal Heart rate

2.Maternal Blood pressure

3.Maternal respiratory rate & oxygen saturation.

4.Pain relief by 11 point verbal numerical rating scale (VNRS)

5.Motor block by Bromage score(0-3)

Clinical outcome studied:

1.Pain relief

2.Motor block

3.Duration of labour

4.Mode of delivery - Vaginal - Spontaneous / Assisted

- Cesarean section

5.Neonatal outcome - APGAR score, NICU admission.

Sample size:

Sample size has been calculated to detect a 40% difference in the

occurrence of motor block between the two groups. The optimal sample size

required would be 25 in each group( 50 in total) with 80% power and 5% level

of significance. The incidence of significant motor block (2 or 3 on a 0–3

scale) was assumed to be 30%. (Owen 1998).

92

Statistical analysis:

All statistical analysis were performed using SPSS(Statistical package

for social sciences) version 17 for windows. The profile of the cases were

compared with the treatment allocation in order to check if there was any

significant imbalance. Descriptive statistics are presented as mean± 1SD.

Component bar and line diagrams were drawn as and when required. Chi-

square test for association was used to compare categorical variables

between treatment allocations.

93

Results and Observation

Our study included 70 pregnant women. They were randomly allocated

to either Group – A(0.1% ropivacaine with 2µg/ml fentanyl) or group-B(0.125%

bupivacaine with 2µg/ml fentanyl).

The initial patient and procedure characteristics were age, weight,

patient ASA grade, patient gravid and parity, vaginal dilatation, site od epidural

placement, comorbid conditions of the patients.

The outcomes measured were hemodynamics of the patient, pain

score, bolus requirement, motor block, mode of delivery, duration of labor,

neonatal outcome, and complications if any.

Profile of the preganant women:

Age :

The patients age ranged from 17-36 years. The average age did not

differ between the two groups. The mean age of women in Group-A was

25.37±3.85 years and that of group-B was 25.23±3.623.The difference was

not statistically significant.(P=0.874)

Weight :

The patients weight ranged from 46-89 kgs at the time of presentation.

The average weight of the women allocated to group-A was 68±8.86 kgs and

that of those in Group-B was 64.29±9.03 kgs. This difference in weight

between the two groups was statistically not significant.(P=0.087)

94

Gravida & parity:

Gravida(p=0.200) and parity(p=0.122) of the women between two

groups were not statistically significant.

25.37

68

25.23

64.29

Age(Years) Weight(Kgs)

Figure-11- Age and Weight by group

Group-A Group-B

19

15

1

26

8

1

0

5

10

15

20

25

30

Gravida 1 Gravida 2 Gravida 3

Figure-12-Gravida by group

Group-A Group-B

21

14

27

4.4

0

5

10

15

20

25

30

Parity 0 Parity 1

Figure-13- Parity by group

Group-A Group-B

95

ASA grade:

Overall, out of the 70 pregnant women, 65(92.9%) had ASA grade I

pregnancy, the rest 5(7.1%) had ASA grade II pregnancy. The distribution of

patients was not statistically significant.(p=0.643)

Comorbid conditions:

Group-A and Group-B each had one women(2.9% in each group) with

GDM( Gestational Diabetes Mellitus). PIH(Pregnancy Induced Hypertension)

was present in one women(2.9%) in group-A and two(5.8%) women in group-

B. Their distribution among groups was not statistically significant.(p=0.840)

Vaginal dilatation:

The average vaginal dilatation of the whole group was 3.44±0.65 cm.

The vaginal dilatation in group-A was 3.37±0.54 cm and in group was

3.51±0.74 cm. This variable did not have any statistically significant

difference.(p=0.206)

ASA-II

ASA-I

0

20

40

60

80

100

Group-A

Group-B

5.7 8.6

94.3 91.4

% o

f w

om

en

Figure-14-ASA grade by group

96

Level of epidural placement:

More than 50% of the patients in both the groups received epidural in

the L3-4 interspace. The distribution of level of epidural catheter placement

among both the groups did not have any statistical significance.(p=0.287)

Outcome measured:

Hemodynamics:

70 patients had their hemodynamics monitored continuously starting at

baseline(befor epidural), 15min, 30min, 45min, 1, 1.5, 2, 3, 4, 5, 6, 7 hours.

