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

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 DEAN GKNM HOSPITAL, COIMBATORE

DR. RAJANI SUNDAR, M.D., D.A., CHIEF ANAESTHESIOLOGIST DEPARTMENT OF ANAESTHESIA GKNM HOSPITAL, COIMBATORE.

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:

Dr.Jayaprakash K Postgraduate in Anaesthesiology

Place:

G.Kuppusamy Naidu Memorial Hospital Coimbatore

ii

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

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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/g - Microgram

iv

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

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 L 1 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:
vi

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.

vii

LIST OF TABLES
S.No 1 2 3 4 TABLES PAIN IN LABOUR PATHWAYS AND MECHANISMS TECHNIQUES OF LABOUR ANALGESIA INDICATION FOR EPIDURAL ANALGESIA CONTRAINDICATIONS FOR EPIDURAL ANALGESIA 5 IMMEDIATE COMPLICATIONS OF EPIDURAL ANALGESIA 6 7 STUDY DRUGS PROTOCOL NUMBER OF PATIENTS AT EACH TIME POINT IN BOTH GROUPS 8 9 COMPARISON OF HEART RATE COMPARISON OF MEAN SYSTOLIC BLOOD PRESSURE 10 COMPARISON OF MEAN DIASTOLIC BLOOD PRESSURE 11 12 13 14 COMPARISON OF MEAN RESPIRATORY RATE COMPARISON OF MEAN PAIN SCORES(VNRS) COMPARISON OF BOLUS REQUIREMENT COMPARISON OF MEAN DURATION OF LABOUR 100 101 101 102 99 98 99 91 98 33 PAGE NO. 8 15 32 32

viii

List of Figures

S.NO 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Figures LABOUR PAIN DURING DIFFERENT STAGES OF LABOUR EFFECTS OF LABOUR PAIN LABOUR PAIN PATHWAYS & REGIONAL BLOCKS USED TECHNIQUE OF LABOUR EPIDURAL ANALGESIA STRUCTURE OF ROPIVACAINE DOSAGE RECOMMENDATIONS FOR ROPIVACAINE IN ADULTS AND CHILDREN STRUCTURE OF BUPIVACAINE STRUCTURE OF FENTANYL EPIDURAL OPIOIDS EPIDURAL TRAY AND EPIDURAL SET MEAN AGE AND WEIGHT BY GROUP GRAVIDA DISTRIBUTION PARITY DISTRIBUTION ASA STATUS DISTRIBUTION LEVEL OF EPIDURAL PLACEMENT DISTRIBUTION BY GROUP MODE OF DELIVERY BETWEEN ROPIVACAINE AND BUPIVACAINE NEONATAL OUTCOME BETWEEN ROPIVACAINE AND BUPIVACAINE

PAGE NO. 7 13 20 31 42 47 49 62 63 89 95 95 95 96 97 102 103

ix

Table of Contents

S.No
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

Contents
BONAFIDE CERTIFICATE DECLARATION BY THE CANDIDATE ACKNOWLEDGEMENT LIST OF ABBREVIATIONS ABSTRACT LIST OF TABLES LIST OF FIGURES INTRODUCTION AIMS AND OBJECTIVES LABOUR PAIN LABOUR ANALGESIA ASSESSMENT OF PAIN LABOUR EPIDURAL ANALGESIA PHARMACOLOGY OF ROPIVACAINE PHARMACOLOGY OF BUPIVACAINE PHARMACOLOGY OF FENTANYL REVIEW OF LITERATURE MATERIALS & METHODS RESULTS & OBSERVATION DISCUSSION SUMMARY CONCLUSION BIBLIOGRAPHY APPENDIX I APPENDIX II THESIS PROFORMA APPENDIX III MASTER CHART

Page no.
i ii iii iv vi viii ix 1 6 7 15 24 25 42 49 62 66 87 94 105 112 114 115 125 126 130

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"

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
2

parturients 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

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
4

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.

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

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)
7

TABLE-1 - Pain in Labour: Pathways and Mechanism (Crawford)12 Site of Origin 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 Mid back Upper abdomen and groin Mechanism Pathway Site of Pain

Peri-uterine tissues, Lumbosacral region Bladder, urethra rectum Vagina Perineum

Pressure often in association with platypelloid pelvis Pressure by presenting part

Lumbosacral plexus L5,S1 (Pelvic

Lowback, thigh

fetal malposition or splanchnic nerves)

S2,3,4

Referred to Perineum and sacral area

Distension, tearing Distention, tearing

Somatic S2,3,4 Pudendal N. S2,3,4 Genitofemoral N.L1,2 Ilioinguinal N. L1 Posterior cutaneous Nerve of thigh, S2,3

Not referred Not referred

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 A 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 T 11 and T12 are involved, but as labour progresses T10 and L1 are recruited.

