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A RANDOMISED CLINICAL TRIAL OF COMPARISON BETWEEN PROPHYLACTIC ORAL EPHEDRINE AND CONTROL (WITHOUT ORAL EPHEDRINE) IN REDUCING THE

INCIDENCE OF HYPOTENSION FOLLOWING SUBARACHNOID BLOCK

By

Dr. RAGHAVENDRA.R., M.B.B.S.


Dissertation Submitted to the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore In partial fulfillment of the requirements for the degree of

M.D. DEGREE IN ANAESTHESIOLOGY


Under the guidance of

Dr. PREMKUMAR.B., D.A, M.D.


Professor, Department of Anaesthesiology

DEPARTMENT OF ANAESTHESIOLOGY

SREE SIDDHARTHA MEDICAL COLLEGE


TUMKUR SEPTEMBER 2006

DECLARATION BY THE CANDIDATE


I hereby declare that this dissertation/thesis entitled A randomized clinical trial of comparison between prophylactic oral Ephedrine and control (without oral ephedrine) in reducing the incidence of hypotension following subarachnoid block is a bonafide and genuine research work carried out by me under the guidance of Dr. Prem Kumar. B.

Date: Place: Tumkur Dr.RAGHAVENDRA.R. Postgraduate in Anaesthesiology, Sree Siddhartha Medical College, Tumkur

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CERTIFICATE BY THE GUIDE

This is to certify that this dissertation entitled A randomized clinical trial of comparison between prophylactic oral Ephedrine and control (without oral ephedrine) in reducing the incidence of hypotension following subarachnoid block is a bonafide research work done by

Dr.RAGHAVENDRA.R. in partial fulfillment of requirement for the degree of Master of Medicine in Anaesthesiology.

Date: Place: Tumkur Dr.PREMKUMAR.B. , DA, MD. Professor, Dept. of Anaesthesiology Sree Siddhartha Medical College, Tumkur

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ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE INSTITUTION


This is to certify that the dissertation entitled A randomized clinical trial of comparison between prophylactic oral Ephedrine and control (without oral ephedrine) in reducing the incidence of hypotension following subarachnoid block is a bonafide research work done by

Dr.RAGHAVENDRA.R. under the guidance of Dr.PREMKUMAR.B.

Seal & Signature of the HOD Name Date:

Seal & Signature of the Principal Name Date:

Place:

Place:

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COPYRIGHT
Declaration by the Candidate

I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka shall have the rights to preserve, use and disseminate this dissertation in print or electronic format for academic / research purpose.

Date: Place: Dr. RAGHAVENDRA.R. Postgraduate in Anaesthesiology Sree Siddhartha Medical College, Tumkur.

Rajiv Gandhi University of Health Sciences, Karnataka

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ACKNOWLEDGEMENT
It is my distinct honor and privilege to have worked under the able guidance, continuous supervision and constant encouragement of Dr. Prem Kumar .B Professor, Department of Anaesthesiology, has made this study possible. It gives me immense pleasure to extend my sincere thanks to

Dr. Manjarekar. R.P. Professor and HOD, department of Anaesthesiology, for his continuous supervision and timely advices. I indeed consider myself very fortunate to get the benefit of the vast experience and valuable guidance of Dr. D.B. Suryanarayana Rao, former Professor and head, department of Anaesthesiology, without his help it could not have been possible to complete this dissertation. I am deeply indebted to Dr. Shivaleela. H., Assistant Professor for her constant guidance and encouragement throughout the study. It gives me immense pleasure to extend my sincere thanks to my Professors Dr. Gangadhar, Dr. Brinda, for their encouragement and help throughout the study. I am thankful to Dr. Paramesh. S and Dr. Ramesh., Asst. Professor, for their timely advice given to me during the course of my post-graduation. My sincere thanks to Dr. Shashikala, Senior Anaesthesiologist, District hospital for her constant help throughout the study. I am thankful to Dr. Ramesh. S, Dr. Manjunath, and Dr. Raja, Lecturers, for their continuous support and professional insight which led me to be an organized person. I express my sincere thanks to Dr.A.G.Srinivasa Murthy, M.D., General Medicine, Principal, Sree Siddhartha Medical College Hospital and Research Centre,

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Tumkur and Dr. Shivaprasad, Hon`ble Director, Sree Siddhartha Medical College for permitting me to carry out this study. Special thanks to Dr. Sridhar Rao for his guidance in Statistical analysis of this study and Mr. Venugopal. V., in helping me to compile the manuscript. I am thankful to my fellow post-graduate colleagues and friends for their co-operation and help during the period of this study. I am extremely thankful to all my patients without whom this dissertation would have never materialized. Lastly I owe my gratitude to my parents, brother and well wishers for their help, encouragement and moral support during my study.

Date: Place: Tumkur Dr.Raghavendra.R

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LIST OF ABBREVIATIONS USED (In Alphabetical order) ASA B. T. Cm CNS CSF C. T. CVS Hb% Hb-sAg HR Inj. I.M. I.V. Kg. L. & T. lts lt/min MAO MAP Mg American Society of Anesthesiologists. Bleeding Time. Centimeter. Central Nervous System. Cerebrospinal Fluid. Clotting Time. Cardiovascular System. Haemoglobin Percent. Hepatitis B Surface Antigen. Heart rate. Injection. Intramuscular. Intravenous. Kilograms. Larsen and Turbo Liters. Litres per minute. Monoamine Oxidase. Mean Arterial Pressure. Milligrams.
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Mg/l milliEq/l ml mmhg mMol/l g/ml Po SAB SBP S.D. Spo2

Milligram per litre. Milliequivivalent per liter. Milliliters. Millimeter of mercury. millimoles per litre. Micrograms per millilitre. Per orally. Subarachnoid Block. Systolic Blood Pressure. Standard Deviation. Saturation of Oxygen.

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ABSTRACT
Background: Spinal anaesthesia enjoys being the most popular anaesthetic technique for elective surgical procedures involving the lower abdomen or lower limbs as it provides rapid, reliable and profound symmetrical sensory and motor block. However, despite crystalloid or colloid preloading, hypotension remains a common complication. Vasopressors are required to treat the spinal induced hypotension among most of these patients. Studies involving prophylactic Ephedrine as an intravenous infusion, bolus or intramuscular routes are in plenty but studies pertaining to prophylactic Oral administration are sparse. Objectives: This study was conducted to evaluate the safety and efficacy of prophylactic oral Ephedrine (30mg given 30minutes before spinal anaesthesia) in preventing spinal anaesthesia induced hypotension. Method: This is a prospective randomized comparative study conducted at the Department of Anaesthesia, Sree Siddhartha Medical College, Tumkur. Hundred

patients aged between 20 to 60 years belonging to ASA grade I/II, scheduled for lower limb and lower abdominal surgeries were randomly allocated into one of the two groups. Group A (n=50) received prophylactic Oral Ephedrine 30mg 30minute before spinal anaesthesia were as Group B (n=50) received a placebo 30minutes before spinal anaesthesia. Results: The study showed no significant changes in respiratory rate and oxygen saturation levels in any of the patients in both the groups. The incidence of hypotension is 8% and 40% in Group A and Group B patients respectively, and hypotension developed within the first 20minutes after intrathecal block. In our study

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18% of patients in Group B required vasopressor supplementation intraoperatively and none in Group A. There was a steady rise in the heart rate of Group B patients from 4th minute onwards when compared with Group A patients. The incidence of nausea and vomiting was 16% in Group B and 2% in Group A.

Conclusion: This study demonstrates that prophylactic Oral Ephedrine 30mg when given 30minutes before spinal anaesthesia is a simple, easy, economical, effective and a reliable method in reducing the incidence of spinal induced hypotension without any deleterious effects.

Keywords Oral Ephedrine; Subarachnoid Block; Bupivacaine; Hypotension.

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TABLE OF CONTENTS

Sl. Particulars No. 1. 2. INTRODUCTION AIMS AND OBJECTIVES REVIEW OF LITERATURE History Anatomy 3. Physiology Pharmacology Review of clinical studies 4. 5. 6. 7. 8. 9. MATERIALS AND METHODS RESULTS AND ANALYSIS DISCUSSION SUMMARY CONCLUSION BIBLIOGRAPHY ANNEXURES 89 10. Proforma 92 Master Chart 16 21 35 47 53 70 78 80 81 4 6 1 3 Pages

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LIST OF TABLES

Sl. Tables No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Concentration and doses of Bupivacaine Age distribution of the two groups of patients Sex distribution of the two groups of patients Height distribution of the two groups of patients Weight distribution of the two groups of patients Statistical comparison of age, height and weight of the two groups of patients Type of surgery carried out on the two groups of patients The cluster-wise distribution of surgeries in the two groups of patients Level of anaesthesia in the two groups of patients Baseline systolic blood pressure in the two groups of patients Baseline diastolic blood pressure in the two groups of patients Baseline mean arterial pressure in the two groups of patients Baseline heart rate in the two groups of patients Statistical comparison of SBP (mmHg) in the two groups Statistical comparison of DBP (mmHg) in the two groups Statistical comparison of MAP (mmHg) in the two groups Statistical comparison of HR (beats/minute) in the two groups Comparison of SBP at baseline with SBP at SAB, at 8 minutes and at 60 minutes Comparison of DBP at baseline with DBP at SAB, at 8 minutes and at 60 minutes Comparison of heart rate at baseline with heart rate at SAB, at 8 minutes and at 60 minutes 24 53 53 54 55 55 56 57 58 58 59 59 60 62 63 64 65 66 66 67 Pages

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LIST OF FIGURES

Sl. Figures No. 1 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Vertebral Column Features of vertebra Saggital section through lumbar vertebra Spinal Cord Exit of spinal nerves Production, Circulation, and Resorption of Cerebrospinal fluid Chemical structure of bupivacaine Chemical Structure of Ephedrine Ephedrine Tablets Intravenous Ephedrine with Essential drugs Spinal Puncture Being Performed. C.S.F Flow through Spinal Needle. 6 7 9 10 11 14 22 29 50 50 51 51 Pages

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LIST OF GRAPHS

Sl. Graphs No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Age distribution of Patients Sex distribution of Patients Height distribution of Patients Weight distribution of patients Graphical representation of types of surgery. Level of Spinal Anaesthesia. The SBP and DBP of patients in Group A at different time Intervals The SBP and DBP of group B patients at different time Intervals. The SBP of the two groups of patients at different time intervals The DBP of the two groups of patients at different time intervals The MAP of the two groups of patients at different time intervals The HR of the two groups of patients at different time intervals Time of onset of hypotension in 20 cases of group B First protracted cases of hypotension Second protracted case of hypotension. 53 54 54 55 57 58 60 61 62 63 64 65 68 69 69 Pages

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INTRODUCTION
Spinal anaesthesia was introduced into clinical practice by August Bier in 1898 even before the break-through of orotracheal intubation by Franz Kuhn in 1901. The only anaesthetic techniques to precede it were topical anaesthesia of the eye by Carl Koller and infiltration anaesthesia by Carl-Ludwig Schleich in 1892 1. Spinal anaesthesia has enjoyed a long history of success and recently celebrated a centennial anniversary.

Regional techniques are the preferred Anaesthetic procedure for surgeries involving abdomen and lower extremities. The various advantages include 2: 1. Blunting of stress response to surgery 2. Avoidance of intubation 3. Decrease in intraoperative blood loss 4. Earlier return of gastrointestinal function 5. Lower incidence of postoperative throboembolic events.

The unavoidable sequence of spinal anaesthesia is blockade of sympathetic preganglionic efferents leading to peripheral venous pooling causing hypotension. Therapies are primarily aimed at reducing the severity of hypotension, they include prophylactic leg elevation and wrapping, use of inflatable boots, preloading of the patient with crystalloids and colloids, lateral uterine displacement in Obstetric patients, and vasopressors used as last resort with varying results.

Ephedrine the most commonly used among vasopressors to treat spinal induced hypotension
2, 3

. Studies in relation to prophylactic parenteral Ephedrine have been

described earlier in plenty compared to oral Ephedrine studies which are sparse. So this prospective randomized study is performed to determine the efficacy of prophylactic oral Ephedrine in preventing spinal hypotension following subarachnoid block in our patient group.

AIMS OF STUDY

To determine the safety and efficacy of prophylactic oral Ephedrine in reducing the incidence of hypotension following subarachnoid block.

REVIEW OF LITERATURE
HISTORY OF SPINAL ANAESTHESIA 3, 4, 5. The concept of local analgesia began with demonstration of anaesthetic properties of cocaine eye drops by Koller in 1884 and neural blockade by Halsted in 1885. The term Spinal anaesthesia was introduced by Corning in1885. Corning with the aim of injecting Cocaine between the spinal processes for means of managing neurologic disorders instead accidentally injected it epidurally in 1885. The present day spinal anaesthesia and technique of lumbar puncture was described by Quincke in 1891. The first two publications on spinal anaesthesia for surgical procedures were made in 1899 by Bier in the first paper later on by Tuffier. Bier had used it for surgeries on the lower limbs and Tuffier to relieve pain of sarcoma of the leg in a young man. Kries in 1900 used spinal analgesia for caesarean section, during the same year W.S.Bainbridge reported his first successful case of paediatric spinal analgesia. Dowitz in 1903 added adrenaline to prolong the anaesthetic effect, substitutes to cocaine emerged due to its toxic effects with Procaine (Novocaine) by Einhorn and Stovaine by Fourneau in 1905. Next series of studies were aimed at achieving higher levels of spinal blockade, formulation of alcohol mixture with local anaesthetic to make it lighter than cerebrospinal fluid.

Labat in 1922 used Babotage; Pitkin introduced Spinocaine (hypobaric) or Gravicaine (hyperbaric) in 1927. High levels of spinal anaesthesia caused hypotension which lead to introduction of Ephedrine to combat it in 1927 by Ockerbland and Dillon, the active principle of the herb Ma huang, known to Chinese medicine for millennia. Ephedrine was isolated in pure form and named by Nagaun in 1887, later introduced into western medicine by Chenn and Carl .F.Schmidt. Lignocaine synthesized by Lofgren of A B Astra, Sweden in 1943 and used in clinical practice in 1948. Bupivacaine was synthesized by A.F.Ekenstein in 1957 used for regional blocks in 1966.

ANATOMY 3, 6, 7, 8

Corning stated in 1900 that I advise those who contemplate practicing spinal anaesthesia to take a look at the skeleton especially the relations of the lumbar vertebrae. An intelligent glance of this sort is worth many words4. The keystone for a successful spinal anaesthesia lies in the detailed knowledge of the anatomy of the vertebral column and its contents. VERTEBRAL COLUMN The vertebral column comprising of 33 vertebrae (7 cervical, 12 thoracic, 5 lumbar, 5 fused sacral and 4 coccygeal) interspaced by 23 intervertebral discs.

Fig.1 Vertebral Column, Lateral (left) and Posterior (right) views, illustrating curvatures and interlaminar spaces4. 6

There are two primary curves thoracic and sacral are convex posteriorly and are present since birth. The two secondary curves cervical and lumbar are convex anteriorly develop after birth due to the differential growth of intervertebral discs. The curves of vertebral column have a significant influence on spread of the local anaesthetic solution injected in turn which determines the level of spinal blockade. Lumbar vertebrae Upper four lumbar vertebrae are typical and bear common features. The fifth lumbar vertebra is atypical. Lumbar vertebrae identified by its large size and by absence of costal facets on the body. Typical lumbar vertebrae is formed by

Fig.2 Features of vertebra8. (a) Large kidney shaped body. (b) The vertebral foramen triangular in shape, larger than in thoracic but smaller compared to cervical region. (c) Two pedicles, directed backwards from the upper part of the body.