The minimum monitoring time was around 3 hrs in both the groups. The

following table will show the number of patients monitored over the time

period of their labour.

0

10

20

30

40

50

60

70

80

90

100

L2-L3 L3-L4 L4-L5

22.9

68.6

8.6

40

51.4

8.6

% o

f w

oe

n

Figure-15-Level of epidural placement by group

Group-A

Group-B

97

PATIENT DISTRIBUTION:

Time Point Number of women measured

Group-A Group-B

Baseline 35 35

15 mins 35 35

30 mins 35 35

45 mins 35 35

1 hour 35 35

1.5 hrs 35 35

2 hrs 35 35

3 hrs 35 35

4 hrs 35 33

5 hrs 19 19

6 hrs 10 8

7 hrs 3 3

COMPARISON OF HEART RATE:

The following table shows the heart rate variations in both groups.

Time Group-A Group-B t value p value

Baseline 93.6±5.5 91.9±5.1 1.350 0.182

15 mins 84.2±6.2 86.1±5.3 -1.295 0.200

30 mins 83.5±5.3 85.3±4.6 -1.508 0.136

45 mins 82.2±6.1 84.5±6.1 -1.572 0.121

1 hr 86.1±6.9 87.7±6.0 -1.043 0.301

1.5 hr 84.4±5.7 86.5±4.5 -1.634 0.107

2 hr 86±6.8 87.3±4.6 -0.926 0.358

3 hr 86±7.4 88.5±5.5 -1.594 0.116

4 hr 89.2±7.4 90.7±4.6 -0.986 0.328

5 hr 88.6±5.5 86.3±7.3 1.100 0.278

6 hr 88.2±9.4 87.5±7.6 0.169 0.868

7 hr 89.6±7.0 79.3±4.2 0.285 0.791

Table-8

Comparison of heart

rate between

ropivacaine and

bupivacaine groups

Table-7

Number of patients

at each time point

98

COMPARISON OF SYSTOLIC BLOOD PRESSURE:

The following table shows the comparison of systolic blood pressure

between the two groups during their labour.

Time Group-A Group-B t value p value

Baseline 115.6±10.5 114.8±11.2 0.308 0.759

15 mins 114.4±8.1 115.4±7.8 -0.538 0.592

30 mins 114.2±6.8 115.1±10.1 -0.442 0.660

45 mins 112.9±8.2 115.4±7.8 -1.314 0.193

1 hr 116.4±7.9 116.5±7.6 -0.092 0.927

1.5 hr 117.2±6.1 117.1±7.8 0.068 0.946

2 hr 114.4±7.8 114.5±6.8 -1.060 0.293

3 hr 114.5±5.5 115.4±10.1 -0.469 0.640

4 hr 114.7±6.3 113.8±7.7 0.538 0.592

5 hr 113.4±7.7 116.3±9.5 -1.009 0.320

6 hr 112±7.8 117.5±7.1 -1.537 0.144

7 hr 110±0.0 103.3±5.7 2.000 0.116

COMPARISON OF DIASTOLIC BLOOD PRESSURE:

The following table shows the comparison of diastolic blood pressure

between the two groups during their labour

Time Group-A Group-B t value p value

Baseline 76.2±7.8 74.2±6.9 1.122 0.266

15 mins 74.7±7.9 75.4±6.1 -0.405 0.087

30 mins 74.4±7.9 74.2±6.9 0.112 0.911

45 mins 74.6±7.7 71 ±12.4 1.319 0.192

1 hr 75.8±7.9 72.5±7.8 1.747 0.085

1.5 hr 77.2±6.8 74.5±6.1 1.693 0.095

2 hr 74.4±7.8 72±7.9 1.303 0.197

3 hr 77.6±6.7 75.4±6.5 1.398 0.167

4 hr 75.7±7.6 73.1±7.8 1.363 0.177

5 hr 76.5±5.9 74.2±5.1 1.290 0.205

6 hr 71.4±3.2 73.7±5.1 -1.176 0.257

7 hr 73.3±5.7 73.3±5.7 1.000 1.000

Table-9

Comparison of mean

systolic blood pressure

between ropivacaine and

bupivacaine groups

Table-10

Comparison of mean

diastolic blood pressure

between ropivacaine

and bupivacaine groups

99

COMPARISON OF RESPIRATORY RATE:

The following table shows the comparison of respiratory rate between

the two groups during their labour

Time Group-A Group-B t value p value

Baseline 21.9±3.2 20.8±4.0 1.267 0.209

15 mins 17.4±2.4 18.1±1.7 -1.407 0.164

30 mins 17.1±1.9 17.7±1.4 -1.534 0.130

45 mins 17.7±2.3 17.7±1.4 -0.100 0.951

1 hr 16.7±2.4 17.6±1.5 -1.745 0.085

1.5 hr 17.4±5.8 17.6±1.4 -0.198 0.849

2 hr 16.8±2.2 17.5±1.3 -1.612 0.112

3 hr 16.8±2.4 17.7±1.6 -1.794 0.077

4 hr 17.4±2.1 18.1±1.5 -1.480 0.144

5 hr 17.6±2.0 17.7±2.2 -0.180 0.882

6 hr 16.6±2.0 17±2.8 -0.307 0.762

7 hr 15.3±1.1 15.3±1.2 0.000 1.000

There was no statistically significant difference in the hemodynamics of

patients among both groups including heart rate, systolic blood pressure,

diastolic blood pressure, respiratory rate. The oxygen saturation (SPO2)

among both groups of patients also did not vary significantly.

Pain relief:

Pain score(verbal numerical rating score):

There was a noticeable decrease in the pain levels immediately after

bolus. The pain levels did not go above VNRS (verbal numerical rating scale)

of 3 during infusion in both the groups. Most of the increase in pain scores

occurred during the second stage of labour. But the pain score variation did

not have any statistical significance.

Table-11

Comparison of mean

respiratory rate between

ropivacaine and

bupivacaine groups

100

Time Group-A Group-B t value p value

Baseline 7.88±0.7 7.65±0.8 1.170 0.246

15 mins 0.31±0.4 0.17±0.3 1.393 0.168

30 mins 0.02±0.1 0.08±0.2 -1.023 0.310

45 mins 0.02±0.1 0.05±0.2 -0.583 0.562

1 hr 0.02±0.1 0.08±0.2 -1.023 0.310

1.5 hr 0.11±0.5 0.05±0.2 -1.358 0.179

2 hr 0.08±0.2 0.02±0.1 1.023 0.310

3 hr 0.20±0.6 0.08±0.3 1.041 0.302

4 hr 0.28±0.8 0.09±0.3 1.235 0.221

5 hr 0.42±0.9 0.52±-.2 -0.289 0.774

6 hr 0.00±0 0.38±1.1 -1.127 0.276

7 hr 0.00±0 0.00±0

Bolus requirement:

7 women in both groups required boluses during their labour.The

proportion of women requiring boluses was comparable in both the groups.

Time Group-A Group-B p value

15 mins Nil Nil

30 mins Nil Nil

45 mins Nil Nil

1 hr Nil Nil

1.5 hr 1 Nil 0.314

2 hr Nil Nil

3 hr 1 2 0.555

4 hr 2 Nil 0.151

5 hr 2 3 0.631

6 hr 1 2 0.396

7 hr Nil Nil

Taable-12

Comparison of mean pain

score (VNRS)between

ropivacaine and

bupivacaine groups

Table-13

Comparison of bolus

requirement between

ropivacaine and

bupivacaine groups

101

Mode of delivery:

There were more spontaneous vaginal deliveries in Group-A (62.9%)

compared to group-B(54.3%). Assisted vaginal deliveries were less in group-

A(25.7%) compared to group-B(37.1%). Four patients in group-A(11.4%) and

three patients in group-B(8.6%) had cesarean deliveries.

Duration of labour:

The following chart shows the average duration of 1st,2nd and 3rd stage

of laour in minutes. All 3 stages of labour were comparable.