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 A and C fibres conduct pain sensations from the uterus and t he spinal cord. The pain of parturition is mainly a visceral pain and therefore is conducted in the A and C fibres to the spinal cord. These fibres make

10

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.
11

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 Fergusons 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.
12

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)

13

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.

14

LABOUR ANALGESIA
Table-2 - TECHNIQUES OF LABOUR ANALGESIA Non-Pharmacologic methods Continuous support in labour Touch and massage TENS Intradermal injections Water bath Upright posture Acupuncture/Acupre -ssure Hypnosis Pharmacological methods Intravenous OpioidsPethidine, Fentanyl, Morphine,Remife ntanyl, Butorphanol, Pentazocine Ketamine Tramadol Benzodiazepines Regional Anaesthetic techniques 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

15

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 patients 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.

16

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

17

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 status 23,24. Remifentanil is a potent short-acting -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 g bolus with a lockout 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

18

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 1960s 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.

19

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
20

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 Tuohys 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.
21

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 1980s 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.
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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.

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ASSESSEMENT OF ACUTE PAIN16

Pain is a uniquely personal symptom with no reliable objective signs, so we have to accept an individuals 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 10being 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.
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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.

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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 Anteriorly - The Sacrococygeal ligament. - 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

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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.
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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 [Tuffiers 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
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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 28cm H2O, even in lateral position. Adequate epidural pain relief minimizes the pressure rise produced during contraction13.

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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

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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)

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.

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INDICATIONS AND CONTRAINDICATIONS FOR EPIDURAL ANALGESIA Indications16: Table-3-Indications for epidural analgesia Maternal 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 Fetal 1. Prematurity 2. Breech presentation 3. Multiple gestation

Contraindications16

Table-4 Contraindications for epidural analgesia

Absolute 1. Patient refusal 2. Local sepsis 3. Severe anemia 4. Coagulopathy 5. Hypovolemia 6. Fixed cardiac output state 7. Inability to cooperate Relative 1. Pre-existing neurological disease 2. Severe deformity of spine

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ADVERSE MATERNAL ANALGESIA13 Maternal Immediate

AND

FETAL

EFFECTS

OF

EPIDURAL

Table-5 Immediate complications of epidural analgesia

Penetrate blood vessel, duramater, During Insertion needle or catheter neural tissue, broken catheter Subarachnoid Due to Injection Intravascular Adverse reaction to local anesthetic Hypotension Motor block Neural blockade Bladder dysfunction Horners syndrome Shivering Inadequate analgesia Progress of labour Total failure Partial failure Prolonged labour Increased instrumental deliveries

Delayed a) Neurological - Epidural abscess Epidural Hematoma Chemical meningitis Damage to nerve roots by needle Ischemia of cords
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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 0.27%49. Though a rare complication, it has disturbing sequelae of post dural puncture headache. Its incidence in obstetrics remains about 1-5% even with

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very small-bore spinal needle and optimized tip. PDPH has a major impact on morbidity and on the patients 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.
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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. Ronbuttler 53 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
36

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
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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
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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 pregnancyIn these conditions an epidural block allows a more controlled delivery because of relaxed pelvic floor muscles and a decreased urge to push.

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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 T 11 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.

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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.

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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

Figure 5 - Structure of Ropivacaine

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.

42

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 C17H26N2OHClH2O 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 25C. 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 halflife 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 g/mL DISTRIBUTION After intravascular infusion, ropivacaine has a steady state volume of distribution of 41 7 litres. Ropivacaine is 94% protein bound, mainly to 1 43

acid glycoprotein. An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of 1-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-dealkylated (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-hydroxymethyl-ropivacaine has been identified but not quantified in the urine. The N-de-alkylated metabolite of ropivacaine (PPX) and 3-OHropivacaine 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,

44

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 A 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
45

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
46

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)

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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.

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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, 1butyl-N-(2, 6- dimethylphenyl)-, monohydrochloride,monohydrate and has the following structure

Figure-7- Structure of bupivacaine

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
49

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-(2,6dimethylphenyl)-,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.