(d) The laminae directed backwards and medially to complete the vertebral foramen posteriorly. (e) Spinous process is thick, broad, quadrilateral in shape and directed backwards. (f) Two transverse processes are thin and tapering. (g) Two upper and two lower articular processes which prevent rotation but allows limited flexion and extension When the spine is fully flexed the cervical and lumbar curves are obliterated, in supine position the 3rd lumbar vertebrae marks the highest point of the lumbar curve, whereas the 5th thoracic is the lowest point of the dorsal curve. Thus hyperbaric solutions deposited at the third lumbar vertebrae will flow away, both cranially and caudally from it. The direction of spinous processes determines the direction in which the spinal needle should be inserted. Intervertebral Disc They form one fourth the length of vertebral column, thickest at cervical and lumbar regions. They are made up of outer collagenous annulus fibrous and inner gelatinous mucoidal mass nucleus pulposes. They mainly act as shock absorbers ensuring even distribution of compressive force and impart flexibility to the vertebral column. THE VERTEBRAL CANAL Bounded in front by bodies of the vertebrae and intervertebral discs, posteriorly by the laminae, ligamenta flava and the arch, which bears spinous process and interspinous ligament, laterally by the pedicles and laminae, size and shape vary being larger at cervical and lumbar region.

The Vertebral Ligaments

Fig.3

Saggital section through lumbar vertebra6

The vertebrae are held together by a series of overlapping ligaments, which not only bind together the vertebral column but assist in protecting the spinal cord. (a)The Anterior longitudinal ligament which runs along the front of vertebral bodies is a strong band being attached to the occiput and the anterior tubercle of the atlas above and to the front of the sacrum below. (b) The posterior longitudinal ligament is attached to the posterior border of the body of the axis above and to the sacrum below. It extends within the vertebral canal on posterior surfaces of the bodies of vertebraes. (c)The ligamentum flavum connects the laminae of the adjacent vertebra and extends from the region of the articular capsules of the intervertebral joints to cover the area of the spine. It consists of a tough, yellow, elastic tissue, which is thickest and displays the greatest degree of recoil in the lumbar region.

(d)The interspinous ligament connects the adjoining spines and extends from the root to the apex of each process. (e)The Supra spinous ligament connects the apices of spinous processes. They extend from the seventh cervical vertebra to the sacrum. The ligamentum nuchae extends from the occipital protrubence and occipital crest above to the spinous process of seventh cervical vertebrae. THE SPINAL CORD

Fig. 4 Spinal Cord 9

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The spinal cord is the lower elongated, cylindrical part of Central nervous system. It occupies the upper two thirds of the vertebral canal. It is about 42- 45cm long. It extends from the level of the upper border of the atlas to the lower border of the first lumbar vertebra or upper border of the second lumbar vertebra. The lower border of the spinal cord is conical and is called the Conus medullaris. The apex of the conus is continued down as the filum terminale.

Fig.5 Exit of spinal nerves 6. The 31 spinal nerves emerge from the spinal cord in pairs-8cervical, 12 thoracic, 5 lumbar, 5 sacral and one pair of coccygeal nerves. The spinal nerves are comprised of anterior and posterior roots that unite in the intervertebral foramina to form the spinal nerve trunks. At the cervical level the nerves arise above their respective vertebra, but starting at first thoracic vertebra they exit below their vertebra. At the cervical and upper thoracic levels the roots emerge from the spinal cords and exit the vertebral foramina nearly at the same level. As the spinal cord normally ends at the first lumbar vertebra, lower nerve roots must travel an increasing distance (within the lumbar and sacral

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subarachnoid and epidural spaces) from the spinal cord to the intervertebral foramina. These lower spinal nerves form the caudaequina. Hence performing a lumbar (subarachnoid) puncture below the first lumbar vertebra in an adult avoids needle trauma to the cord. THE SPINAL MENINGES The spinal cord is ensheathed by three membranes or meninges. (a)Duramater The duramater which ensheaths the spinal cord consists of two layers, the inner meningeal layer is the continuation of the cerebral dura made up of dense fibrous tissue, the outer endosteal layer is the periosteal lining the vertebral canal. In between the two is the potential extradural space. The extradural space extends from foramen magnum above to second sacral vertebrae below. Dural fibers run longitudinally, thus it is important to direct the spinal needle bevel, so as to split these fibers rather than cut them, thus decreasing the incidence of postspinal headache. (b)Arachnoid mater It is closely adherent to the dura mater. The space between the dura and the arachnoid is the subdural space. It is a potential space containing some amount of serous fluid. (c)Piamater: This is a thin vascular membrane closely investing the spinal cord. Cerebro Spinal Fluid (CSF) is contained between the pia and the arachnoid mater in the subarachnoid space. The spinal subarachnoid space is a poorly demarcated.

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BLOOD SUPPLY TO SPINAL CORD The blood supply to the spinal cord and nerve roots is derived from the single anterior spinal artery and paired posterior spinal arteries. The anterior spinal artery arises from the vertebral artery and supplies the anterior two thirds of the cord. The anterior and posterior spinal arteries do not anastomose, thrombosis of this anterior artery causes Anterior spinal artery syndrome in which there is motor paralysis sparing the posterior columns (joint position, touch and vibration sense). The posterior spinal arteries arise from the posterio inferior cerebellar arteries and supply the posterior one thirds of the cord. The spinal veins comprise of anterior and posterior plexus, which drain through the intervertebral foramina into vertebral, azygos and lumbar veins. THE SUBARACHNOID SPACE This is the space lying between the arachnoid and pia mater. It consists of the spinal nerve roots, denticulate ligaments, cerebrospinal fluid, and spongy reticulum of fibers connecting the pia with the arachnoid mater. The nerve roots within the dura have no epineural sheaths and are therefore easily affected by analgesic drugs. The posterior aspect of the arachnoid and dura have no nerve supply. So there is no pain experienced on dural puncture.

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THE CEREBROSPINAL FLUID (CSF) Cerebrospinal fluid is a modified tissue fluid present in the cerebral ventricles, spinal cord and subarachnoid spaces.

Fig.6 Production, Circulation, and Resorption of Cerebrospinal fluid 3. It is produced by choroid plexus in the lateral, third and fourth ventricles by a combination of filtration and secretion, and later absorbed in arachnoid granulations over the cerebral hemispheres. In adults the normal total CSF production is about 21 ml /hr

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(500 ml /day),about 130 to 150 ml is present at all times of which 25-35 ml is present in the vertebral canal. The normal CSF pressure measured with the patient lying in lateral position is 7 15 cm of water. COMPOSITION OF CSF Specific gravity: 1.005(1.003- 1.007) at 37degree Centigrade. pH: 7.33 Volume: 120-140 ml Glucose (Fasting): 2.5 4.5 mMOl/L Sodium: 144-152 miliEq/L Calcium: 1.1-1.3 miliEq/L Chloride: 123-128 miliEq/L Bicarbonate: 24-32 miliEq/L Proteins: 200-400 mg/l Urea: 2.0-7.0 miliMOL/L Osmolality: 289 miliMOL/kg of H2O FUNCTIONS OF CSF 1. It acts as a buffer separating the brain and the spinal cord from the hard bony skull and the vertebral canal. 2. Nutrition and oxygen supply to the nerve cells to some extent. 3. Drainage of metabolites. 4. pH changes in CSF, regulates pulmonary ventilation. 5. Reduces effective weight of the brain.

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PHYSIOLOGY OF SPINAL HYPOTENTION 10, 11


Understanding the mechanisms involved in control of arterial pressure in a normal individual and the pathophysiology of hypotension during spinal anaesthesia is the key to safe and appropriate management of the patients.

Control of Arterial Pressure 12: Arterial pressure: is the product of cardiac output and systemic vascular resistance and both these variables are influenced by many other factors. Cardiac output: is determined by venous return according to Frank Starling law. Venous return is influenced by gravity, the calf muscle pump, intrathoracic pressure and the degree of venomotor tone; this is matched to the circulating blood volume. Systemic Vascular Resistance: is determined by sympathetic vasomotor tone and by the influence of hormones such as rennin, angiotensin, aldosterone and antidiuretic hormone. The vasomotor centre in the brain stem controls the degree of sympathetic tone in a feedback loop involving the baroreceptors. Organ Perfusion There are two main mechanisms which control autoregulation and perfusion they are: Myogenic autoregulation: acts via stretch receptors in the vessel walls which cause them to constrict when pressure is decreased. Chemical autoregulation: is mediated by the local concentration of vasoactive metabolites. In the presence of vasodilatation, as produced by sympathetic block, an increase in flow washes out the metabolites and produces reflex vasoconstriction.

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Although it is arterial pressure that we measure and adjust, it is important to remember that organ flow is the vital factor. Compensatory mechanisms mentioned before ensure that the flow to vital organs is maintained over a wide range of pressures. Cerebral blood flow: Autoregulation occurs between 50 to 180mm Hg mean arterial pressure. Since these vessels are devoid of sympathetic nerve supply they autoregulate by myogenic mechanism. The stimulation of vasomotor centre leads to increase sympathetic tone and systemic vascular resistance in an attempt to restore arterial pressure. Coronary blood flow: It is mainly mediated by chemical autoregulation between 60 to 150 mm Hg mean arterial pressure. As the cardia becomes hypoxic, adenosine diphosphate gets accumulated. This gets converted to adenosine, a potent coronary vasodilator, restoring the local blood flow. Renal autoregulation: occurs between 60 to 160mm of Hg mean arterial pressure. The afferent glomerular arteriole has a myogenic response to stretch and constricts with hypertension and dilates with hypotension.

Physiology of Central Neural Blockade. The physiological response to intradural blockade results from autonomic blockade with its major effects on both the vascular beds and cardiac action; from abolition of somatic pain and its reflex mediated response, and blockade of motor fibers. Order of blockade of nerve fibers 5: First to be blocked is autonomic pre ganglionic nerve fibers (B fibers). Second to be blocked are temperature and pain fibers (A and C fibers). Third to be blocked pinprick fibers.

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Fourth to be blocked fibers conveying pain greater than pinprick. Fifth to be blocked touch fibers (A fibers). Sixth to be blocked deep pressure fibers. Seventh to be blocked somatic motor fibers. Eight to be blocked, fibers conveying vibratory sense and proprioception impulses (A fibers). During recovery, return of sensitivity in the reverse order was assumed, but it has

been suggested that sympathetic activity returns before other sensation

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. The most

important physiologic response to spinal anaesthesia involves the cardiovascular system; they include hypotension and bradycardia 13. Primary Mechanisms of Hypotension are 14: (a) Sympathetic preganglionic denervation leading to peripheral venous pooling and decreased venous return. (b) Vasodilatation of arterioles and post arteriolar capillaries (c) Catecholamine depletion due to sympathetic denervation to adrenal medulla (T8 to L1). (d) Splenic venous pooling. (e) Compression of great vessels within abdomen due to muscular paralysis, which is exaggerated by pregnant uterus and abdominal tumors. (f) High blocks lead to sympathetic nerve block to the cardia (T1-T4) leads to decreased contractility.

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Opposing Factors Affecting Heart Rate are 13, 15 I. The decrease in systolic arterial pressure which causes a baroreceptor reflex and an increase in heart rate II. Changes in the preload causing volume receptor reflexes which alter heart rate III. Vagal responses which reduce heart rate. IV. Sympathetic block of Cardio-acceleratory nerves causing a reduction in heart rate. V. The central effect of reduced sensory input to the cortex resulting from subarachnoid block which reduces heart rate. VI. The specific actions on heart rate of the different treatments used in the prevention and treatment of hypotension.

The major factor in the development of hypotension is the level of blockade of sympathetic outflow tract, which is between T1 to L2.Sympathetic preganglionic efferent blockade which extends 2 to 6 dermatomes cephalad to sensory block leads to venous and arteriolar dilation, among which venodilation predominates; this is because of limited amount of smooth muscle in venules and large amount of blood in venous capacitance (approximately 75% of total blood volume). The body senses this fall by the baroreceptors present in carotid sinus and aortic arch and tries to compensate by tachycardia (Mareys law). If the sympathetic blockade extends above fifth thoracic vertebrae level it becomes progressively difficult to compensate as the cardio accelerator fibers arising from T1 to T4 are also blocked. Additionally the heart rate may further decrease as a

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result of fall in right atrial filling. Hypotension usually occurs in the first 10-15 minutes following spinal anaesthesia. Fall in blood pressure is more marked in higher levels of block, geriatric group, pregnancy, hypertensive and hypovolumic states.

Prevention of Hypotension 12: (a) 10 -15 degree lateral tilt or wedge placement under the right buttock in case of supine hypotension syndrome. (b) Adequate preloading with crystalloids (15-20 ml/kg) or colloids (5-7ml/kg). (c) Prophylactic administration of parenteral vasopressors.

Treatment of Hypotension 12: (a) Oxygenation of the patient. (b) Foot end elevation, which should be <20, since extreme trendlenburg leads to increase of internal jugular venous pressure diminishing cerebral perfusion pressure. (c) Rapid infusion of intravenous fluids. (d) Injection of vasopressor with predominant effect on venoconstrictive properties without major undesirable effects on the ratio between myocardial supply and demand. Eg: Ephedrine, Mephentermine. (e) Injection Atropine if bradycardia predominates.

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PHARMACOLOGY
Local anesthetic drugs Local anesthetics are drugs that produce reversible depression of nerve conduction when applied to nerve fiber 16. Local anesthetics consist of a liphophilic group; usually a benzene ring- separated from the hydrophilic group usually a tertiary amine by an intermediate chain that includes an ester or amide linkage. BUPIVACAINE 16, 17, 18: Bupivacaine has probably had the greatest influence on the practice of regional anaesthesia due to the combined properties of an acceptable onset, long duration of action, profound conduction blockade, and significant separation of sensory to motor block. It was synthesized by Ekenstein in 1957 and used in clinical practice by Widman and Telino in 1963. Chemistry: Bupivacaine is 1-n-butyl-DL-piperidine-2-carboxylicacid-2, 6 dimethylanilide hydrochloride. Bupivacaine is a homologie of mepivacaine with molecular formulae of C18 .N2O.H28.Hcl, differing only in a butyl group substituted for a methyl group on the piperidine nitrogen.