Duration(in

minutes)

Group-A Group-B t value p value

Stage-I 467.4±95.8 467.6±87.8 -0.007 0.995

Stage-II 33.5±8.5 31.1±8.9 1.116 0.269

Stage-III 6.8±1.7 6.1±1.2 1.769 0.082

0

10

20

30

40

50

60

70

80

90

100

Group-A Group-B

62.9 54.3

25.7 37.1

11.4 8.6

% o

f w

om

en

Figure-16-Mode of delivery between Ropivacaine and Bupivacaine

Cesarean

Vaginal assisted

Vaginal spontaneous

Table-14

Comparison of

Duration of labour

between ropivacaine

and bupivacaine

groups

102

Neonatal outcome:

The neonatal outcome was rated with Apgar acore at 1 & 5 minutes.

The average Apgar score during 1st minute assessment was 7.65±0.59 and

7.68±0.47 in group-A and group-B respectively. At 5 minutes, the Apgar score

was 8.94±0.23 and 9 in group-A & B respectively. The difference in mean

values were not statistically significant at both 1 minute (p-0.460) and 5

minutes(0.221).

NICU admission:

Five neonates(14.3%) in group-A and three neonates(8.6%) in group-B

were admitted in NICU. The difference was not statistically significant

(p-0.845). The indications for admission in NICU in group-A were cord around

the neck, IUGR, respiratory distress and meconium stained liquor.

Corresponding indications in group-B were cord around the neck, respiratory

distress and meconium stained liquor.

Group-A

Group-B

0

2

4

6

8

10

Minute 1 Minute 5

7.65 8.94

7.68 9

Mea

n A

PG

AR

sco

re

Figure-17-Comparison of neonatal outcome by groups

Group-A

Group-B

103

Motor block:

Motor blockade of Bromage score-1 was observed in 3 persons

belonging to group-B. This was observed during the 5th hour in all 3 patients.

There was no clinically observable motor blockade in Group-A. However this

was not statistically significant(p-=0.071).

Numbness:

Numbness was seen in 2 patients in group-B and compared to none in

group-A. It was seen in 6th and 7th hour. The numbness rate was not

statistically significant.

Pruritis:

Pruritis was not seen in any patients in both the groups.

104

Discussion

The recently published cochrane review34 on epidural versus non-

epidural or no analgesia in labour has concluded that epidural offered better

pain relief, a reduction in the need for additional pain relief , a reduced risk of

acidosis and a reduced risk of naloxone administration.

In our study we have compared bupivacaine with ropivacaine for labor

epidural analgesia. Bupivacaine is a proven drug for effective labor analgesia.

We decided to compare bupivacaine with ropivacaine, which is marketed as a

levo-enantiomer because ropivacaine has a better sensory-motor

differentiation and less cardiotoxic potential compared to bupivacaine.

Many studies state that the potency of ropivacaine is 60% as that of

bupivacaine.8,9 There have been many studies which compare equal

concentrations of both drugs10,95,96,99 (i.e.0.125% bupivacaine vs 0.125%

ropivacaine). There have also been many studies which state to have

compared equi-potent concentrations of both drugs106,107.(i.e 0.1%

bupivacaine vs 0.15% ropivacaine). Most of the studies have found that both

drugs did not differ significantly except ropivacaine had less motor block on

prolonged infusion.

The recommended dose of bupivacaine in labor epidural analgesia is

0.0625%-0.125% and that of ropivacaine is 0.08%-0.2% at the rate of 8-

15ml/hour.16

105

We used 6ml of 0.2% ropivacaine for initiation(Beillin1999)94 and 6ml/hr

of 0.1% ropivacaine with 2µg/ml fentanyl(Benhamou 1997,Cascio 1997)92,93

for maintenance.

Neuraxial local anesthetics and opioids act synergistically to provide

neuraxial analgesia. This combination decreases the MLAC of local

anaesthetics used.88 We used fentanyl in a concentration of 2 µg/ml as it was

used most commonly in previous studies.

We decided to compare 0.1% ropivacaine with fentanyl and 0.125%

bupivacaine with fentanyl to see whether a less potent ropivacaine offers the

same pain relief and if it offers any significant advantage over bupivacaine at

this concentration.

The parturients were comparable in regards to age, weight, gravida,

parity, vaginal dilatation in both groups.

Pain relief:

Pain is a subjective phenomenon and it is difficult to measure. There

are many different scales to measure pain - verbal rating scale, numerical

rating scale (NRS), visual analog scale(VAS) etc. In our study we used NRS

as the pain scoring system because it was easy to use along with patients’

understanding and compliance being better.