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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 preganglionic 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

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moderately larger total doses and sometimes prolonging the duration of action. The onset of action with bupivacaine is rapid and anaesthesia is longlasting. 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.

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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
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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
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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
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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.

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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
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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
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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 1980s 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 810mcg/ml.68
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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 23mcg/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
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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).

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FENTANYL It is a phenyl piperidine derivative, synthetic opiod agonist which is 75125 times more potent than morphine.78 STRUCTURAL FORMULA

Figure-8-Structure of Fentanyl

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.

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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 drugs 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. 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.
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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 is 1-2.5 minutes and t1/2 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

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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 g/kg provides analgesia. In doses 2-20g/kg, it blunts the pressor response to laryngoscopy and surgical stimulation along with inhalational agents. Used in total intravenous anaesthesia with loading dose 4-20g/kg and maintainenance infusion rate of 2-10g/kg/hr or additional boluses of 25-100g. EPIDURAL DELIVERY: Fentanyl is used in the dose of 50-100g for

initiation of epidural analgesia. For maintenance a dose 1-4g/ml is used.87,From previous studies a dose of 2g/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
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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

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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
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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, doubleblinded 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 g sufentanil or 10ml of 0.125% ropivacaine, plus 7.5 g sufentanil. The duration of analgesia, visual analogue scores for pain, motor blockade (using a sixpoint 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 2g/ml Fentanyl and 0.125% Bupivacaine with 2g/ml Fentanyl for epidural Labour Analgesia. They chose 50 laboring women and randomized them to receive either 0.125% Ropivacaine with Fentanyl 2g/ml or 0.125% Bupivacaine with Fentanyl 2g/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 2g/ml Fentanyl or 0.08% Ropivacaine and 2g/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 2g/ml Fentanyl (BF) or 20ml of 0.08% Ropivacaine and 2g/ml Fentanyl (RF) to initiate epidural analgesia. They found that 0.08% Ropivacaine and 2g/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 2g/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 g/ml sufentanil with that of 0.1% bupivacaine and 0.5 g/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 g/ml sufentanil produce less motor block but are clinically less potent than 0.1% bupivacaine and 0.5 g/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 bupivacainefentanyl 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 g/ml fentanyl. Another group received 10 ml of 0.2% ropivacaine bolus and infusion of 0.1% ropivacaine with 2 g/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 g/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 g/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 (Senantiomer) 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 g/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 g of sufentanil added to it. A continuous infusion of a 0.1% study drug infusion with 0.6 g/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 g 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. Fernndez-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 50g of fentanyl for both the groups. Continuous epidural infusion of 0.0625% bupivacaine with fentanyl 2 g/ml or 0.1% ropivacaine with fentanyl 2 g/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 g/ml versus 0.10% bupivacaine plus sufentanil 0.5 g/ml. No differences was observed between the two groups for pain scores, total volume of anaesthetic solution used, duration of labour, mode of delivery, sideeffects 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 g/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 g/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 g/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 g/ml (B/F), or ropivacaine 0.2% with fentanyl 2 g/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 g/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 g/mL of sufentanil with that of 0.1% ropivacaine plus 0.5 g/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 g/mL of sufentanil given via patient-controlled epidural anesthesia for labor analgesia was equally as effective as ropivacaine 0.15% plus 0.5 g/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 g/ml, ropivacaine 0.125% or 0.175% with sufentanil 0.75 g/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 sideeffects. 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 2g/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 g/ml at 10ml/ h(Group R1, n = 38) or 0.2% ropivacaine with fentanyl 2 g/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 (100g) followed by infusion of 12 ml/hr of local anesthetic with 2g/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 g/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 0.5g/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 + 2.5g/ml Fentanyl. Sufentanil group (S) received 0.625% Bupivacaine + 0.25g/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,
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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 g/ml had the same effects as 0.08% ropivacaine and fentanyl 2 g/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 g/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 g/ml for labor epidural analgesia of nulliparous women.
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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.
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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 - 100g. 10. Emergency kit with working laryngoscope, cuffed endotracheal tubes of appropriate size, airway, suction apparatus with suction catheter, Inj.Adrenaline, Oxygen cylinder. 11. Monitor for continuous monitoring for Non-invasive blood pressure, ECG, Respiratory rate, Oxygen saturation. Inj.Atropine, Inj.Thiopentone, Inj.Succinyl choline,

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Figure-10 - Epidural tray and epidural set

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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.