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Chemical structure:

Fig.7 Chemical structure of bupivacaine 17. Physiochemical Properties: The base is sparingly soluble, but the hydrochloride salt is readily soluble in water. Bupivacaine is highly stable and can withstand repeated autoclaving. Mechanism of Action: The primary action of local anesthetics is on the cell membrane of the axon. The large transient increase in the permeability to sodium ions, necessary for propagation of impulses is prevented. Thus the resting membrane potential is maintained and depolarization in response to stimulation is inhibited. The mechanism by which local anesthetics block sodium conductance is as follows: (a) Local anesthetics in the cationic form act on the receptors within the sodium channels, on the cell membrane and block it. The local anesthetics can reach the sodium channels either via the lipophilic pathways directly across the lipid membrane or via the axoplasmic opening. The mechanism accounts for 90% of nerve blocking effects of amide local anesthetics. (b) The second mechanism of action is by membrane expansion. This is a nonspecific drug receptor interaction

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Anaesthetic Properties: (a) Potency: Bupivacaine is approximately three to four times more potent than Lidocaine or Mepivacaine and eight times more than Procaine. It appears to have a slow nerve penetrating power leading to slow onset, more prolonged duration of sensory anaesthesia due to its lipid solubility and protein binding properties. Muscle relaxation is not profound with 0.5% as seen with Lidocaine. (b) pKa: is 8.2. (c) pH of saturated solution is 5.2 (d) Anaesthetic Index: It is defined as ratio between potency/toxicity of a local anaesthetic drug. It is 3.0 to 4.0 for Bupivacaine. Pharmacodynamics: Onset of action is between 3 to 4 minutes and complete spinal anaesthesia ensues by 6 to 8 minutes. The duration of spinal anaesthesia varies from 75 to 150 minutes. Pharmacokinetics: Plasma levels of the drug depend on the route, concentration and the total dose administered. The amount of drug absorbed is minimal when administered through subarachnoid route, plasma bupivacaine concentrations within 1 to 2 hours after administration is 1 to 2g/ml. Bupivacaine is distributed throughout all body tissues. T of bupivacaine is 2-7 minutes. T is 28minutes, T is 3-5hrs. Volume of distribution is 72 lts; clearance is 0.47lt/min. The more highly perfused organs show a higher concentration of the drug. The blood concentration of the drug decreases markedly as it passes through the pulmonary vasculature. 23

Plasma Binding: About 90to 95% of the drug is bound to protein, unbound drug is about 1/7 that of Lidocaine and 1/5 that of Mepivacaine. Metabolism and Elimination: Bupivacaine is an amide; liver is the primary site of metabolism. It is metabolized by N-dealkylation and the metabolite, pipecolyloxylidine is excreted in the urine. About 10% of the drug is excreted unchanged in the urine and the remaining is conjugated with glucuronide and excreted Dose: Suggested maximum safe dose of Bupivacaine in a 70kg adult with adrenaline is 5mg that is 2.5 to 3.0mg/kg and without adrenaline 175mg that is 2 to 2.5mg/kg body weight. Type of block Local infiltration Minor nerve block Major nerve block Epidural Spinal 0.75 2-3 15-22.5 Table I. Concentration and doses of Bupivacaine 19. Concentration (In percent %) 0.25-0.5 0.25 0.25-0.5 0.25-0.75 0.5 Dose (in ml) 25-30 5-20 30-50 15-30 3-4 Dose (in mg) 2 12.5-50 400 37.5-225 15-20

24

Actions on different systems: a) Central nervous system: An overdose of bupivacaine produces light-headedness and dizziness followed by visual and auditory disturbances such as difficult to focus and tinnitus. Disorientation and drowsiness can also occur. Shivering, tremors of muscles of face and distal part of the extremities can occur. Ultimately generalized convulsions of tonic-clonic nature can occur. Further increase in dose causes respiratory arrest. b) Cardio vascular system: Electrophysiological studies on the effect of local anesthetic have demonstrated that bupivacaine is associated with more pronounced depolarization changes. Bupivacaine blocks cardiac sodium channels and alters mitochondrial function. Its high degree of protein binding makes resuscitation prolonged and difficult. Bupivacaine is highly arrythmogenic. This drug reduces the cardiac contractility. This is done by blocking the calcium transport. Low concentration of bupivacaine produces vasoconstriction while high doses cause vasodilatation. c) Autonomous nervous system: Myelinated preganglionic beta fibers are more sensitive to the action of local anesthetic including bupivacaine. Involvement of preganglionic sympathetic fibers is the cause of widespread vasodilatation and subsequent hypotension that occurs in epidural and paravertebral block. When used for conduction blockade, all local anesthetics particularly bupivacaine produce higher incidence of sensory than motor block.

25

d) Respiratory system: Respiratory depression may be caused if excessive plasma level is reached which in turn results in depression of medullary respiratory centers. Respiratory depression may also be caused by paralysis of respiratory muscles as may occur in high spinal or total spinal anesthesia.

e) Neuro-muscular junction: Local anesthetics can affect transmission at neuro-muscular junction and block motor nerve fibers if present in sufficient concentration. TOXICITY: Local anesthetics are relatively safe if administered in appropriate dosage in the correct anatomical location. However accidental intravascular, intrathecal injection or administration of excessive doses results in toxicity. In humans bupivacaine is about 4-5 times more toxic than lidocaine and they manifest by their effects on the CNS and CVS. The CNS effects are characterized by excitation or depression. The first manifestation may be nervousness, dizziness, blurred vision or tremors followed by convulsions, unconsciousness and probably respiratory arrest. Other effects may be nausea, vomiting, chills, constriction of the pupils and tinnitus. The CVS manifestations include myocardial depression, hypotension and cardiac arrest. In obstetrics, fetal bradycardia may occur. Allergic reactions include urticaria, bronchospasm and hypotension. 26

Treatment of toxic reactions: Treatment is mainly symptomatic. Main goal of treatment is to maintain near normal circulation and to support ventilation with oxygen or controlled ventilation if required. Supportive treatment with IV fluids and vasopressors restore the cardiovascular stability, convulsions may be controlled with diazepam or thiopentone sodium and controlled ventilation with oxygen. Corticosteroids may be helpful when allergic reactions are suspected.

27

EPHEDRINE PHARMACOLOGY20, 21, 22, 23


History 24 Introduction of Ephedrine to western medicine was in 1926 by Chenn and Carl F Schmidt following a visit to china. Used for the first time to counter spinal hypotension in 1927 by Ockerblad and Dillon and by Rudolf and Graham in separate setups, was the greatest boost to spinal analgesia. During this era intravenous infusions were rarely employed to tackle spinal hypotension, and only pressor agents available were adrenaline and Methyl guanidine. They have the adverse effects of severe tachycardia and decrease in ratio of myocardial oxygen need to supply. Since then many pressor agents have come and gone but Ephedrine still remains the preferred drug due to its dual action on both alpha and beta-adrenergic receptors. Chemistry: The active principle of the herb Ma-Huang belonging to the species Ephedra, known to Chinese medicine for a millennia. It was isolated in pure state and named by Nagaun in 1887. Structural formula: C10H15NO.1/2H2O

28

Fig.8 Chemical Structure of Ephedrine 23. Chemical Name: (1R, 2S)-2 Methylamino -1 Phenylpropan 1 ol Hemi hydrate Physiochemical properties: It is an alkaloid initially extracted from the Chinese herb Ma-Huang. Now it is synthetically prepared. It is a colourless white crystalline powder or granules with a bitter taste. It is odourless or may have a slight aromatic odour. Melting Point: 217 to 220 Solutions are sterilized by autoclaving or by filtration. It has a self life of 36 months when stored at temperature of 25 or below it, stored in tight containers and protected from light. Mechanism of Action 23, 25, 26: Direct Action: It is a nonselective sympathetomimetic agent acting on both Alpha and beta receptors. Indirect Action: (a) Peripheral postsympathetic norepinephrine release (b) Central nervous stimulation

29

(c) Inhibition of norepinephrine reuptake. Pharmacokinetics 23: Ephedrine is resistant to degradation by mono amino oxidase (MAO) in the gastrointestinal tract since it is a Noncatechol Phenylisopropylamine; and resistant to degradation by Catechol-o-methyltransferase (COMT) due to the absence of catecholamine nucleus, this enables the drug to be rapidly and completely absorbed after oral administration. Maximum peak plasma concentrations of 45 to 140 mg/L are obtained after a single dose of 22mg Ephedrine hydrochloride. Peak plasma concentration is achieved within 25 to 30 minutes following oral administration. It is extensively distributed throughout the body; volume of distribution being 122 to 320L. It accumulates in the liver, lungs, kidneys, spleen and brain. The mean plasma half life is 6hours (3 to 11 hours), clearance is 13.6 to 44.3 L/hour. Up to 95% of the drug is excreted in the urine in 24 hours and is pH dependent (since it is slightly alkaline its excretion is increased in acidic urine and a decrease of about 20 to 35% in alkaline urine); 55 to 75 % as unchanged and the rest as metabolites. Renal disease is likely to impair the elimination of the drug. Intra muscular injections of ephedrine are also acceptable since drug induced local vasoconstriction is insufficient to delay systemic absorption. Placental transfer of Ephedrine occurs and fetal blood levels of approximately 70% of maternal blood levels have been reported.

30

Action on different systems: (a) Cardiovascular system: It increases the arterial blood pressure by peripheral vasoconstriction and cardiac stimulation (increase in the heart rate and cardiac output). (b) Central nervous system: It is a potent CNS stimulant which can lead to apprehension and tremors. It increases the minimum alveolar concentration of anaesthetic agents. Insomnia is a common side effect of therapeutic doses therefore administration of the drug to be avoided after four in the evening. Amphetamine like psychoses can occur rarely in chronic abuse. (c) Respiratory system: It relaxes bronchial smooth muscles and increases the specific airway conductance within one hour following administration in obstructive airway disease patients. Significant bronchodilatory effects were maintained over 4 to 5 hours. It has a stimulant effect on the respiratory centre. (d) Alimentary and urinary tract: Ephedrine reduces the intestinal tone and motility. Stimulation of the alpha adrenergic receptors of smooth muscle cells in the bladder base and relaxation of the detrusor muscle increases the resistance to the outflow of urine. (e) Uterus: it causes uterine relaxation and preserves the uterine blood flow by its beta adrenergic activity. (f) Musculoskeletal: It stimulates oxygen uptake and thermo genesis. (g) Eyes: It dilates the pupil (mydriasis) but does not alter the light reflexes.

31

Therapeutic Uses: (1) As a pressor drug to treat spinal hypotension. (2) Prevention of bronchial spasm in asthma patients. (3) Treatment of narcolepsy. (4) Treating allergic disorders such as hay fever or urticaria. (5) Nasal decongestant. (6) Enuresis. Dosage: Ephedrine in the doses of 15 to 60mg by mouth 3 to 4 times a day is of value in preventing bronchial asthma and narcolepsy. Contraindications: (1) Ischemic heart disease. (2) Hypertensive patients. (3) Benign prostatic hypertrophy patients. (4) Thyrotoxic patients. (5) In lactating mothers and for long durations in pregnant women.

32

Drug Interactions 27: a) Hypertensive crises when administered with Mono Amino Oxidase (MAO) inhibitors. b) The plasma half life of dexamethasone was decreased when administered with ephedrine. c) Increase of risk of arrhythmias if patient is on digoxin. d) Increased response in cocaine users. e) Response to indirect effects of Ephedrine may be reduced if patient is on reserpine or guanethidine. f) Decreased response in patients receiving -blockers.

Adverse Effects: In large doses ephedrine gives rise to side effects such as giddiness, headache, nausea, vomiting, sweating, thirst, tachycardia, precordial pain, palpitations, muscular weakness and tremors, anxiety, restlessness and insomnia.

Overdose and Treatment: (1) Protection of patients airway and to support ventilation if required with 100% oxygen. (2) Monitoring and maintaining, within acceptable limits, patients vital signs, blood gases, and serum electrolytes.

33

(3) Electrocardiogram to be continuously monitored for supra and ventricular tachyarrhythmia, administration of beta-adrenergic blocker such as Propranalol by slow intravenous infusion; however in asthmatic patients a cardio selective beta-adrenergic blocker (Acebutolol, Atenolol,

Metoprolol) is more appropriate. (4) In alert patients removing Ephedrine from stomach by inducing emesis with Ipecac, followed by activated Charcoal (as long as ileus is not present); in depressed or hyperactive patients it should be done with airway protected gastric lavage. (5) Marked hypertension to be treated with vasodilators. (6) Convulsions to be controlled using Diazepam, Seizures refractory should be treated with Thiopentone and Neuro-muscular blocking agents. (7) Pyrexia controlled by cold intravenous infusion, tepid sponging and dexamethasone.

34

REVIEW OF CLINICAL STUDIES


Spinal anaesthesia has celebrated the centennial anniversary and still enjoys the status of being the highest performed anaesthetic procedure since its introduction by August Bier in 1898 due the following reasons 13. (a) Mastering the technique is easier. (b) Quicker in onset no period of waiting. (c) The consequences of multiple drugs avoided. (d) Intubation avoided. (e) Offers high quality sensory and motor block. (f) The patient is awake and will be able to communicate. (g) It is cost effective.

As we are all familiar that none of the technique is ideal, spinal anaesthesia also has a set of disadvantages. The most common serious side effects being hypotension and bradycardia, Methods developed in due course to combat are (1) Physical methods used to increase venous return 12, 29: Foot end elevation
28

wrapping of patients legs with elastocrit bandage 28, inflatable boots application, left uterine displacement are the various physicals methods used, they are less successful in combating hypotension.

35

(2) Volume Expansion 29: Are achieved either by infusing crystalloids or colloids, crystalloids comparatively are cheaper, they improve peripheral circulation and decreases hypotension to a certain extent by virtue of filling up the venous capacitance vessels. They have disadvantages like haemodilution which can hamper oxygen supply, they lead to abnormal rise in central venous pressure
30

and the problem is further increased as the need for catheterization arises as a result of urinary retention when combined with spinal block. Colloid like Albumin has eliminated hypotension in various studies but the major set back is they are very expensive for daily use in all patients. Hetastarch 6% or haemaccel do not have better results in comparison to crystalloids in preventing hypotension, added to this are the side effects like anaphylactic reaction, disturbance in coagulation cascade and interference in blood group cross matching. (3) Vasoconstrictors 31: The spinal hypotension was initially thought due to anterior abdominal wall paralysis causing decreased intra thoracic pressure during inspiration. Later it was confirmed that the cause was due to blockade of sympathetic preganglionic fibers, this lead to treatment of spinal hypotension with vasopressors. Epinephrine was the vasopressor initially used, due its cardiac side effects it was replaced by Ephedrine on its introduction into clinical practice by Ockerland and Dillon, and by Rudolf and Graham in 1927
24

. Since then it has

remained the vasopressor of choice to combat spinal hypotension. 36

Datta et al in 1982 32 assessed the effectiveness of intravenous Ephedrine in prevention of hypotension, nausea alone, or with vomiting. Method: Sixty healthy parturients, scheduled for caesarean section at term were studied. They were assigned into three groups according to the blood pressure levels after spinal anaesthesia. In group A (n=22), there was no change of blood pressure so none received Ephedrine, group B (n=18) due to hypotension received Inj. Ephedrine 10mg intravenously, it was repeated until blood pressure rose to at least 100mm Hg. In group C (n=20), Ephedrine was administered (10-30mg) intravenously as soon as any fall of blood pressure from base line. Result: The incidence of nausea or with vomiting was clearly correlated with the development of maternal hypotension. None of the parturients in group A complained of nausea alone or with vomiting, two mothers (10%) had these symptoms in Group C, where as two-thirds of patients (66%) in group B developed nausea or both nausea and vomiting (P<0.01). They concluded that prompt intravenous administration of Ephedrine as soon as fall in base line blood pressure was detected prevents further fall in blood pressure and markedly reduces the incidence of nausea alone or with vomiting.

Kang et al in 1982

33

assessed whether prophylactic intravenous infusion of Ephedrine

can effectively maintain maternal blood pressure without adversely affecting the mother or fetus. Method: Forty four healthy parturients undergoing elective caesarean section under spinal anesthesia were randomly assigned into two groups. Twenty patients received

37

Ephedrine infusion (5mg/min, 0.01% solution) and twenty four patients (control group) received 20mg of Ephedrine as an intravenous bolus. Results: In patients given the infusion, systolic blood pressure did not change significantly from the baseline and reactive hypertension did not occur. Nausea and/ or vomiting occurred in nine women in the control group and one patient in the infusion group (p<0.001). They concluded that prophylactic intravenous infusion of Ephedrine was safe and effective in healthy parturients undergoing cesarean section under spinal anaesthesia, without causing significant maternal tachycardia, hypertension, nausea and vomiting, or fetal compromise.

Hemmingsen .C et al in 1989

34

conducted a study to determine the clinical use of

prophylactic Ephedrine before spinal anaesthesia. Method: Forty eight patients scheduled to undergo surgical procedures on the lower extremities/ limb under spinal anaesthesia were allocated into three groups of 16 each according to American Society of anesthesiologists (ASA) classification of I-II-III
rd

grade. Each patient received a fluid load of 7ml/kg and either

Ephedrine 12.5mg I.V and 37.5mg I.M or placebo. Result: They found twelve patients in the placebo group development a maximal decrease in mean arterial blood pressure exceeding 20%, five of them developed a decrease exceeding 33% and required treatment. In ASA III, all patients in placebo group had a decrease in mean arterial blood pressure exceeding 33%. They concluded that it is

38

appropriate to administer prophylactic Ephedrine I.V and I.M. routinely at induction of spinal anaethesia especially in ASA class III patients to prevent hypotension.

Gajraj et al in 1993

35

designed a study to compare the efficacy of Ephedrine infusion

with crystalloid administration for reducing the incidence of hypotension during spinal anesthesia. Method: Fifty four ASA grade I patients undergoing postpartum tubal ligation were randomly allocated to two groups. Group 1 received lactated ringers solution, 15ml/kg. Group 2 did not receive any crystalloid before the spinal anesthesia, but received Ephedrine infusion (50mg in 50ml of lactated ringers solution) using syringe pump. Result: they found the incidence of hypotension was 55% in the crystalloid group and 22% in the infusion group. They concluded that Ephedrine infusion was found more effective than crystalloid administration in preventing hypotension in this patient population, and did so without unwanted side effects such as hypertension or tachycardia.