In our study we found that the mean pain level was 7.8±0.7 in

ropivacaine group and 7.6±0.8 in bupivacaine group. After epidural it came

down to 0.31 in ropivacaine and 0.17 in bupivacaine group. The pain score

went upto 0.42 in ropivcaine and 0.52 in bupivacaine group at the end of 5

106

hours. There was no clinically demonstrable difference in the onset of pain

relief. This was consistent with the results obtained by Meister et al 200096.

They compared equal concentrations of 0.125% bupivacaine and 0.125%

ropivacaine along with fentanyl in both groups. They found that mean NRS

scores which were around 9 in bupivacaine and 8 in ropivacaine respectively,

came down to 0.4 & 0.3 post epidural. This study finding was echoed in the

study done by Fernandez et al 2001106 when they compared 0.0625%

bupivacaine with fentanyl and 0.1% ropivacaine and fentanyl.

There were no clinically demonstrable differences in the onset of pain

relief. Patient satisfaction was also comparable in both groups

Though our study used a less potent concentration of ropivacaine,

there was no statistically significant difference in the pain relief offered.

Motor blockade:

When Halpern et al 2003123 did a meta-analysis comparing ropivacaine

and bupivacaine he found that 19 out of 23 studies favoured ropivacaine to

have minimal motor block and 5 of those studies were statistically significant.

In our study, only 2 patients in bupivacaine group had demonstrable

Bromage score-I motor block. There was no clinically demonstrable motor

block in the ropivacaine group. This difference was not clinically significant.

The incidence of motor block in our study was low in ropivacaine and

also significantly lower than bupivacaine in many of the comparative

studies(Gautier 1999,Fischer 2000,Meister 2000,Campbell 2000)95,96,97,99

This may be because the volume of drug used in our study was low(6 ml

107

bolus and 6-8ml/hr infusion) thereby resulting in a lesser concentration of

drugs.

Duration of labour:

Duration of 1st stage of labour:

The duration of labour is determined by the intensity of uterine

contraction, the dilatation of cervix and the descent of the presenting part of

fetus.

A meta-analysis by Halpern et al(1988)122 concluded that epidural

analgesia prolonged 1st stage of labour by 42 minutes.

But other studies including the recent Cochrane review34 comparing

epidural and non-epidural methods of labour analgesia did not find any

difference in the length of 1st stage of labour.

In our study the duration of first stage of labour was 467.7±95.8

minutes in ropivacaine group and 467.6±87.8 minutes in the bupivacaine

group. There was no statistically significant difference in the mean duration.

Many studies compared varying concentrations of bupivacaine with

ropivacaine. They did not find any difference in the duration of 1st stage of

labour between bupivacaine and ropivacaine (Feranandez 2001,Owen 2002,

Boselli 2003).106,109,113

The results of our study correlate well with the above mentioned

studies.

108

In contrast Lee et al 2002110 in their study compared found that the

bupivacaine group had longer first stage of labour than ropivacaine group.

However they concluded that the difference may be of limited clinical

significance.

Duration of 2nd stage of labour:

According to ACOG guidelines, second stage of labour is said to be

prolonged when the duration was more than 3 hours for primipara and more

than 2 hours for multipara with regional anaesthesia.

A metanalysis done by Halpern et al122 on 2400 parturients who

received either epidural analgesia or parenteral opioid analgesia found that

the second stage of labour was prolonged by 14 minutes. A recent Cochrane

review34 on epidural versus non-epidural or no analgesia in labour found that

women who had epidural were more likely to have a longer second stage of

labour.

In our study there was no difference in the duration of second stage of

labour in both groups. The mean duration was 33.5 min in ropivacaine group

and 31.1 min in bupivacaine group. This difference was not statistically

significant. Our result coincides well with the meta-analysis done by Halpern

et al in 2003123 which took into account 23 studies comparing ropivacaine and

bupivacaine for labour epidural analgesia. They found that neither

bupivacaine nor ropivacaine group had any difference in the duration of

second stage of labour.