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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 6ml A Ropivacaine 6ml B Bupivacaine 2g/ml fentanyl of fentanyl 0.25% 6-8ml/hr of 0.125% Bupivacaine with of Infusion 0.2% 6-8ml/hr of 0.1% Ropivacaine with 2g/ml

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.

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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).

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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. Chisquare test for association was used to compare categorical variables between treatment allocations.

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Results and Observation Our study included 70 pregnant women. They were randomly allocated to either Group A(0.1% ropivacaine with 2g/ml fentanyl) or group-B(0.125% bupivacaine with 2g/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 25.373.85 years and that of group-B was 25.233.623.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 688.86 kgs and that of those in Group-B was 64.299.03 kgs. This difference in weight between the two groups was statistically not significant.(P=0.087)

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Figure-11- Age and Weight by group

68 64.29

25.37

25.23

Age(Years) Group-A Group-B

Weight(Kgs)

Gravida & parity: Gravida(p=0.200) and parity(p=0.122) of the women between two groups were not statistically significant.

Figure-12-Gravida by group
30 25 20 15 10 5 0 Gravida 1 Gravida 2 Gravida 3 Group-A Group-B 8 1 1 19 15 15 10 5 0 26 30 25 20

Figure-13- Parity by group

27 21 14

4.4

Parity 0 Group-A

Parity 1 Group-B

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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)

94.3 100 80 % of women 60 40 20 0 Group-A Group-B 5.7 8.6

91.4

ASA-I ASA-II

Figure-14-ASA grade by group

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 groupB. Their distribution among groups was not statistically significant.(p=0.840) Vaginal dilatation: The average vaginal dilatation of the whole group was 3.440.65 cm. The vaginal dilatation in group-A was 3.370.54 cm and in group was 3.510.74 cm. This variable did not have any statistically significant difference.(p=0.206)
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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) Figure-15-Level of epidural placement by group
100 90 80 70 % of woen 60 50 40 30 20 10 0 L2-L3 L3-L4 L4-L5 22.9 8.6 8.6 40 51.4 Group-A Group-B 68.6

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.

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PATIENT DISTRIBUTION: Time Point Baseline 15 mins 30 mins 45 mins 1 hour 1.5 hrs 2 hrs 3 hrs 4 hrs 5 hrs 6 hrs 7 hrs Number of women measured Group-A Group-B 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 19 10 3 35 33 19 8 3

Table-7 Number of patients at each time point

COMPARISON OF HEART RATE: The following table shows the heart rate variations in both groups. Time Baseline 15 mins 30 mins 45 mins 1 hr 1.5 hr 2 hr 3 hr 4 hr 5 hr 6 hr 7 hr Group-A 93.65.5 84.26.2 83.55.3 82.26.1 86.16.9 84.45.7 866.8 867.4 89.27.4 88.65.5 88.29.4 89.67.0 Group-B 91.95.1 86.15.3 85.34.6 84.56.1 87.76.0 86.54.5 87.34.6 88.55.5 90.74.6 86.37.3 87.57.6 79.34.2 t value 1.350 -1.295 -1.508 -1.572 -1.043 -1.634 -0.926 -1.594 -0.986 1.100 0.169 0.285 p value 0.182 0.200 0.136 0.121 0.301 0.107 0.358 0.116 0.328 0.278 0.868 0.791
Table-8 Comparison of heart rate between ropivacaine and bupivacaine groups

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COMPARISON OF SYSTOLIC BLOOD PRESSURE: The following table shows the comparison of systolic blood pressure between the two groups during their labour. Time Baseline 15 mins 30 mins 45 mins 1 hr 1.5 hr 2 hr 3 hr Group-A 115.610.5 114.48.1 114.26.8 112.98.2 116.47.9 117.26.1 114.47.8 114.55.5 Group-B 114.811.2 115.47.8 115.110.1 115.47.8 116.57.6 117.17.8 114.56.8 115.410.1 t value 0.308 -0.538 -0.442 -1.314 -0.092 0.068 -1.060 -0.469 p value 0.759 0.592 0.660 0.193 0.927 0.946 0.293 0.640
Table-9 Comparison of mean systolic blood pressure between ropivacaine and bupivacaine groups