Kafle .S.K, Malla .S.M and Lekhak in 1994

36

conducted a study to demonstrate the

efficacy of oral ephedrine in preventing hypotension following subarachnoid block. Method: Two hundred female patients of ASA I and II scheduled to undergo elective lower abdominal surgery (abdominal hysterectomy, tuboplasty, ovarian tumor) were randomly divided into two groups. Group I patients in addition to routine premedication were given Ephedrine 30mg PO, thirty minutes before subarachnoid block. Both group of patients received preload of 10ml/kg crystalloid solution.

39

Result: they deducted that the total dose of Ephedrine supplemented in group I was 4.3 4.8mg compared with 11.6 9.4mg in group II (P<0.01). Also 55 patients in group I required intraoperative inotrope supplement compared to 83 in group II (P<0.01). They concluded that oral Ephedrine given 30-45 minutes before surgery is a simple and effective method of reducing the incidence of hypotension during spinal anaesthesia. They suggested that it is an acceptable alternative to other techniques used for this purpose in ASA I or II patients.

Critchley et al in 1995

37

compared the haemodynamic effects of Ephedrine alone with

Ephedrine and colloid for the treatment of spinal hypotension. Method: 30 ASA II-III patients aged 60-90 years with fracture of the neck of femur were divided into two groups. Group one received Ephedrine as an initial bolus dose of 0.2mg/kg followed by an infusion of 0.5mg/kg/hour. Group two received Ephedrine and colloid (polygeline, haemaccel) 8ml/kg. If necessary, up to three rescue bolus doses of Ephedrine (0.1mg/kg) and then colloid solution (8ml/kg) were given to maintain systolic pressure above 75% of baseline. Result: in patients receiving Ephedrine only central venous pressure, and stroke index decreased and heart rate increased (P<0.0001). Five patients in the same group required colloid, the effect of which was to restore central venous pressure, increase cardiac index and stroke index. In patients receiving Ephedrine and colloid solution , systemic vascular resistance index decreased and cardiac index, stroke index and heart rate increased(P<0.0001). They concluded that Ephedrine in the doses used in the study had

40

limited action on peripheral vasoconstriction and relied on its ability to increase cardiac output in order to maintain systolic arterial pressure.

Sterno et al in 1995

38

conducted a study to investigate the efficacy of intramuscular

Ephedrine in elderly patients undergoing hip arthroplasty under spinal anaesthesia. Method: Ninety eight patients with age group ranging from 37-89 years and belonging to the entire ASA grade were included in the study. Fifty patients received Ephedrine 0.6mg/kg body weight, deep in the paravertebral muscles immediately after spinal anaesthesia; the remaining forty eight received an equal volume of saline. Patients in both groups were given the same volume of fluid before spinal blockade. Result: They found systolic arterial pressure during the first 60 minutes after anaesthesia remained significantly more stable in the Ephedrine group, and there were also a significantly smaller number of patients in this group who had decreases of pressure of more than 30% preblock levels, and fewer required rescue I.V. Ephedrine. They concluded that Ephedrine 0.6 mg/kg body weight administered in the paravertebral muscles immediately after plain Bupivacaine spinal anaesthesia is a simple and effective means of reducing the incidence of hypotensive episodes in elderly patients. Chan .W.S et al in 1997
39

compared the efficacy of prophylactic ephedrine infusion

over fluid preloading in prevention of maternal hypotension during spinal anaesthesia for caesarean section.

41

Method: Forty six women scheduled to undergo elective caesarean section at term were allocated randomly to receive either Hartman solution preloading 20ml/kg (fluid group) or prophylactic intravenous Ephedrine 0.25mg/kg (ephedrine group). Result: There was lower incidence of severe hypotension in the Ephedrine group when compared to fluid group (35% vs. 65%, P=0.04). Mean umbilical venous pH was higher in the Ephedrine group than in fluid group (7.33 vs. 7.29, p=0.02) and the number of patients shivering was lower in the ephedrine group (2 vs. 9, P=0.02). They concluded that prophylactic Ephedrine infusion is a quick and simple technique which also confers the advantages of reducing the incidence of severe hypotension and neonatal acidosis. They further questioned the need for intravenous fluid preloading.

Webb and Shipton in 1998

40

assessed the safety and efficacy of 37.5 mg Ephedrine

I.M. in preventing hypotension associated with spinal anaesthesia for caesarean section. Method: Double-blind randomized study, 40 patients (20 in each group) were given either 37.5mg Ephedrine (study group) or 1.5ml Normal saline (control group) I.M. into the left deltoid. Result: Incidence of hypertension was 30% in study group compared with 20% for the control group. Incidence of hypotension was lower in study group (50%) than in the control group (80%) and the incidence of delayed hypotension was only 10% in the study group patients compared with 50% (P<0.05) in the control group patients. They concluded that 37.5mg Ephedrine I.M. (10 minutes) prior to spinal anaesthesia was not

42

associated with reactive hypertension or tachycardia. Intramuscular Ephedrine provided more sustained cardiovascular support than intravenous Ephedrine.

Marcel. P.Vercauteren et al in 2000

41

evaluated the effectiveness of prophylactic

Ephedrine for the prevention of hypotension associated with spinal anesthesia in patients undergoing cesarean section. Method: Fifty parturients were divided into equal groups and received either Ephedrine 5mg or Saline I.V. immediately after induction of spinal anaesthesia. Result: More number of patients in the saline group were found to develop hypotension (58% vs. 25%, P<0.05).Only two patients (8%) in the Ephedrine group developed Systolic blood pressure values <90mm hg, whereas 10 patients (42%) in the saline group experienced hypotension of this severity (p<0.05). In addition incidence of nausea was also higher in the saline group. They suggested that the incidence and severity of hypotension are significantly reduced by the I.V. administration of prophylactic dose of 5mg Ephedrine in patients receiving small-dose spinal anesthesia for cesarean delivery.

Ngan Kee et al in 2000 42 designed a randomized, double blinded study to determine the efficacy and optimal dose of I.V. Ephedrine for prevention of hypotension during spinal anesthesia for cesarean delivery. Method: Eight women who received an I.V. crystalloid preload preceding spinal anesthesia for elective cesarean section. One minute after the intrathecal injection, patients were given saline control, or Ephedrine 10, 20 or 30mg I.V.

43

Result: They found that systolic arterial pressure in the first 12 minutes was greater in 30mg group when compared to other groups. Hypotension occurred in 7 patients (35%) in the 30mg group compared with 19 (95%), 17(85%) and 16(80%) patients in the control and 10. 20mg groups respectively. Reactive hypertension occurred in 9 patients (45%) in the 30mg group compared with 2(10%), 1(5%) and 5(25%) patients in the other groups. Heart rate changes, total Ephedrine requirement, incidence of nausea and vomiting, and neonatal outcome were similar among all groups. They concluded that in patients having spinal anesthesia for cesarean section after I.V. Crystalloid preload, the minimum

effective dose of I.V. Ephedrine given one minute after the spinal anesthesia to reduce the incidence of hypotension was 30mg and it caused reactive hypertension in some patients. Further investigation of other methods of reducing the incidence of hypotension during spinal anesthesia for cesarean delivery was indicated.

Loughrey et al in 2002

43

evaluated the efficacy and optimal dose of prophylactic

intravenous Ephedrine for prevention of hypotension associated with spinal anaesthesia for caesarean section. Method: Sixty six patients were randomized into three groups according to which they received a bolus of 0.9% saline I.V. (Group C, n=20), Ephedrine 6mg (Group E-6, n=24) Or ephedrine 12mg (Group E-12, n=22) simultaneously with the subarachnoid block. Result: There was a significantly higher incidence of hypotension in Group C compared with Group E-12 (60% vs. 27.3%, P<0.05). Less rescue doses of ephedrine were required in Group E-12 compared with the control group (1.8 1.2 vs. 3.3 2.1, p<0.05). They

44

concluded that prophylactic bolus of Ephedrine 12mg I.V. is safe and efficacious in reducing the incidence of maternal hypotension compared to I.V. rescue boluses alone.

Erogulu et al in 2003 44 investigated the prophylactic effects of systemic oral Ephedrine in spinal anesthesia induced hypotension during transurethral prostatectomy. Method: Sixty ASA grade II and III patients were randomized into two groups. Patients in Group I (n=30) received oral Ephedrine 50mg in addition to routine premedication, whilst those in Group II (n=30) received only premedication 30 min before spinal anaesthesia. Result: Systolic arterial pressure values were significantly lower in Group II during the spinal anesthesia, post-spinal and intraoperative periods (p<0.0001). The incidence of hypotension was halved in Group I compared to Group II (23.33% vs. 50%, P=0.003). Six patients in Group II also received Inj. Atropine I.V. because of severe bradycardia. They concluded that a prophylactic oral dose of Ephedrine 50mg is effective for minimizing and managing spinal anesthesia-induced hypotension during transurethral prostatectomy.

Loughrey et al in 2005

45

evaluated the hypothesis that an I.V. bolus of Phenylephrine

combined with Ephedrine, when compared to Ephedrine alone, could reduce the incidence and severity of hypotension during spinal anesthesia for cesarean delivery.

45

Method: Forty three ASA grade I & II non-laboring patients were randomized into two groups. Group E (n=20) received bolus I.V. Ephedrine 10mg and Group EP (n=20) received Ephedrine 10mg and Phenylephrine 40g I.V. Result: The overall hypotension was 80% in Group E vs. 95% in Group EP. They concluded that combination of Ephedrine and Phenylephrine given as intravenous bolus at the doses mentioned is not superior to Ephedrine alone in preventing or treating hypotension in healthy parturients undergoing cesarean delivery.

46

MATERIALS AND METHODS


This is a randomized, prospective study performed over a period of one year from June 2004 to June 2005.The study was carried out in one hundred patients between the age group of 20-60 years belonging to American society of Anesthesiologist (ASA) grade I and II who were scheduled for elective surgery being performed over the lower abdomen or the lower limbs under spinal anaesthesia. After institutional Ethical committee approval and informed consent from each patient, the study was conducted at Sree Siddartha Medical College Hospital and Government District hospital (General Hospital), Tumkur. Inclusion Criteria: 1. Patients belonging to ASA grade I and II posted for elective surgery on the lower abdomen or lower limbs under spinal anaesthesia. 2. Patients between the age group 20-60 years of both sexes 3. Patients weighing between 40 to 80kgs.

Exclusion Criteria: 1. Patient refusal. 2. Patients having systemic cardiovascular, respiratory, hepatic, renal or central nervous system disorders. 3. Patients on MAO-inhibitor antidepressants and -blockers.

47

4. Patients with haemorrhagic disorders or patients who are on anticoagulant therapy. 5. Disease and deformities of spinal cord or vertebral column. 6. Patients with haemoglobin less than 10gm/dl. 7. A patient in whom more than 10% blood loss is anticipated or occurs on table during the study. 8. Patients who were chronic smokers and alcohol dependent. The selection of patients was carried out randomly. Patients were explained in there own language the anaesthetic procedure they are going to undergo the next day, following which an informed written consent was obtained from each patient. Pre- anesthetic examination was done the previous day to surgery which included patients height and weight, general examination, systemic examination of cardio vascular system, respiratory system, CNS and examination of spine. Basic investigations like heamoglobin percentage, total blood count, differential blood count, urine routine, bleeding and clotting time, blood Sugars (if urine sugar positive). Blood urea, serum creatinine and electrocardiogram were carried out before taking up for surgery in patients aged above 40 years. All patients were pre-medicated with Tab. Ranitidine 150mg Po the night before surgery and 2hrs before surgery. Tab. Diazepam 10mg Po was administered the night before surgery. All patients were kept nil orally before surgery.

48

The baseline Heart rates (HR), Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were recorded for all patients using the L. & T. monitor. Patients then were randomly allocated into two groups. Group A (n=50) were given Tab. Ephedrine 30mg orally with a sip of water 30 minutes before surgery. Group B (n=50) were given a placebo to be taken orally with a sip of water 30 minute before surgery. Patients were shifted to the operation theatre, intravenous access was obtained using a 18 gauge canula, an infusion of ringer lactate was started. The pre subarachnoid block Heart rates (HR), Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were recorded for all patients and continuous monitoring done with L. & T. monitor. Patient was then put to left lateral position. Under strict aseptic precaution lumbar puncture was performed using 25-gauge disposable Quincke type of spinal needle at L3-L4 spinal intervertebral space by midline approach. After the free flow of cerebrospinal fluid, 3ml of Bupivacaine Hydrochloride was injected intrathecally and the time noted. The patients were repositioned, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) were recorded in all patients at every 2 minutes interval for 10 minutes, then at every 10 minutes interval up to 45minutes and then at every 15 minutes till the end of surgery. Level of sensory blockade was checked using a 23G hypodermic needle, Success of the block was defined as pinprick analgesia extending cranially at least to the T8 dermatome. Following subarachnoid block the following vitals were monitored during

49

Fig: 9 Oral Ephedrine Tablets.

Fig: 10

Intravenous Ephedrine and Other Essential Drugs.

50

Fig: 11

Spinal Puncture Being Performed.

Fig: 12

C.S.F Flow through Spinal Needle.

51

Peri-operative period. They included hypotension, Nausea, vomiting, desaturation or hypoxemia (SpO2<90%) and blood loss during the surgical procedure.

Hypotension was defined as a decrease in systolic blood pressure (SBP) more than 20% from the base line. If hypotension occurred in any of the patients they were treated first with foot end elevation, then infusion of ringer lactate was increased. If hypotension continued following these measures finally they were treated with Inj. Ephedrine administered intravenously in 5mg boluses at 2 minute interval until the SBP returned to within 20% of the base line values. Inj. Atropine 0.6mg was administered intravenously to any patient if the heart rate decreased below 60 beats/minute. Statistical analysis: The observations are expressed as Mean one standard deviation. The baseline haemodynamic values and the postspinal haemodynamic changes at various time intervals were compared using Unpaired t and Chi-square tests. The values of p<0.05 were considered statistically significant.

52

RESULTS AND ANALYSIS


Age distribution of the patients Age (years) 21-30 31-40 41-50 51-60 Group A Number 19 22 9 0 Group B Number 14 21 13 2

% 38 44 18 0

% 28 42 26 4

Table: II. Age distribution of the two groups of patients The age range was 21-48 years in group A and 20-56 years in group B.
Age Distribution of Patients
25 20 15 10 5 0 21-30 31-40 41-50 51-60 Age(years) Group A Group B

Number of Patients

Graph: 1 Age Distribution of Patients

Sex distribution of the patients SEX


MALE FEMALE

Group A Number %
23 27 46 54

Group B Number %
24 26 48 52

Table: III. Sex distribution of the two groups of patients. There were 23 males and 27 females in Group A and 24 males and 26 females in Group B. The two groups are thus almost perfectly matched.