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Mode of delivery:

Instrumental vaginal delivery:

Halpern et al 1988122 in their meta analysis found that women with

epidural were twice as likely to have an instrumental vaginal delivery as

compared to control groups. Cambic and Wong 2010124 in their review on

labour analgesia and obstetric outcomes concluded that effective second

stage analgesia might be associated with an increased rate of instrumental

vaginal delivery.

In our study we had an instrumental delivery rate of 25.7% in

ropivacaine group and 37.1% in bupivacaine group which was not statistically

significant. In majority of cases, maternal failure was the cause of instrumental

delivery. Our study results coincide with the study done by Finegold et al in

2000100, which used a similar concentration of drugs as our study. They had a

instrumental vaginal delivery rate of 18% in ropivacaine group and 28% in

bupivacaine. In both our studies though the instrumental delivery rates were

less in ropivacaine, the differences were not statistically significant.

The meta-analysis of 23 studies comparing ropivacaine and

bupivacaine in 2003 by Halpern et al123 also did not find any difference in

the mode of delivery between the two drugs.

However a meta-analysis of 6 studies comparing 0.25% ropivacaine

and 0.25% bupivacaine done by Writer et al125 in 1998 found that there were

fewer instrumental vaginal deliveries in the ropivacaine group. This may be

because of the higher concentration of bupivacaine used and difference in the

motor blocking potency of ropivacaine.

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Caesarean delivery:

Epidural analgesia is not associated with an increased rate of cesarean

delivery. This has been the conclusion of a meta-analysis by Halpern et al

1988122 and the recent Cochrane review 201134 done on epidural vs non-

epidural and no analgesia in labour.

In our study,we had a cesarean delivery rate of 11.4% in ropivacaine

and 8.6% in bupivacaine group. The main reasons for the cesarean delivery

among both groups were failure to progress, fetal distress due to cord around

the neck and meconium stained liquor.

Beilin et al in 2007117 compared ropivacaine with bupivacaine and their

effect on outcome of delivery. Bupivacaine group had a cesarean rate of 33%

against a 30% rate in ropivacaine group.

The meta-analysis by Halpern et al 2003123 also found no difference in

cesarean delivery rates between ropivacaine and bupivacaine when used for

labor epidural.

Fetal and neonatal outcome:

The recent Cochrane review34 which compared epidural analgesia with

other forms of analgesia including inhaltional and intravenous(mainly opioids)

observed that there was less fetal acidosis and less naloxone administration

in babies born to mothers having labour epidural analgesia.

In our study the fetal heart rate during the process of labour analgesia

was within normal limits. There was no incidence of post epidural fetal

bradycardia. The mean APGAR score was 7.65 & 7.68 in ropivacaine and

111

bupivacaine groups respectively. At 5 minutes it averaged to 8.94 & 9

respectively. There was no significant difference in NICU admission in both

groups.

Beilin and Halpern in 2010126 did a focused review with various studies

that compared bupivacaine and ropivacaine and concluded that there was no

evidence that neonatal outcome is adversely affected when ropivacaine or

bupivacaine is used for labor analgesia.

Writer et al.125 found a difference in the neurologic and adaptive

capacity score, favoring ropivacaine, at 24 hours after birth, but not at 2 hours

after birth. But recent evidence suggests that the neurologic and adaptive

capacity score is unreliable.127

The incidence of low Apgar scores at 5 minutes is approximately 2%

for both drugs.123 In addition, the umbilical artery and vein pH are well

maintained regardless of which local anesthetic is used. 110Also, the incidence

of need for neonatal resuscitation is low and similar with both drugs.117

The incidence of complications were very minimal in both groups.

112

Summary

This study was undertaken to compare continuous epidural ropivacaine

with fentanyl and continuous epidural bupivacaine with fentanyl in labour

analgesia.

A total of 120 patients were randomly allocated into 2 groups. Group A

received 6ml of 0.2% ropivacaine as the initial bolus followed by 6ml/hr

infusion of 0.1% ropivacaine with 2µg/ml fentanyl. Group B received 6ml of

0.25% bupivacaine as initial bolus followed by 6ml/hr infusion of 0.125%

bupivacaine with 2µg/ml fentanyl. Various parameters and complications if

any were recorded every 15 minutes in the 1st hour, every 30 minutes in the

2nd hour and every hour later on.