4 hr 114.76.3 113.87.7 0.538 0.592 5 hr 113.47.7 116.39.5 -1.009 0.320 6 hr 1127.8 117.57.1 -1.537 0.144 7 hr 1100.0 103.35.7 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 Baseline 15 mins 30 mins 45 mins 1 hr 1.5 hr 2 hr 3 hr 4 hr 5 hr 6 hr 7 hr Group-A 76.27.8 74.77.9 74.47.9 74.67.7 75.87.9 77.26.8 74.47.8 77.66.7 75.77.6 76.55.9 71.43.2 73.35.7 Group-B 74.26.9 75.46.1 74.26.9 71 12.4 72.57.8 74.56.1 727.9 75.46.5 73.17.8 74.25.1 73.75.1 73.35.7 t value 1.122 -0.405 0.112 1.319 1.747 1.693 1.303 1.398 1.363 1.290 -1.176 1.000 p value 0.266 0.087 0.911 0.192 0.085 0.095 0.197 0.167 0.177 0.205 0.257 1.000
Table-10 Comparison of mean diastolic blood pressure between ropivacaine and bupivacaine groups

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COMPARISON OF RESPIRATORY RATE: The following table shows the comparison of respiratory rate between the two groups during their labour Time Baseline 15 mins 30 mins 45 mins 1 hr 1.5 hr 2 hr 3 hr 4 hr 5 hr 6 hr 7 hr Group-A 21.93.2 17.42.4 17.11.9 17.72.3 16.72.4 17.45.8 16.82.2 16.82.4 17.42.1 17.62.0 16.62.0 15.31.1 Group-B 20.84.0 18.11.7 17.71.4 17.71.4 17.61.5 17.61.4 17.51.3 17.71.6 18.11.5 17.72.2 172.8 15.31.2 t value 1.267 -1.407 -1.534 -0.100 -1.745 -0.198 -1.612 -1.794 -1.480 -0.180 -0.307 0.000 p value 0.209 0.164 0.130 0.951 0.085 0.849 0.112 0.077 0.144 0.882 0.762 1.000

Table-11 Comparison of mean respiratory rate between ropivacaine and bupivacaine groups

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.
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Time Baseline 15 mins 30 mins 45 mins 1 hr 1.5 hr 2 hr 3 hr 4 hr 5 hr 6 hr 7 hr

Group-A 7.880.7 0.310.4 0.020.1 0.020.1 0.020.1 0.110.5 0.080.2 0.200.6 0.280.8 0.420.9 0.000 0.000

Group-B 7.650.8 0.170.3 0.080.2 0.050.2 0.080.2 0.050.2 0.020.1 0.080.3 0.090.3 0.52-.2 0.381.1 0.000

t value 1.170 1.393 -1.023 -0.583 -1.023 -1.358 1.023 1.041 1.235 -0.289 -1.127

p value 0.246 0.168 0.310 0.562 0.310 0.179 0.310 0.302 0.221 0.774 0.276

Taable-12 Comparison of mean pain score (VNRS)between ropivacaine and bupivacaine groups

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 15 mins 30 mins 45 mins 1 hr 1.5 hr 2 hr 3 hr 4 hr 5 hr 6 hr 7 hr Group-A Nil Nil Nil Nil 1 Nil 1 2 2 1 Nil Group-B Nil Nil Nil Nil Nil Nil 2 Nil 3 2 Nil p value

0.314 0.555 0.151 0.631 0.396

Table-13 Comparison of bolus requirement between ropivacaine and bupivacaine groups

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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 groupA(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. Figure-16-Mode of delivery between Ropivacaine and Bupivacaine

100 90 80 70 60 50 40 30 20 10 0

11.4 25.7

8.6 37.1 Cesarean Vaginal assisted

% of women

62.9

Vaginal spontaneous 54.3

Group-A

Group-B

Duration of labour: The following chart shows the average duration of 1 st,2nd and 3rd stage of laour in minutes. All 3 stages of labour were comparable. Duration(in minutes) Stage-I Stage-II Stage-III 467.495.8 33.58.5 6.81.7 467.687.8 31.18.9 6.11.2 -0.007 1.116 1.769 0.995 0.269 0.082
Table-14 Comparison of Duration of labour between ropivacaine and bupivacaine groups

Group-A

Group-B

t value

p value

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Neonatal outcome: The neonatal outcome was rated with Apgar acore at 1 & 5 minutes. The average Apgar score during 1st minute assessment was 7.650.59 and 7.680.47 in group-A and group-B respectively. At 5 minutes, the Apgar score was 8.940.23 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). Figure-17-Comparison of neonatal outcome by groups
9 7.68 7.65 8.94

Mean APGAR score

10 8 6 4 2 0 Minute 1

Group-A Group-B Group-B Group-A Minute 5

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.