53

Sex Distribution

27 26 25 Number of 24 Patients 23 22 21 MALE FEMALE Group A Group B

Graph: 2 Sex Distribution. Height distribution of the patients Height Group A Group B (cm) Number % Number % 141-150 3 6 5 10 151-160 28 56 27 54 161-170 18 36 17 34 171-180 1 2 1 2 Table: IV. Height distribution of the two groups of patients. In group A, the height range was 148-172 cm and in the other group, 146-172 cm.
Height Distribution of Patients
30 25 20 Number of 15 Patients 10 5 0 141-150 151-160 161-170 171-180 Height(Cms) Group A Group B

Graph: 3 Height Distribution

54

Weight distribution of the patients Group A Group B Weight Number % Number % (kg) 40-45 2 4 2 4 46-50 9 18 4 8 51-55 8 16 11 22 56-60 15 30 22 44 61-65 10 20 9 18 66-70 6 12 2 4 Table V. Weight distribution of the two groups of patients The range of weight in group A was 44-79 kg and in group B, it was 43-70 kg.
Weight Distrbution of Patients
25 20 15 10 5 0 40-45 46-50 51-55 56-60 61-65 66-70 Weight(Kgs) Group A Group B

Number of Patients

Graph 4 Weight Distribution

55

Statistical comparison of age, height and weight of the two groups of patients

t p Group A Group B Mean S.D. Mean S.D. value value Age (years) 33.54 8.14 36.68 8.87 1.844 0.0682 Height (cm) 159.00 5.44 158.96 5.64 0.0361 0.9713 Weight (kg) 57.32 7.32 56.52 5.57 0.6150 0.5400 Table VI. Statistical comparison of age, height and weight of the two groups of patients In Table VI the mean, the standard deviation (S.D) and the unpairedt test value of age, height and weight of the two groups of patients are presented. It is seen that the groups are matched in respect of these parameters. Type of surgery Presents the kind of surgical interventions carried out on the patients in both the groups Type of surgery Group Group A B Appendicectomy 12 11 Herniorraphy 8 8 Fissurectomy & 7 5 Lords dilatation Haemorrhoidectomy 6 3 Hydrocele excision 3 3 Hysterectomy, 3 2 vaginal Anatomical repair 2 2 Curettage & skin 1 3 grafting Venous stripping 1 2 Fistulectomy Multiple subfacial ligation Ovariectomy Drainage Excision Mesh repair Varicocelectomy K wire fixation 1 1 1 1 1 0 1 1 4 2 0 1 2 2 0 0

Parameter

Table VII. Type of surgery carried out on the two groups of patients

56

14 12 10 8 6 4 2 0 Ovariectomy Anatomical repair Multiple subfacial Lords dilatation Venous stripping Haemorroidectomy Curettage & skin Appendicectomy Hysterectomy, Varicocelectomy Fissurectomy & K wire fixation Herniorraphy Fistulectomy Mesh repair Hydrocele Drainage Excision Group A Group B

Graph 5 Type of surgery carried out on the two groups of patients

Appendicectomy, herniorraphy, fissurectomy and Lords dilatation (A/H/F) constituted 54% of all operations in Group A and 48% of operations in the other group of patients. The next common cluster of surgeries comprised haemorrhoidectomy, hydrocele excision and hysterectomy vaginal (H/H/H); they accounted for 24% of cases in Group A and 16%, in Group B. The frequency based cluster-wise distribution of operations is shown in Table VIII. The difference in the surgeries between groups is statistically not significant.

Surgery clusters Group A Group B A/H/F 27 24 H/H/H 12 8 Others 11 18 Table VIII. The cluster-wise distribution of surgeries in the two groups of patients x2 = 2.666, p= 0.2637

57

Level of sensory block The level of anaesthesia in the two groups of patients is given in Table IX and Graph 6

Level of Group A Group B anesthesia Number % Number % T6 16 32 20 40 T8 34 68 29 58 T10 0 0 1 2 Table IX. Level of anaesthesia in the two groups of patients

35 30 25 Num ber of 20 Patients 15 10 5 0 T6 T8 Level of Block T10

Group A Group B

Graph 6 Level of Spinal anaesthesia

Blood pressure Baseline status Systolic Blood Pressure (SBP) Systolic BP Group A Group B (mmHg) Number % Number % 100-110 4 8 12 24 111-120 20 40 11 22 121-130 21 42 10 20 131-140 5 10 17 34 Table X. Baseline systolic blood pressure in the two groups of patients The range of SBP was 110-136 mmHg in group A and 104-140 mmHg in group B. 58

Diastolic Blood Pressure (DBP) Diastolic BP Group A Group B (mmHg) Number % Number % 61-70 2 4 8 16 71-80 30 60 20 40 81-90 18 36 22 44 Table XI. Baseline diastolic blood pressure in the two groups of patients The range of DBP was 70-92 mmHg in group A and 68-90 mmHg in group B. Mean Arterial Pressure (MAP)

Meal arterial pressure Group A Group B (mmHg) Number % Number % < 86 0 0 5 10 86-90 13 26 14 28 91-95 27 54 11 22 96-100 8 16 9 18 > 101 2 4 11 22 Table XII. Baseline mean arterial pressure in the two groups of patients The range of MAP was 87.33-105.33 mmHg in group A and 82-106.66 in the other group.

59

Heart Rate (HR)

Heart rate Group A Group B (beats/min) Number % Number % 61-70 7 14 8 16 71-80 25 50 12 24 81-90 12 24 26 52 91-100 6 12 4 8 Table XIII. Baseline heart rate in the two groups of patients In group A, HR range was 64-100 beats/minute, and in group B, it was 62-96 beats/minute.

SBP and DBP in the same group of patients The SBP and DBP patients at different time periods of Group A are shown in Graph 7 and those of Group B in Graph 8.

135 125 115

mmHg

105 95 85 75 65 Baseline At SAB 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes

Systolic BP Diastolic BP

Time

Graph 7. The SBP and DBP of patients in Group A at different time Intervals.

60

130 120 110

mmHg

100 90 80 70 60 Baseline At SAB 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes

SBP DBP

Time

Graph 8. The SBP and DBP of group B patients at different time Intervals.

The two blood pressure curves of Group A (Graph 7) are almost of similar shape. They first rise slightly and then show a gradual and steady decline. The two curves of Group B (Graph 8) are more or less similar. At first they are horizontal and then they dip down to form concavities. The concavity of the curve for SBP is deeper than that for DBP.

61

Comparison of BP in the two groups The SBP of the patients at different times is presented in Graph 9 and Table XIV. In group A the lowest SBP was 115.6 mmHg at 60 minutes; and in group B the lowest SBP was 100.1 at 8 minutes.

140 130

mm Hg

120 110 100 90 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes Baseline At SAB

Group A Group B

Time

Graph 9. The SBP of the two groups of patients at different time intervals Group A Group B t value p value Significant Mean S.D. Mean S.D. Baseline 121.98 7.36 123.85 11.45 0.9715 No 0.3337 At SAB 127.14 7.36 123.96 10.47 No 1.757 0.820 2 minutes 128.74 8.18 116.2 10.95 Yes 6.487 <0.0001 4 minutes 126.84 7.90 107.72 9.73 10.787 <0.0001 Yes 6 minutes 121.94 10.10 102.52 9.56 Yes 9.874 <0.0001 8 minutes 120.34 11.84 100.1 11.09 Yes 8.822 <0.0001 10 minutes 118.7 11.44 100.78 8.91 Yes 8.739 <0.0001 20 minutes 118.6 9.10 101.18 7.87 10.238 <0.0001 Yes 30 minutes 119.92 8.14 104.18 7.44 Yes 9.695 <0.0001 40 minutes 118.84 6.60 107.46 7.28 Yes 8.189 <0.0001 50 minutes 117.74 6.90 109.72 6.76 Yes 5.871 <0.0001 60 minutes 115.6 7.53 118.33 10.41 No 1.503 0.1364 Table XIV. Statistical comparison of SBP (mmHg) in the two groups The differences are highly significant except at baseline, at SAB and at 60 minutes. 62 Period

The DBP of the two groups of patients at different time intervals are presented in Graph 10 and Table XV. The lowest DBP was 73. 2 mmHg at 60 minutes in group A, and 66.4 mmHg at 10 minutes in the other group.

85 80

mmHg

75 70 65 60 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes Baseline At SAB

Group A Group B

Time

Graph 10. The DBP of the two groups of patients at different time intervals

Group A Group B t value p value Significant Mean S.D. Mean S.D. Baseline 79.32 4.97 79.0 6.73 No 0.271 0.7874 At SAB 81.7 5.95 78.82 6.60 No 1.496 0.1379 2 minutes 81.72 7.59 75.66 6.25 Yes 4.358 <0.0001 4 minutes 80.44 7.69 71.76 5.54 Yes 6.476 <0.0001 6 minutes 77.78 7.58 68.46 6.4 Yes 6.643 <0.0001 8 minutes 76.5 7.40 67.38 7.92 Yes 5.590 <0.0001 10 minutes 75.54 7.49 66.4 6.53 Yes 6.504 <0.0001 20 minutes 75.44 6.01 67.6 6.01 Yes 6.522 <0.0001 30 minutes 75.78 5.20 67.62 4.25 Yes 8.592 <0.0001 40 minutes 75.76 6.10 70.1 5.19 Yes 4.997 <0.0001 50 minutes 75.48 5.76 70.96 4.88 Yes 4.234 <0.0001 60 minutes 73.2 3.27 76.66 6.66 Yes 3.298 0.0014 Table XV. Statistical comparison of DBP (mmHg) in the two groups The differences are highly significant except at baseline and at SAB.

Period

63

The MAP of the two groups of patients at different time intervals is presented in Graph 11 and Table XVI. In group A, the lowest MAP was 87.33 mmHg at 60 minutes, and the highest was 97.39 mmHg at 2 minutes. In group B, the lowest was 78.88 mmHg at 6 minutes, and the highest was 103.44 mmHg at 60 minutes

110

100

mmHg

90

Group A GroupB

80

70 Baseline At SAB 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes

Time

Graph 11. The MAP of the two groups of patients at different time intervals Period Baseline At SAB 2 minutes 4 minutes 6 minutes 8 minutes 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes Table XVI. Group A Group B T value P value Significant Mean S.D. Mean S.D. 93.54 5.19 93.95 7.27 No 0.325 0.7458 96.84 6.01 93.80 7.26 Yes 2.281 0.0247 97.39 7.17 89.17 7.13 Yes 5.748 <0.0001 95.91 7.36 83.75 6.33 Yes 8.857 <0.0001 92.5 8.05 78.88 8.01 Yes 8.481 <0.0001 91.11 9.29 94.87 5.51 Yes 2.462 0.0156 89.92 8.25 94.99 5.31 Yes 3.654 0.0042 89.82 6.45 95.90 5.12 Yes 5.221 <0.0001 90.49 5.23 96.11 5.31 Yes 5.332 <0.0001 89.21 8.66 96.11 5.06 Yes 4.864 <0.0001 89.57 5.70 96.31 5.07 Yes 6.247 <0.0001 87.33 4.52 103.44 5.7 Yes 15.659 <0.0001 Statistical comparison of MAP (mmHg) in the two groups

The differences are highly significant except at baseline

64

The HR of the two groups of patients at different time intervals is presented in Graph 12 and Table XVII.

Graph 12. The HR of the two groups of patients at different time intervals

Group A Group B t value p value Significant Mean S.D. Mean S.D. Baseline 78.34 7.97 81.14 8.05 No 1.748 0.0836 At SAB 81.98 8.29 83.2 6.77 No 0.806 0.4222 2 minutes 83.08 8.33 85.26 7.35 No 1.388 0.1684 4 minutes 83.2 8.76 88.32 8.3 Yes 3.000 0.0034 6 minutes 83.3 8.27 89.58 8.66 Yes 3.708 0.0003 8 minutes 82.56 8.11 92.26 9.07 Yes 5.637 <0.0001 10 minutes 82.62 8.04 92.1 8.41 Yes 5.761 <0.0001 20 minutes 81.84 6.48 93.26 7.63 Yes 8.067 <0.0001 30 minutes 81.6 6.56 92.08 7.87 Yes 7.233 <0.0001 40 minutes 80.56 5.95 90.44 6.96 Yes 7.826 <0.0001 50 minutes 81.26 5.53 89.6 6.59 Yes 6.855 <0.0001 60 minutes 79.2 4.55 96.0 12.49 Yes 8.937 <0.0001 Table XVII. Statistical comparison of HR (beats/minute) in the two groups The differences are highly significant from 4th minute onwards.

Period

65

Intra-group comparison at selected periods The comparison of SBP, DBP and heart rate at baseline with the corresponding values at SAB, at 8 minutes and at 60 minutes is presented in Tables XVIII, XIX and XX. Time Group A
Mean (mm Hg) S.D (mm Hg)

T value

p value

Group B
Mean (mm Hg) S.D. (mm Hg)

t value

p value

Baseline 122 7.36 3.505 0.0007 123.9 11.45 0.05 0.9601 SAB 127.1 7.36 124 10.47 Baseline 122 7.36 0.832 0.4075 123.9 11.45 10.54 <0.0001 8 min 120.3 11.84 100.1 11.09 Baseline 122 7.36 4.284 <0.0001 123.9 11.45 2.522 0.0133 60 min 115.6 7.53 118.3 10.41 Table XVIII. Comparison of SBP at baseline with SBP at SAB, at 8 minutes and at 60 minutes

Time

Group A
Mean (mmHg) S.D (mmHg)

t value

p value

Group B
Mean (mmHg) S.D. (mmHg)

t value

p value

Baseline SAB Baseline 8 min Baseline 60 min

79.32 81.7 79.32 76.5 79.32 73.3

4.97 5.95 4.97 7.4 7.36 3.27

2..171 2..237

0.0324 0.0276

7.274 <0.0001

79.06 78.82 79.06 67.38 79.06 76.66

6.73 6.6 6.73 7.92 6.73 6.66

0.135

0.8929

7.906 <0.0001 1.748 0.0897

Table XIX. Comparison of DBP at baseline with DBP at SAB, at 8 minutes and at 60minutes

66

Time

Group A
Mean (beats / min) S.D (beats/ min)

t value

p value

Group B
Mean (beats/ min) S.D (beats / min).

t value

p value

2..624 0.0101 6.484 <0.0001 8 min 82.56 8.11 92.26 9.07 Baseline 78.34 7.97 8.05 0.662 0.5091 81.14 7.071 <0.0001 60 min 79.2 4.55 96 12.49 Table XX. Comparison of heart rate at baseline with heart rate at SAB, at 8 minutes and at 60 minutes

Baseline SAB Baseline

78.34 81.98 78.34

7.97 8.29 7.97

2..238

0.0275

81.14 83.2 81.14

8.05 6.77 8.05

1.385

0.1692

The Haemodynamic variations pertaining specifically to spinal anaesthesia occur during the first 30minutes following the block 10. In intra group comparison of Group A even though SBP at 60 minutes and DBP at 8 and at 60 minutes were statistically significant none of the values are less than 80% of the baseline. In Group B values are statistically significant and the values are less than 80% of the baseline values. . In my Study its been proved beyond doubt that prophylactic Oral Ephedrine is effective in preventing spinal induced hypotension during this period.

The heart rate at SAB and at 8 minutes differed significantly from the baseline value in Group A; in group B, the heart rate at 8 minutes and at 60 minutes differed significantly from the baseline value.

67

Hypotension There were 4 cases of hypotension in Group A, and 20 in Group B. This difference is statistically highly significant (x2 = 12.336, p = < 0.0001) Of the 20 cases of hypotension in Group B, 6 were noted at the 4th minute, another 6 at the 6th minute, 4 at the 8th minute, 2 at the 10th minute and the remaining 2 at the 20th minute (see Graph 13).

2 2 6
4 minutes 6 minutes 8 minutes 10 minutes

20 minutes

Graph 13. Time of onset of hypotension in 20 cases of group B

In 4 patients the hypotension was controlled in less than 6 minutes. In another 4 patients, normal blood pressure was restored in 7- 24 minutes. Ten patients needed 25-48 minutes before regaining normotensive status.

68

Two cases had hypotension lasting for more than 48 minutes. These are shown diagrammatically in Graph 14 and Graph 15.

150 140 130 mmHg Case 1 80% baseline value 120 110 100 90 80 sab 2 4 6 Baseline 8 10 20 30 40 50
50

Time (minutes)

Graph 14. First protracted cases of hypotension

140 120 100 80 10 20 30 40 Baseline sab 60 2 4 6 8

Case 2 80% baseline value

Graph 15. Second protracted case of hypotension. Non-haemodynamic side-effects There was one case of nausea and vomiting in Group A and eight cases in Group B. This difference is statistically significant (x2 = 0.4396, p = 0.036).