The observations noted were as follows:

Pain relief as observed by verbal numerical rating scale was as low as

0.02 in both the groups till 2 hours. The mean score went upto 0.42 in

Group-A(ropivacaine) and 0.52 in Group-B(bupivacaine). The

fluctuations in pain were not clinically or statistically significant between

the two study groups.

The number of patients who required bolus were 7(20%) in both the

groups.

The spontaneous deliveries were more, 62.9% in Group-A as

compared to 54.3% in Group-B. The instrumental delivery rates were

less, 25.7% in Group-A as compared to 37.1% in Group-B.Cesarean

sections were performed in 4(11.4%) women in Group-A as compared

113

to 3(8.4%) patients in Group-B. These differences were not statistically

significant.

The duration of first stage of labour was 467 minutes in both the

groups. The mean duration of second stage of labour was 33 minutes

in Group-A as compared to 31 minutes in Group-B. The third stage of

labour was 6 minutes in both the groups.

No adverse neonatal outcome(because of the drugs used) in the form

of low Apgar scores or admission to NICU were noticed in both the

groups.

Motor block was observed in 3 patients (8.5%) in Group B(bupivacaine)

only. There was no clinically observable motor blockade in Group-

A(ropivacaine). This difference was not statistically significant.

The incidence of complications was minimal and comparable in both

groups.

Drawbacks of our study:

We did not double-blind this study.

We relied upon Apgar score for assessing the neurobehavioural

outcome of the baby.

We did not measure the umbilical cord pH to know the effect of drugs

on the acid base status of the newborn due to financial constraints.

114

Conclusion

Obstetric analgesia strives at making childbirth, a pleasurable and

painless event. As a means toward this end, we should ideally adopt the best

possible technique, something that would provide excellent analgesia with

minimal side effects and absolute safety to the mother and child.

The observations of this study show that pain relief offered by epidural

ropivacaine is as good and effective as epidural bupivacaine. Also the

duration of labour, mode of delivery, neonatal outcome and complications are

comparable between the two groups.

From this study it can be concluded that though ropivacaine is less

potent than bupivacaine, ropivacaine is as efficacaious as bupivacaine in the

concentrations used in our study.

115

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113. Boselli E, Debon R, Duflo F, Bryssine B, Allaouchiche B, Chassard D.Ropivacaine 0.15% plus sufentanil 0.5 microg/mL and ropivacaine 0.10% plus sufentanil 0.5 microg/mL are equivalent for patient-controlled epidural analgesia during labor. Anesth Analg. 2003 Apr;96(4):1173-7.

114. Gogarten W, Van de Velde M, Soetens F, Van Aken H, Brodner G, Gramke HF, Soetens M, Marcus MA. A multicentre trial comparing different concentrations of ropivacaine plus sufentanil with bupivacaine plus sufentanil for patient-controlled epidural analgesia in labour. Eur J Anaesthesiol. 2004 Jan;21(1):38-45.

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Epidural infusion preparation:

Group-A

0.1% ropivacaine with 2µg/ml fentanyl

25 ml of 0.2 % ropivacaine + 23 ml of normal saline + 2ml (100 µg) of fentanyl

Group-B

0.125% bupivacaine with 2µg/ml fentanyl

25 ml of 0.25% bupivacaine + 23 ml of normal saline + 2ml (100 µg) of

fentanyl

Motor blockade - Bromage score:

Score Criteria

0 Free movement of legs and feet

1 Just able to flex knees with free movement of feet

2 Unable to flex knees, but with free movement of feet

3 Unable to move legs or feet

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INSTRUCTIONS FOR LABOUR WARD STAFF

1. Stop infusion if:

1. Systolic BP < 90 mm Hg or 20% below baseline BP

2. Heart rate< 50/min

3. Respiratory rate < 10/min

4. SpO2< 90%

2. Inform anaesthetist if:

1. Hypotension (Systolic < 90 mm of Hg / 20% below base

line )

2. Respiratory depression (RR < 10/min )

3. Motor Blockade

4. Patchy Block

5. Pruritis

6. Nausea / Vomitting

7. Urinary Retention

3. If hypotension:

1. Stop infusion

2. Rush fluids

3. IV ephedrine 6mg

4. Nausea/vomiting/itching : IV ondansetron 4mg

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