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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.

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Discussion
The recently published cochrane review34 on epidural versus nonepidural 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 815ml/hour.16

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We used 6ml of 0.2% ropivacaine for initiation(Beillin1999)94 and 6ml/hr of 0.1% ropivacaine with 2g/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 g/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 7.80.7 in ropivacaine group and 7.60.8 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
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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
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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 467.795.8 minutes in ropivacaine group and 467.687.8 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.

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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 nonepidural 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
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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.
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Also, 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.

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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 2g/ml fentanyl. Group B received 6ml of 0.25% bupivacaine as initial bolus followed by 6ml/hr infusion of 0.125% bupivacaine with 2g/ml fentanyl. Various parameters and complications if any were recorded every 15 minutes in the 1 st 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

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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 GroupA(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.

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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.

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89. Stienstra R, Jonker T, Bourdrez P, Kuijpers J, van Kleef J, Lundberg U. Ropivacaine 0.25% Versus Bupivacaine 0.25% for Continuous Epidural Analgesia in Labor: A Double-Blind Comparison. Anesth Analg 1995;80(2):285-9. 90. McCrae AF, Jozwiak H, McClure JH. Comparison of ropivacaine and bupivacaine in extradural analgesia for the relief of pain in labour. Br J Anaesth. 1995 Mar;74(3):261-5. 91. Eddleston JM, Holland JJ, Griffin RP, Corbett A, Horsman EL, Reynolds F. A double-blind comparison of 0.25% ropivacaine and 0.25% bupivacaine for extradural analgesia in labour. Br J Anaesth. 1996 Jan;76(1):66-71. 92. Benhamou D, Hamza J, Eledjam JJ, Dailland P, Palot M, Seebacher J, Milon D,Heeroma K. Continuous extradural infusion of ropivacaine 2 mg ml-1 for pain relief during labour. Br J Anaesth. 1997 Jun;78(6):74850. 93. Cascio MG, Gaiser RR, Camann WR, Venkateswaran P, Hawkins J, McCarthy D.Comparative evaluation of four different infusion rates of ropivacaine (2 mg/mL) for epidural labor analgesia. Reg Anesth Pain Med. 1998 Nov-Dec;23(6):548-53. 94. Beilin Y, Galea M, Zahn J, Bodian CA. Epidural ropivacaine for the initiation of labor epidural analgesia: a dose-finding study.Anesth Analg 1999;88:13405. 95. Gautier P, De Kock M, Van Steenberge A, Miclot D, Fanard L, Hody JL. A double-blind comparison of 0.125% ropivacaine with sufentanil and 0.125% bupivacaine with sufentanil for epidural labor analgesia. Anesthesiology. 1999 Mar;90(3):772-8 96. Meister G C, D Angelo R, Owen M, Nelson K E, Gaver R. A comparison of epidural analgesia with 0.125% Ropivacaine with Fentanyl versus 0.125% Bupivacaine with Fentanyl during labor. Anesth Analg 2000; 90: 632-37. 97. Campbell DC, Zwack RM, Crone LL, Yip RW. Ambulatory labor epidural analgesia: bupivacaine versus ropivacaine. Anesth Analg 2000; 90: 13849. 98. Fettes PDW, Moore CS, Whiteside JB, Mcleod GA, Wildsmith JAW. Intermittent vs continuous administration of epidural ropivacaine with fentanyl for analgesia during labour. Br J Anaesth 2000; 97: 35964. 99. Fischer C, Blanie P, Jaouen E, Vayssiere C, Kaloul I, Coltat J. Ropivacaine, 0.1%, Plus Sufentanil, 0.5 g/ml, versus Bupivacaine, 0.1%, Plus Sufentanil, 0.5 g/ml, Using Patient-controlled Epidural
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110. Lee BB, Ngan Kee WD, Lau WM, Wong AS. Epidural infusions for labor analgesia: a comparison of 0.2% ropivacaine, 0.1% ropivacaine, and 0.1% ropivacaine with fentanyl. Reg Anesth Pain Med. 2002 Jan-Feb;27(1):31-6. 111. Asik I, Goktug A, Gulay I, Alkis N, Uysalel A: Comparison of bupivacaine 0.2% and ropivacaine 0.2% combined with fentanyl for epidural analgesia during labour. Eur J Anaesthesiol. 2002 Apr; 19(4):263-70. 112. Fernandez C, Sala X, Plaza A, Lopez A, Celemin M, Gomar C: Epidural anesthesia with ropivacaine vs. bupivacaine in continuous perfusion for the treatment of labor pains. Rev Esp Anestesiol Reanim. 2003 Feb; 50(2):70-6. 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. 115. Atienzar MC, Palanca JM, Borras R, Esteve I, Fernandez M, Miranda A.Ropivacaine 0.1% with fentanyl 2 microg mL(-1) by epidural infusion for labour analgesia. Eur J Anaesthesiol. 2004 Oct;21(10):7705. 116. Neera Sah, Vallejo M, Phelps A, Finegold H, Mandell G, Ramanathan. Efficacy of ropivacaine, bupivacaine, and levobupivacaine for labor epidural analgesia .S. Journal of Clinical Anesthesia 2007; 19: 21417. 117. WANG Li-zhong, CHANG Xiang-yang, LIU Xia, HU Xiao-xia and TANG Bei-lei. Comparison of bupivacaine, ropivacaine and levobupivacaine with sufentanil for patient-controlled epidural analgesia during labor: a randomized clinical trial. Chin Med J 2010;123(2):17883. 118. Beilin Y, Guinn NR, Bernstein HH, Zahn J, Hossain S, Bodian CA. Local anesthetics and mode of delivery: bupivacaine versus ropivacaine versus levobupivacaine. Anesth Analg. 2007 Sep;105(3):756-63.