60

69

DISCUSSION
Anaesthesiologists master spinal anaesthesia early during there training with achievement of competence (>90% technical success rate) after only 40-70 supervised attempts 13. The ease and long history of success has made Subarachnoid block the anaesthetic procedure of choice for surgeries involving the lower abdomen / lower limbs. Though spinal anaesthesia has a wide range of advantages like the simplicity of technique, its rapid onset of action, economical and minimal postoperative complications, it is not without the risk of physiological side effects on the various systems 46. The most common serious side effects from spinal anaesthesia are hypotension and bradycardia
47

. Large surveillance studies typically observed incidence of

hypotension around 33% and bradycardia around 13% in non-obstetric patient group 13. Hypotension is due to the combined effects of autonomic denervation and the added effect of vagal nerve predominance 10. These lead to: Peripheral venous pooling causing decrease in preload. Arteriolar vasodilatation leading to decrease in afterload. Blockade of cardio-accelerator fibers (T1-T4) leading to bradycardia and decrease in contractility further reducing the blood pressure.

70

Risk factors for hypotension include 13: Spinal block height. Age of 40years and above Baseline systolic blood pressure <120mm of Hg. Spinal puncture above L3-4 intervertebral space. Inferior venacaval vein compression in obstetric patients leading to hindrance to venous return from lower part of the body.

Spinal anaesthesia induced hypotension is treated physiologically by improving the venous return so as to increase the preload thereby restoring the cardiac output. Mechanical methods like head down or leg elevation (10-15) or leg wrapping with elastocrit bandages and splints does not abolish the incidence of hypotension 28, 48. Volume preloading studies have proved beyond doubt that colloids are no better than crystalloids in preventing the incidence of hypotension 49 and has the added set of draw backs like : Increased cost in comparison to crystalloids 50. Anaphylactic reactions 50, 51. Interference with the clotting cascade 52. Interference to Blood Grouping and cross matching studies 53.

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Crystalloids on the other hand are required in great volumes (>15ml/kg) to decrease the incidence of hypotension effects like : Increased central venous pressure 55, 56. Blood dilution leading to decrease in oxygen carrying capacity 57. Release of atrial natriuretic peptide initiating diuresis, thereby attenuating the effect of volume load on blood pressure 58. In due consideration to the above statements it seems appropriate that prophylactic administration of a pharmacologic agent is more effective than prehydration for prevention of hypotension 56, 59, 60. Among the Vasopressors a mixed adrenergic agonist such as Ephedrine more ideally corrects the non cardiac circulatory sequelae of spinal anaesthesia than does either a pure -or -adrenergic agonist 31. There are mixed results to prophylactic administration of I.M. Ephedrine as to its postoperative incidences of hypertensive episodes and alleged unpredictable absorption from the site of injection 61. The belief that a relative overdose may result in hypertension, tachycardia or both postoperatively, and may therefore be detrimental 62. Nevertheless, administration of Ephedrine 37.5mg I.M. was not associated with reactive hypertension or tachycardia in women undergoing caesarean section 40. In other studies patients aged >60years received I.M. Ephedrine for prevention of hypotension. Although the incidence of hypotensive episodes was effectively reduced, all patients experienced a significant decrease in systolic pressure after spinal anesthesia 38.
54

. These huge volumes have detrimental

72

Studies related to prophylactic bolus or infusions of I.V. Ephedrine have proved their efficacy in preventing the episodes of hypotension without unwanted side effects 41, 42, 43. Studies relating to Oral route of prophylactic Ephedrine are sparse. So we conducted this study to determine the safety and efficacy of prophylactic Oral Ephedrine in reducing the incidence of hypotension after subarachnoid block. Changes in Respiratory rate and Oxygen saturation: In the present study all patients were monitored clinically in the intra operative. It was recorded that none of the patients in both the groups had changes in respiratory rate or oxygen saturation.

Incidence of Hypotension: In our study, incidence of hypotension is 8% in Group A patients and 40% in patients of Group B. All these patients who developed hypotension showed a fall in systolic arterial pressure of more than 20% of the base line value within the first 20minutes of intrathecal block. The incidence of hypotension is greater in Group B when compared to Group A which is statistically highly significant (x2 = 12.336, p = < 0.0001) Kafle et al 1994 36 in there study found the incidence of hypotension to be 55% in Group I (ephedrine group) and 83% in Group II (control group). These high incidences of hypotension may be attributed to the high level of sensory block T3-T4 level, higher doses of bupivacaine heavy 0.5% (3.2 to 3.6ml) used and non exclusion of patients who had intraoperative bleeding above 10% in both the groups.

73

Eroglu et al 2003

44

in there study found the incidence of hypotension to be

23.33% in Group I (ephedrine group) and 50% in Group II (control group). These values differ in comparison to my values as the patients enrolled into there study were aged >60years (range 60-87) and belonged to ASA Grades II and III. Both the studies have shown that the incidence of hypotension is statistically lower in patients who have received prophylactic Oral Ephedrine before Subarachnoid block; this is in support to my finding. Intraoperative Supplemental Pressor Agent: In our study patients in whom we noticed a fall in blood pressure, we adopted active measures like head down position, increasing the rate of infusion and oxygenation. If the hypotension continued despite the above measures Inj. Ephedrine hydrochloride 5mg bolus were administered I.V. at 2 minute interval until the blood pressure returned to within 80% of baseline values. In our study 18% of patients in Group B required vasopressors therapy and larger volumes of additional intravenous fluid. In Group A none of the patients received vasopressors and the 8% of patients who had hypotensive episodes were rectified by application of active measures. Kafle et al 1994
36

in there study supplemented Inj. Ephedrine I.V. as soon as

there was a fall in blood pressure and did not use any form of measures used in my study. Patients in Group I (ephedrine group) received 4.34.8mg I.V. Ephedrine and Group II (control group) received 11.69.4mg I.V. Ephedrine which was statistically significant (p<0.01).

74

Eroglu et al 2003 44 in there study supplemented Inj. Ephedrine I.V. as soon as there was a fall in blood pressure and did not use any form of measures used in my study. Patients in Group I (ephedrine group) received 3.420.97mg I.V. Ephedrine and Group II (control group) received 8.861.24mg I.V. Ephedrine which was statistically highly significant (p<0.0001). In both the above mentioned studies there is a statistically significant reduction in the supplemental doses of intraoperative I.V. Ephedrine in patients who received prophylactic oral Ephedrine which is consistent with my study. Heart rate: In our study even though both the groups had a statistically non significant variation in the heart rate up to the 2nd minute, there was a steady rise in the heart rate of Group B patients from 4th minute onwards when compared with Group A patients who had none. This can be explained by the intravenous supplements of Ephedrine boluses and increased infusion of Ringer solution in Group B patients who had blood pressure < 80% of baseline values. Kafle et al 1994
36

found in there study that tachycardia did occur in patients

given intravenous Ephedrine to treat the hypotension and none of the patients who received oral Ephedrine prophylactically had tachycardia. This finding is consistent with my study. Eroglu et al 2003 44 recoded six cases of bradycardia in Group II (control group) who responded to Inj. Atropine Intraoperatively. These cases of bradycardia were

75

attributed to the high level of sensory block (T4 level). None of there patients who received Oral Ephedrine had episodes of tachycardia which is consistent with my study. Non-Haemodynamic side effects: The incidence of nausea alone or with vomiting during spinal anaesthesia in our study was 16% in Group B and 2% in Group A which is statistically significant (x2 = 0.4396, p = 0.036). Major causes of nausea and vomiting has been ascribed in part to a reduction in medullary blood flow to the chemoreceptor trigger zone, and therefore Ephedrine is commonly employed to increase mean arterial pressure and presumably improve medullary blood flow. An increase in gastric peristalsis due to preganglionic sympathetic denervation of the stomach may also provoke nausea and vomiting during spinal anesthesia, but whether Ephedrine could mitigate this mechanism remains unknown. Sanjay Datta et al 1982
32

conducted a study on Sixty healthy parturients

scheduled for caesarean section and assessed the effectiveness of intravenous Ephedrine in prevention of hypotension, nausea alone, or with vomiting. They concluded that prompt intravenous administration of Ephedrine as soon as fall in base line blood pressure was detected prevents further fall in blood pressure and markedly reduces the incidence of nausea alone or with vomiting. Kang et al 1982 33 Rothenberg et al 1991 63 designed a study to determine the antiemetic effect of ephedrine in a prospective, randomized, and double blind fashion in patients under going outpatient gynecologic laparoscopy. Before reversal of neuromuscular blockade

76

patients either received placebo (0.9% saline I.M.), 0.04mg/kg I.M. Droperidol, or 0.5mg/kg I.M. Ephedrine. They concluded that Ephedrine is an effective prophylactic antiemetic agent in patients having general anaesthesia for outpatient laparoscopy. Gajraj et al 1993 35 Vercauteren et al 2000
41

in there study have shown lower incidence of

nausea in patients who received prophylactic 5mg Inj. Ephedrine I.M. this is consistent with my study. In all the above mentioned studies have demonstrated lower incidence of nausea alone or with vomiting which is in accordance to my study. Central nervous system stimulation and Arrhythmias. In our study group none of the patients who received prophylactic oral Ephedrine had episode of excitability, restlessness or arrhythmias. Kafle et al 1994 36 Eroglu et al 2003 44 Both the above studies did not show any form of central nervous system stimulation or arrhythmias which is consistent with my study. In the present study prophylactic administration of Oral Ephedrine 30mg 30minutes before spinal anaesthesia not only reduced the incidence of hypotension effectively in patients undergoing various elective lower abdomen / lower limb surgeries involving blood loss <10% but also reduces the incidence of Intraoperative nausea and vomiting considerably without any unwanted side effects like central nervous system stimulation, tachycardia or arrhythmias. 77

SUMMARY
This prospective randomized comparative study was designed to know the efficacy and safety of prophylactic oral Ephedrine in prevention of spinal anesthesia induced hypotension. Patients belonging to ASA Grade I & II undergoing elective surgeries on the lower abdomen / lower limb under spinal anaesthesia were randomly allocated into two groups of 50 each. Group A: Received prophylactic Oral Ephedrine 30mg with a sip of water 30minutes before SAB with 3ml of 0.5% hyperbaric bupivacaine hydrochloride. Group B: Received a Placebo (control) with a sip of water 30minutes before SAB with 3ml of 0.5% hyperbaric bupivacaine hydrochloride.

Intraoperatively and postoperatively no significant changes were noted in respiratory rate and oxygen saturation levels in any of the patients in both the groups. Incidence of hypotension was 8% in Group A patients and 40% in Group B patients respectively. Among the hypotensive patients in Group B 12% were recorded at 4th minute, another 12% at 6th minute, 8% at 8th minute, 4% at 10th minute and the remaining 4% at the 20th minute. The numbers of patients receiving vasopressor therapy intraoperatively were higher among Group B (18%) in comparison to Group A which received none. 78

There was incidence of tachycardia in Group B when compared with Group A after the 4th minute of SAB, which was statistically significant (p<0.005) Incidence of non-haemodynamic side effects like Intraoperative nausea and vomiting was 16% in Group B and 2% in Group A respectively. Which is statistically significant (x2 = 0.4396, p = 0.036).

79

CONCLUSION
The prophylactic administration of oral Ephedrine in ASA Grade I & II patients undergoing elective surgery under spinal anaesthesia is an effective measure in preventing hypotension without causing untoward side effects like central nervous system stimulation, tachycardia or arrhythmias. To conclude, this study demonstrates that prophylactic Oral Ephedrine is a simple, easy, economical, effective and reliable method not only in preventing the incidence of hypotension but also reduces the incidence of intraoperative nausea and vomiting considerably.

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8. Ellish H, Feldman S and Griffiths OHW, eds. The vertebral canal and its contents. In: Anatomy for Anaesthetists. 8th ed .Oxford: Blackwell Publishing. 2004; Part 3; 95135. 9. Brown LD. Spinal, epidural and caudal anesthesia. In: Miller DR Edt. Millers Anesthesia. 6th ed. Philadelphia: Elsevier Churchill Livingstone. 2005; 1653-1683. 10. Greene.N. M, Brull. S. J, Gillies. J, The cardiovascular system. In: Greene N.M. and Brull S.J Edt. Physiology of Spinal Anesthesia. 4th ed. Baltimore:

Williams & Wilkins, 1993:85-199. 11. Lee. J. A, Atkinson. R. S, Watt. M. J. Edt: Physiology of central neural blockade. In: Atkinson and Lee- Sir Robert Macintoshs Lumbar Puncture and Spinal Analgesia Intradural and extradural. 5thedition. New York: Churchill Livingstone, 1985:98-117. 12. McCrae A.F, Wildsmith J.A.W. Prevention and Treatment of Hypotension during Central Neural Block. British J. Anaesth. 1993; 70:672-680. 13. Liu S.S, McDonald S.B. Current Issues in Spinal Anesthesia.

Anesthesiology.2001; 94:5:888-907. 14. Rout C.C and Rocke D.A. Prevention of Hypotension Following Spinal Anesthesia for Cesarean Section. International Anesthesiology Clinics. 1994; 32:117-135. 15. Critchley L.A.H. Hypotension, Subarachnoid block and the elderly patient. Anaesthesia. 1996; 51, 1139-1143. 16. Margaret W. Local anesthetic agents. In: Wood M and Wood JJA Edt. Drugs and anesthesia. Pharmacology for Anaesthesiologist. 2nd ed, London: Williams and Wilkins. 319-345. 82

17. Morgan. E. G, Mikhail. S. M, Murray JM Edt: Local Anaesthetics. in: Clinical Anesthesiology. 3rd Ed. New Delhi: Lange Medical Book. McGraw Hill Medical Publishing Division. 2002:233-241. 18. Stoelting RK. Local anesthetics. In: Robert KS. Robert KS Ed. Pharmacology and physiology in anesthetic practice. 3rd ed. New York: Lippincott Raven 1999; 158-181. 19. Strichartz. G. R, Berde. C. B. Local Anesthetics. In: Miller. R.D Edt: Brown LD. Spinal, epidural and caudal anesthesia. In: Miller DR Edt. Millers Anesthesia. 6th ed. Philadelphia: Elsevier Churchill Livingstone. 2005; 573-603. 20. Reynolds. J. E. F. Edt: Sympathomimetics In: MARTINDALE, The Extra Pharmacopoeia. 30th ed, London: The Pharmaceutical press. 1993:1244-45. 21. www.medsafe.govt.NZ/prof/Datasheet/e/Ephedrine 21st Jan 2006. 22. Westfall. T. C and Westfall. D. P. Adrenergic agonists and antagonists. Hydrochloride tablets.

In: Burton. L.L, Lazo. J. s, Parker. K.L. Edt: Goodman and Gilmans. The Pharmacological Basis of Therapeutics. 11th ed. McGraw-Hill; New York; 2006, 237-295. 23. Hoffman. B. B. Adrenoceptor- Activity and other Sympathomimetic Drugs. In: Katzung. B. G. Edt: Basic and Clinical Pharmacology. 6th ed, Lange medical book; New York; 1995; 115-131. 24. Lee. J. A, Aitkinson. R. S, Watt. M. J. Edt: Pharmacology In: Atkinson and LeeSir Robert Macintoshs Lumbar Puncture and Spinal Analgesia Intradural and extradural. 5thedition. New York: Churchill Livingstone, 1985:119-150.

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25. Foex. P. Drugs acting on the cardiovascular system. In: Hialy. T. E. J, Knight.P.R Edt: Wylie and Churchill- Davidsons. A Practice of Anesthesia, 7th ed, London, Arnold Publications. 2003:145-166. 26. Aitkenhead RA, Rowbotham JD and Smith G Edt.Drugs acting on the Cardiovascular and autonomic nervous system. In: Text book of anesthesia. 4th ed, London: Churchill Livingstone. 2001; 65-100. 27. Jacobsohn.E. Ephedrine. In: Roizen.M. F, Fleisher. L.A. Edt: Essence of Anesthesia practice, Philadelphia, W.B. Saunders Company 1997:498. 28. Rout C.C, Rocke D.A, Gouws E. Leg elevation and wrapping in the prevention of hypotension following spinal anaesthesia for elective Caesarean section.