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119. Kalra S, Saraswat N, Agnihotri GS. Comparison of efficacy of bupivacaine and fentanyl with bupivacaine and sufentanil for epidural labor analgesia. Saudi J Anaesth. 2010 Sep;4(3):178-81. 120. Ngan Kee WD, Ng FF, Khaw KS, Lee A, Gin T. Determination and comparison of graded dose-response curves for epidural bupivacaine and ropivacaine for analgesia in laboring nulliparous women. Anesthesiology. 2010 Aug;113(2):445-53. 121. Lee HL, Lo LM, Chou CC, Chuah EC: Comparison between 0.08% ropivacaine and 0.06% levobupivacaine for epidural analgesia during nulliparous labor: a retrospective study in a single center. Chang Gung Med J. 2011 May-Jun;34(3):286-92. 122. Halpern SH, Leighton BL, Ohlsson A, Barrett JF, Rice A. Effect of epidural vs parenteral opioid analgesia on the progress of labor: a meta-analysis. JAMA. 1998 Dec 23-30;280(24):2105-10. 123. Halpern SH, Walsh V. Epidural ropivacaine versus bupivacaine for labor: a meta-analysis. Anesth Analg. 2003 May;96(5):1473-9 124. Cambic CR, Wong CA. Labour analgesia and obstetric outcomes. Br J Anaesth.2010 Dec;105 Suppl 1:i50-60. 125. Writer WD, Stienstra R, Eddleston JM, Gatt SP, Griffin R, Gutsche BB, Joyce TH, Hedlund C, Heeroma K, Selander D. Neonatal outcome and mode of delivery after epidural analgesia for labour with ropivacaine and bupivacaine: a prospective meta-analysis. Br J Anaesth. 1998 Nov;81(5):713-7. 126. Beilin Y, Halpern S. Focused review: ropivacaine versus bupivacaine for epidural labor analgesia. Anesth Analg. 2010 Aug;111(2):482-7. 127. Halpern SH, Littleford JA, Brockhurst NJ, et al. The neurologic and adaptive capacity score is not a reliable method of newborn evaluation. Anesthesiology 2001;94:95862.

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Epidural infusion preparation:

Group-A

0.1% ropivacaine with 2g/ml fentanyl 25 ml of 0.2 % ropivacaine + 23 ml of normal saline + 2ml (100 g) of fentanyl

Group-B

0.125% bupivacaine with 2g/ml fentanyl 25 ml of 0.25% bupivacaine + 23 ml of normal saline + 2ml (100 g) of fentanyl

Motor blockade - Bromage score: Score 0 1 2 3 Criteria Free movement of legs and feet Just able to flex knees with free movement of feet Unable to flex knees, but with free movement of feet 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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