Anaesthesia. 1993; 48:304-308. 29. Morgan P. The role of Vasopressors in the management of hypotension induced by spinal and epidural anaesthesia. Can. J. Anaesth. 1994; 41:5:404-13. 30. Wouman.S. B, Marx. G. F. Acute hydration for prevention of hypotension of Spinal anesthesia in parturients. Anesthesiology 1967:29:374-380. 31. Butterworth J.F, Piccione W, Berrizbeitia L.D, Dance. G, Shemin. R. J and Cohn. L. H. Augmentation of Venous Return by Adrenergic Agonists during Spinal Anesthesia. Anesth Analg. 1986; 65:612-6. 32. Datta S, Alpher M.H, Ostheimer G.W, Weiss J.B. Method of Ephedrine Administration and Nausea and Hypotension during Spinal Anesthesia for Cesarean Section. Anesthesiology.1982; 56:68-70.

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33. Kang Y G, Abouleish E, Caritis S. Prophylactic Intravenous Ephedrine Infusion during Spinal Anesthesia for Cesarean Section. Anesth Analg. 1982; 61: 839-42. 34. Hemmingsen C, Poulsen J.A, Risbo.A. Prophylactic Ephedrine during Spinal Anaesthesia: Double-blinded study in patients in ASA Groups I-III.

British J. Anaesth.1989; 63:340-342. 35. Gajraj N.M, Victory R.A, Pace N.A, Van Elstraete. A. C and Wallace. D. H. Comparison of an Ephedrine infusion with Crystalloid Administration for Prevention of Hypotension during Spinal Anesthesia .Anesth Analg.1993; 76:1023-6. 36. Kafle S.K, Malla S.M, Lekhak B.D. Prophylactic Oral Ephedrine reduces the incidence of hypotension after subarachnoid block.

Can. J. Anaesth.1994; 41:11: 1091-3. 37. Critchley L.A.H, Stuart J.C, Conway.F, Short.T. G. Hypotension during Subarachnoid anaesthesia: Haemodynamic effects of Ephedrine.

British J. Anaesth. 1995; 74:373-378. 38. Sternlo J.E, Rettrup A, Sandin R. Prophylactic i.m. ephedrine in bupivacaine spinal anaesthesia. British J. Anaesth.1995; 74:517-520. 39. Chan W.S, Irwin M.G, Tong W.N, Lam. Y. H. Prevention of hypotension during spinal anaesthesia for Caesarean section: ephedrine infusion versus fluid preload. Anaesthesia.1997; 52:908-913. 40. Webb A.A, Shipton E.A. Re-evaluation of I.M. ephedrine as prophylaxis against hypotension associated with spinal anaesthesia for Caesarean section.

Can. J. Anaesth.1998; 45:4:367-69.

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41. Vercauteren M.P, Copejans H.C, Hoffmann V.H, Adriaensen.H. A. Prevention of Hypotension by Single 5-mg Dose of Ephedrine during Small-Dose Spinal Anesthesia in Prehydrated Cesarean Delivery Patients. Anesth Analg. 2000; 90:324-7. 42. Ngan Kee W.D, Khaw K.S, Lee B.B, Lau. T. K, Gin. T. A Dose-Response Study of Prophylactic Intravenous Ephedrine for the Prevention of Hypotension during Spinal Anesthesia for Cesarean Delivery. Anesth Analg.2000; 90:1390-5. 43. Loughrey J.P.R, Walsh F, Gardiner J. Prophylactic intravenous bolus ephedrine for elective Caesarean Section under spinal anaesthesia.

European J. Anaesthesiology.2002; 19:63-68. 44. Erogulu. F, Yavuz. L, Ceylan. B.C, Sevin. G, Soyupek. S. Prophylactic Effects of oral Ephedrine in Spinal Anesthesia-induced Hypotension during Transurethral

Prostatectomy. Scand. J. Urol Nephrol, 2003; 37, 145-150. 45. Loughery J.P.R, Yao N, Datta S. Hemodynamic effects of spinal anesthesia and simultaneous intravenous bolus of combined phenylephrine and ephedrine versus ephedrine for cesarean delivery.

International Journal of Obstetric Anesthesia. 2005; 14:43-47. 46. Carpenter R.L, Caplan R.A, Brown D.L and Rae Wu. Incidence and Risk Factors for side Effects of Spinal Anesthesia. Anesthesiology. 1992; 76:906-916. 47. Arndt J.O, Bomer W, Krauth J, Marquardt. B. Incidence and Time course of cardiovascular side effects during Spinal Anesthesia after Prophylactic administration of Intravenous Fluids or Vasoconstrictors. Anesth Analg. 1998; 87:347-54.

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48. Morgan P.J, Halpern S.H, Tarshis J. The Effects of an Increase of Central Blood Volume before Spinal Anesthesia for Cesarean Delivery: A Qualitative Systematic Review. Anesth Analg. 2001; 92:997-1005. 49. Murray A.M, Moragan M, Whitwam J.G. Crystalloid versus Colloid for circulatory preload for epidural Caesarean Section. Anaesthesia. 1989; 44:463-466. 50. Ngan Kee W.D, Khaw K.S, Lee B.B, Wong. M. M. S. Randomized controlled study of Colloid preload before spinal anaesthesia for Caesarean section.

British J. Anaesth. 2001; 87:772-4. 51. McHugh G.J. Anaphylactoid reaction to pentastarch.Can.J.Anaesth.1998; 45:3:270-2. 52. Caruso. J. L, Kirby. R.R. Fluid, Electrolytes, Blood, and Blood substitutes. In: Kirby. R. R, Gravenstein. N, Lobato. E. B, Gravenstein. J. S. Edt: Clinical Anaesthesia Practice, 2nd edition, Philadelphia, W.B.Saunders Company 2002; 770-789. 53. Mc Daniel. L. B, Prough. D. S. Fluid therapy during and after anaesthesia. In: Prys-Roberts. C and Brown Jr. B. R. Edt: International practice of Anaesthesia. Oxford, Butterworth- Heinemann 1996, Volume 1/ Chapter 47/ 1-17. 54. Coe. A.J, Revanas. U.B, Centrallaserettet. K. A. Is Crystalloid preloading useful in spinal anaesthesia in the elderly? Anaesthesia 1990; 45:241-243. 55. Rout C.C, Akoojee S.S, Rocke D.A, Gouws. E. Rapid Administration of Crystalloid Preload does not Decrease the Incidence of Hypotension after Spinal Anaesthesia for Elective Caesarean Section. British J. Anaesth. 1992; 68:394-397. 56. Jackson R, Reid J.A, Thorburn J. Volume preloading is not essential to prevent spinal-induced hypotension at Caesarean section .British J. Anaesth.1995;75:262-265. 87

57. Veyama. H, Yan-lung He, Tanigami. H, Mashimo. T. Effects of Crystalloid and colloid preload on blood volume in the parturient undergoing Spinal anesthesia for elective Cesarean Section. Anesthesiology 1999; 91:6:1571-76. 58. Pouta A.M, Karinen J, Vuolteenaho O.J. Effect of intravenous fluid preload on vasoactive peptide secretion during Caesarean Section under spinal anaesthesia. Anaesthesia. 1996; 51:128-132. 59. Buggy D. Higgins P, Moran C, OBrien. D McCarroll. M. Prevention of Spinal Anesthesia-Induced Hypotension in the Elderly: Comparison between Preanesthetic administration of Crystalloids, Colloids, and No Prehydration.

Anesth Analg. 1997; 84:106-10. 60. Ueyama. H, Yan-Ling. H, Hironobu. T, Mashimo. T, Yoshmya. I. Spinal Hypotension Associated with Cesarean section. Anesthesiology 1999; 91:6:1565-67. 61. Ayoride. B. T, Buczkowski. D, Brown. J, Shan. J, Buggy. D. T. Evaluation of preemptive Intramuscular Phenylephrine and Ephedrine for reduction of spinal anaesthesia induced hypotension during Caesarean section.

Br. J. Anaesth. 2001; 86:372-6. 62. Rolbin. S. H, Cole. A.F. D, Hew. E. M, Pollard. A, Virgint. S. Prophylactic Intramuscular Ephedrine before Epidural anaesthesia for Caesarean section; Efficacy and actions on the foetus and Newborn. Can. Anaesth. Soc. J. 1982; 29:2:148-153. 63. Rothenberg D.M, Parnass M.S, Litwack K. Efficacy of Ephedrine in the Prevention of Postoperative Nausea and Vomiting. Anesth Analg.1991; 72:58-61.

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PROFORMA
Name: Age: Ward: Anaesthesiologist: Diagnosis: Surgery Performed: IP No. Sex: M / F ASA Grade: I / II Surgeon:

General Physical Examination Height: Built & Nourishment: Weight: Heart Rate: BP:

Pallor/Icterus/Cyanosis/Clubbing/Edema

Systemic Examination Cardiovascular System: Central Nervous System: Respiratory System: Gastrointestinal System: Investigations Hb%: Differential Leukocyte count: Blood Grouping: HIV (ELISA): Total Leukocyte Count: Urine routine: B.T & C.T: Hb-S Ag:

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If Patient above 40years: Blood Urea: Serum Creatinine: ECG:

Blood Sugars (if urine sugars positive):

Pre-Medication: Tab. Ranitidine 150mg 1 H.S Tab. Diazepam 10mg 1 H.S Night before surgery for Both the Groups

Group A. Tab Ranitidine 150mg 2hours before surgery. Tab. Ephedrine 30mg with sip of water 30minutes before SAB. Group B. Tab Ranitidine 150mg 2hours before surgery. Placebo with sip of water 30minutes before SAB. Baseline Values: Heart rate: Respiratory rate: Regional Anaesthesia: Procedure: SAB Posture: Lateral position Right / Left Site of Injection: L3-L4 intervertebral space. Drug: Inj. Bupivacaine heavy 3ml. Level of Blockade: SBP: Spo2: DBP: MAP:

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Parameters Recorded:

Time At SAB 2 min 4 min 6 min 8 min 10 min 20 min 30 min 40 min 50 min 60 min 75 min 90 min

SBP

DBP

MAP

HR

RR

Spo2

Drugs used

Side Effects

I.V. Fluids used: IF BP falls > 20% baseline (1) Head low: (3) Total Inj. Ephedrine Dose Used: (2) Increase I.V. Fluids:

91

92

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A RANDOMISED CLINICAL TRIAL OF COMPARISON BETWEEN PROPHYLACTIC ORAL EPHEDRINE AND CONTROL (WITHOUT ORAL EPHEDRINE) IN REDUCING THE INCIDENCE OF HYPOTENSION FOLLOWING SUBARACHNOID BLOCK

By

Dr. RAGHAVENDRA.R., M.B.B.S.


Dissertation Submitted to the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore In partial fulfillment of the requirements for the degree of

M.D. DEGREE IN ANAESTHESIOLOGY


Under the guidance of

Dr. PREMKUMAR.B., D.A, M.D.


Professor, Department of Anaesthesiology

DEPARTMENT OF ANAESTHESIOLOGY

SREE SIDDHARTHA MEDICAL COLLEGE


TUMKUR SEPTEMBER 2006

DECLARATION BY THE CANDIDATE


I hereby declare that this dissertation/thesis entitled A randomized clinical trial of comparison between prophylactic oral Ephedrine and control (without oral ephedrine) in reducing the incidence of hypotension following subarachnoid block is a bonafide and genuine research work carried out by me under the guidance of Dr. Prem Kumar. B.

Date: Place: Tumkur Dr.RAGHAVENDRA.R. Postgraduate in Anaesthesiology, Sree Siddhartha Medical College, Tumkur

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CERTIFICATE BY THE GUIDE

This is to certify that this dissertation entitled A randomized clinical trial of comparison between prophylactic oral Ephedrine and control (without oral ephedrine) in reducing the incidence of hypotension following subarachnoid block is a bonafide research work done by

Dr.RAGHAVENDRA.R. in partial fulfillment of requirement for the degree of Master of Medicine in Anaesthesiology.

Date: Place: Tumkur Dr.PREMKUMAR.B. , DA, MD. Professor, Dept. of Anaesthesiology Sree Siddhartha Medical College, Tumkur

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ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE INSTITUTION


This is to certify that the dissertation entitled A randomized clinical trial of comparison between prophylactic oral Ephedrine and control (without oral ephedrine) in reducing the incidence of hypotension following subarachnoid block is a bonafide research work done by

Dr.RAGHAVENDRA.R. under the guidance of Dr.PREMKUMAR.B.

Seal & Signature of the HOD Name Date:

Seal & Signature of the Principal Name Date:

Place:

Place:

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COPYRIGHT
Declaration by the Candidate

I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka shall have the rights to preserve, use and disseminate this dissertation in print or electronic format for academic / research purpose.

Date: Place: Dr. RAGHAVENDRA.R. Postgraduate in Anaesthesiology Sree Siddhartha Medical College, Tumkur.

Rajiv Gandhi University of Health Sciences, Karnataka

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ACKNOWLEDGEMENT
It is my distinct honor and privilege to have worked under the able guidance, continuous supervision and constant encouragement of Dr. Prem Kumar .B Professor, Department of Anaesthesiology, has made this study possible. It gives me immense pleasure to extend my sincere thanks to

Dr. Manjarekar. R.P. Professor and HOD, department of Anaesthesiology, for his continuous supervision and timely advices. I indeed consider myself very fortunate to get the benefit of the vast experience and valuable guidance of Dr. D.B. Suryanarayana Rao, former Professor and head, department of Anaesthesiology, without his help it could not have been possible to complete this dissertation. I am deeply indebted to Dr. Shivaleela. H., Assistant Professor for her constant guidance and encouragement throughout the study. It gives me immense pleasure to extend my sincere thanks to my Professors Dr. Gangadhar, Dr. Brinda, for their encouragement and help throughout the study. I am thankful to Dr. Paramesh. S and Dr. Ramesh., Asst. Professor, for their timely advice given to me during the course of my post-graduation. My sincere thanks to Dr. Shashikala, Senior Anaesthesiologist, District hospital for her constant help throughout the study. I am thankful to Dr. Ramesh. S, Dr. Manjunath, and Dr. Raja, Lecturers, for their continuous support and professional insight which led me to be an organized person. I express my sincere thanks to Dr.A.G.Srinivasa Murthy, M.D., General Medicine, Principal, Sree Siddhartha Medical College Hospital and Research Centre,

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Tumkur and Dr. Shivaprasad, Hon`ble Director, Sree Siddhartha Medical College for permitting me to carry out this study. Special thanks to Dr. Sridhar Rao for his guidance in Statistical analysis of this study and Mr. Venugopal. V., in helping me to compile the manuscript. I am thankful to my fellow post-graduate colleagues and friends for their co-operation and help during the period of this study. I am extremely thankful to all my patients without whom this dissertation would have never materialized. Lastly I owe my gratitude to my parents, brother and well wishers for their help, encouragement and moral support during my study.

Date: Place: Tumkur Dr.Raghavendra.R

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LIST OF ABBREVIATIONS USED (In Alphabetical order) ASA B. T. Cm CNS CSF C. T. CVS Hb% Hb-sAg HR Inj. I.M. I.V. Kg. L. & T. lts lt/min MAO MAP Mg American Society of Anesthesiologists. Bleeding Time. Centimeter. Central Nervous System. Cerebrospinal Fluid. Clotting Time. Cardiovascular System. Haemoglobin Percent. Hepatitis B Surface Antigen. Heart rate. Injection. Intramuscular. Intravenous. Kilograms. Larsen and Turbo Liters. Litres per minute. Monoamine Oxidase. Mean Arterial Pressure. Milligrams.
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Mg/l milliEq/l ml mmhg mMol/l g/ml Po SAB SBP S.D. Spo2

Milligram per litre. Milliequivivalent per liter. Milliliters. Millimeter of mercury. millimoles per litre. Micrograms per millilitre. Per orally. Subarachnoid Block. Systolic Blood Pressure. Standard Deviation. Saturation of Oxygen.

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ABSTRACT
Background: Spinal anaesthesia enjoys being the most popular anaesthetic technique for elective surgical procedures involving the lower abdomen or lower limbs as it provides rapid, reliable and profound symmetrical sensory and motor block. However, despite crystalloid or colloid preloading, hypotension remains a common complication. Vasopressors are required to treat the spinal induced hypotension among most of these patients. Studies involving prophylactic Ephedrine as an intravenous infusion, bolus or intramuscular routes are in plenty but studies pertaining to prophylactic Oral administration are sparse. Objectives: This study was conducted to evaluate the safety and efficacy of prophylactic oral Ephedrine (30mg given 30minutes before spinal anaesthesia) in preventing spinal anaesthesia induced hypotension. Method: This is a prospective randomized comparative study conducted at the Department of Anaesthesia, Sree Siddhartha Medical College, Tumkur. Hundred

patients aged between 20 to 60 years belonging to ASA grade I/II, scheduled for lower limb and lower abdominal surgeries were randomly allocated into one of the two groups. Group A (n=50) received prophylactic Oral Ephedrine 30mg 30minute before spinal anaesthesia were as Group B (n=50) received a placebo 30minutes before spinal anaesthesia. Results: The study showed no significant changes in respiratory rate and oxygen saturation levels in any of the patients in both the groups. The incidence of hypotension is 8% and 40% in Group A and Group B patients respectively, and hypotension developed within the first 20minutes after intrathecal block. In our study

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18% of patients in Group B required vasopressor supplementation intraoperatively and none in Group A. There was a steady rise in the heart rate of Group B patients from 4th minute onwards when compared with Group A patients. The incidence of nausea and vomiting was 16% in Group B and 2% in Group A.

Conclusion: This study demonstrates that prophylactic Oral Ephedrine 30mg when given 30minutes before spinal anaesthesia is a simple, easy, economical, effective and a reliable method in reducing the incidence of spinal induced hypotension without any deleterious effects.

Keywords Oral Ephedrine; Subarachnoid Block; Bupivacaine; Hypotension.

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TABLE OF CONTENTS

Sl. Particulars No. 1. 2. INTRODUCTION AIMS AND OBJECTIVES REVIEW OF LITERATURE History Anatomy 3. Physiology Pharmacology Review of clinical studies 4. 5. 6. 7. 8. 9. MATERIALS AND METHODS RESULTS AND ANALYSIS DISCUSSION SUMMARY CONCLUSION BIBLIOGRAPHY ANNEXURES 89 10. Proforma 92 Master Chart 16 21 35 47 53 70 78 80 81 4 6 1 3 Pages

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LIST OF TABLES

Sl. Tables No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Concentration and doses of Bupivacaine Age distribution of the two groups of patients Sex distribution of the two groups of patients Height distribution of the two groups of patients Weight distribution of the two groups of patients Statistical comparison of age, height and weight of the two groups of patients Type of surgery carried out on the two groups of patients The cluster-wise distribution of surgeries in the two groups of patients Level of anaesthesia in the two groups of patients Baseline systolic blood pressure in the two groups of patients Baseline diastolic blood pressure in the two groups of patients Baseline mean arterial pressure in the two groups of patients Baseline heart rate in the two groups of patients Statistical comparison of SBP (mmHg) in the two groups Statistical comparison of DBP (mmHg) in the two groups Statistical comparison of MAP (mmHg) in the two groups Statistical comparison of HR (beats/minute) in the two groups Comparison of SBP at baseline with SBP at SAB, at 8 minutes and at 60 minutes Comparison of DBP at baseline with DBP at SAB, at 8 minutes and at 60 minutes Comparison of heart rate at baseline with heart rate at SAB, at 8 minutes and at 60 minutes 24 53 53 54 55 55 56 57 58 58 59 59 60 62 63 64 65 66 66 67 Pages

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LIST OF FIGURES

Sl. Figures No. 1 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Vertebral Column Features of vertebra Saggital section through lumbar vertebra Spinal Cord Exit of spinal nerves Production, Circulation, and Resorption of Cerebrospinal fluid Chemical structure of bupivacaine Chemical Structure of Ephedrine Ephedrine Tablets Intravenous Ephedrine with Essential drugs Spinal Puncture Being Performed. C.S.F Flow through Spinal Needle. 6 7 9 10 11 14 22 29 50 50 51 51 Pages

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LIST OF GRAPHS

Sl. Graphs No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Age distribution of Patients Sex distribution of Patients Height distribution of Patients Weight distribution of patients Graphical representation of types of surgery. Level of Spinal Anaesthesia. The SBP and DBP of patients in Group A at different time Intervals The SBP and DBP of group B patients at different time Intervals. The SBP of the two groups of patients at different time intervals The DBP of the two groups of patients at different time intervals The MAP of the two groups of patients at different time intervals The HR of the two groups of patients at different time intervals Time of onset of hypotension in 20 cases of group B First protracted cases of hypotension Second protracted case of hypotension. 53 54 54 55 57 58 60 61 62 63 64 65 68 69 69 Pages

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INTRODUCTION
Spinal anaesthesia was introduced into clinical practice by August Bier in 1898 even before the break-through of orotracheal intubation by Franz Kuhn in 1901. The only anaesthetic techniques to precede it were topical anaesthesia of the eye by Carl Koller and infiltration anaesthesia by Carl-Ludwig Schleich in 1892 1. Spinal anaesthesia has enjoyed a long history of success and recently celebrated a centennial anniversary.

Regional techniques are the preferred Anaesthetic procedure for surgeries involving abdomen and lower extremities. The various advantages include 2: 1. Blunting of stress response to surgery 2. Avoidance of intubation 3. Decrease in intraoperative blood loss 4. Earlier return of gastrointestinal function 5. Lower incidence of postoperative throboembolic events.

The unavoidable sequence of spinal anaesthesia is blockade of sympathetic preganglionic efferents leading to peripheral venous pooling causing hypotension. Therapies are primarily aimed at reducing the severity of hypotension, they include prophylactic leg elevation and wrapping, use of inflatable boots, preloading of the patient with crystalloids and colloids, lateral uterine displacement in Obstetric patients, and vasopressors used as last resort with varying results.

Ephedrine the most commonly used among vasopressors to treat spinal induced hypotension
2, 3

. Studies in relation to prophylactic parenteral Ephedrine have been

described earlier in plenty compared to oral Ephedrine studies which are sparse. So this prospective randomized study is performed to determine the efficacy of prophylactic oral Ephedrine in preventing spinal hypotension following subarachnoid block in our patient group.

AIMS OF STUDY

To determine the safety and efficacy of prophylactic oral Ephedrine in reducing the incidence of hypotension following subarachnoid block.

REVIEW OF LITERATURE
HISTORY OF SPINAL ANAESTHESIA 3, 4, 5. The concept of local analgesia began with demonstration of anaesthetic properties of cocaine eye drops by Koller in 1884 and neural blockade by Halsted in 1885. The term Spinal anaesthesia was introduced by Corning in1885. Corning with the aim of injecting Cocaine between the spinal processes for means of managing neurologic disorders instead accidentally injected it epidurally in 1885. The present day spinal anaesthesia and technique of lumbar puncture was described by Quincke in 1891. The first two publications on spinal anaesthesia for surgical procedures were made in 1899 by Bier in the first paper later on by Tuffier. Bier had used it for surgeries on the lower limbs and Tuffier to relieve pain of sarcoma of the leg in a young man. Kries in 1900 used spinal analgesia for caesarean section, during the same year W.S.Bainbridge reported his first successful case of paediatric spinal analgesia. Dowitz in 1903 added adrenaline to prolong the anaesthetic effect, substitutes to cocaine emerged due to its toxic effects with Procaine (Novocaine) by Einhorn and Stovaine by Fourneau in 1905. Next series of studies were aimed at achieving higher levels of spinal blockade, formulation of alcohol mixture with local anaesthetic to make it lighter than cerebrospinal fluid.

Labat in 1922 used Babotage; Pitkin introduced Spinocaine (hypobaric) or Gravicaine (hyperbaric) in 1927. High levels of spinal anaesthesia caused hypotension which lead to introduction of Ephedrine to combat it in 1927 by Ockerbland and Dillon, the active principle of the herb Ma huang, known to Chinese medicine for millennia. Ephedrine was isolated in pure form and named by Nagaun in 1887, later introduced into western medicine by Chenn and Carl .F.Schmidt. Lignocaine synthesized by Lofgren of A B Astra, Sweden in 1943 and used in clinical practice in 1948. Bupivacaine was synthesized by A.F.Ekenstein in 1957 used for regional blocks in 1966.

ANATOMY 3, 6, 7, 8

Corning stated in 1900 that I advise those who contemplate practicing spinal anaesthesia to take a look at the skeleton especially the relations of the lumbar vertebrae. An intelligent glance of this sort is worth many words4. The keystone for a successful spinal anaesthesia lies in the detailed knowledge of the anatomy of the vertebral column and its contents. VERTEBRAL COLUMN The vertebral column comprising of 33 vertebrae (7 cervical, 12 thoracic, 5 lumbar, 5 fused sacral and 4 coccygeal) interspaced by 23 intervertebral discs.

Fig.1 Vertebral Column, Lateral (left) and Posterior (right) views, illustrating curvatures and interlaminar spaces4. 6

There are two primary curves thoracic and sacral are convex posteriorly and are present since birth. The two secondary curves cervical and lumbar are convex anteriorly develop after birth due to the differential growth of intervertebral discs. The curves of vertebral column have a significant influence on spread of the local anaesthetic solution injected in turn which determines the level of spinal blockade. Lumbar vertebrae Upper four lumbar vertebrae are typical and bear common features. The fifth lumbar vertebra is atypical. Lumbar vertebrae identified by its large size and by absence of costal facets on the body. Typical lumbar vertebrae is formed by

Fig.2 Features of vertebra8. (a) Large kidney shaped body. (b) The vertebral foramen triangular in shape, larger than in thoracic but smaller compared to cervical region. (c) Two pedicles, directed backwards from the upper part of the body.

(d) The laminae directed backwards and medially to complete the vertebral foramen posteriorly. (e) Spinous process is thick, broad, quadrilateral in shape and directed backwards. (f) Two transverse processes are thin and tapering. (g) Two upper and two lower articular processes which prevent rotation but allows limited flexion and extension When the spine is fully flexed the cervical and lumbar curves are obliterated, in supine position the 3rd lumbar vertebrae marks the highest point of the lumbar curve, whereas the 5th thoracic is the lowest point of the dorsal curve. Thus hyperbaric solutions deposited at the third lumbar vertebrae will flow away, both cranially and caudally from it. The direction of spinous processes determines the direction in which the spinal needle should be inserted. Intervertebral Disc They form one fourth the length of vertebral column, thickest at cervical and lumbar regions. They are made up of outer collagenous annulus fibrous and inner gelatinous mucoidal mass nucleus pulposes. They mainly act as shock absorbers ensuring even distribution of compressive force and impart flexibility to the vertebral column. THE VERTEBRAL CANAL Bounded in front by bodies of the vertebrae and intervertebral discs, posteriorly by the laminae, ligamenta flava and the arch, which bears spinous process and interspinous ligament, laterally by the pedicles and laminae, size and shape vary being larger at cervical and lumbar region.

The Vertebral Ligaments

Fig.3

Saggital section through lumbar vertebra6

The vertebrae are held together by a series of overlapping ligaments, which not only bind together the vertebral column but assist in protecting the spinal cord. (a)The Anterior longitudinal ligament which runs along the front of vertebral bodies is a strong band being attached to the occiput and the anterior tubercle of the atlas above and to the front of the sacrum below. (b) The posterior longitudinal ligament is attached to the posterior border of the body of the axis above and to the sacrum below. It extends within the vertebral canal on posterior surfaces of the bodies of vertebraes. (c)The ligamentum flavum connects the laminae of the adjacent vertebra and extends from the region of the articular capsules of the intervertebral joints to cover the area of the spine. It consists of a tough, yellow, elastic tissue, which is thickest and displays the greatest degree of recoil in the lumbar region.

(d)The interspinous ligament connects the adjoining spines and extends from the root to the apex of each process. (e)The Supra spinous ligament connects the apices of spinous processes. They extend from the seventh cervical vertebra to the sacrum. The ligamentum nuchae extends from the occipital protrubence and occipital crest above to the spinous process of seventh cervical vertebrae. THE SPINAL CORD

Fig. 4 Spinal Cord 9

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The spinal cord is the lower elongated, cylindrical part of Central nervous system. It occupies the upper two thirds of the vertebral canal. It is about 42- 45cm long. It extends from the level of the upper border of the atlas to the lower border of the first lumbar vertebra or upper border of the second lumbar vertebra. The lower border of the spinal cord is conical and is called the Conus medullaris. The apex of the conus is continued down as the filum terminale.

Fig.5 Exit of spinal nerves 6. The 31 spinal nerves emerge from the spinal cord in pairs-8cervical, 12 thoracic, 5 lumbar, 5 sacral and one pair of coccygeal nerves. The spinal nerves are comprised of anterior and posterior roots that unite in the intervertebral foramina to form the spinal nerve trunks. At the cervical level the nerves arise above their respective vertebra, but starting at first thoracic vertebra they exit below their vertebra. At the cervical and upper thoracic levels the roots emerge from the spinal cords and exit the vertebral foramina nearly at the same level. As the spinal cord normally ends at the first lumbar vertebra, lower nerve roots must travel an increasing distance (within the lumbar and sacral

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subarachnoid and epidural spaces) from the spinal cord to the intervertebral foramina. These lower spinal nerves form the caudaequina. Hence performing a lumbar (subarachnoid) puncture below the first lumbar vertebra in an adult avoids needle trauma to the cord. THE SPINAL MENINGES The spinal cord is ensheathed by three membranes or meninges. (a)Duramater The duramater which ensheaths the spinal cord consists of two layers, the inner meningeal layer is the continuation of the cerebral dura made up of dense fibrous tissue, the outer endosteal layer is the periosteal lining the vertebral canal. In between the two is the potential extradural space. The extradural space extends from foramen magnum above to second sacral vertebrae below. Dural fibers run longitudinally, thus it is important to direct the spinal needle bevel, so as to split these fibers rather than cut them, thus decreasing the incidence of postspinal headache. (b)Arachnoid mater It is closely adherent to the dura mater. The space between the dura and the arachnoid is the subdural space. It is a potential space containing some amount of serous fluid. (c)Piamater: This is a thin vascular membrane closely investing the spinal cord. Cerebro Spinal Fluid (CSF) is contained between the pia and the arachnoid mater in the subarachnoid space. The spinal subarachnoid space is a poorly demarcated.

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BLOOD SUPPLY TO SPINAL CORD The blood supply to the spinal cord and nerve roots is derived from the single anterior spinal artery and paired posterior spinal arteries. The anterior spinal artery arises from the vertebral artery and supplies the anterior two thirds of the cord. The anterior and posterior spinal arteries do not anastomose, thrombosis of this anterior artery causes Anterior spinal artery syndrome in which there is motor paralysis sparing the posterior columns (joint position, touch and vibration sense). The posterior spinal arteries arise from the posterio inferior cerebellar arteries and supply the posterior one thirds of the cord. The spinal veins comprise of anterior and posterior plexus, which drain through the intervertebral foramina into vertebral, azygos and lumbar veins. THE SUBARACHNOID SPACE This is the space lying between the arachnoid and pia mater. It consists of the spinal nerve roots, denticulate ligaments, cerebrospinal fluid, and spongy reticulum of fibers connecting the pia with the arachnoid mater. The nerve roots within the dura have no epineural sheaths and are therefore easily affected by analgesic drugs. The posterior aspect of the arachnoid and dura have no nerve supply. So there is no pain experienced on dural puncture.

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THE CEREBROSPINAL FLUID (CSF) Cerebrospinal fluid is a modified tissue fluid present in the cerebral ventricles, spinal cord and subarachnoid spaces.

Fig.6 Production, Circulation, and Resorption of Cerebrospinal fluid 3. It is produced by choroid plexus in the lateral, third and fourth ventricles by a combination of filtration and secretion, and later absorbed in arachnoid granulations over the cerebral hemispheres. In adults the normal total CSF production is about 21 ml /hr

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(500 ml /day),about 130 to 150 ml is present at all times of which 25-35 ml is present in the vertebral canal. The normal CSF pressure measured with the patient lying in lateral position is 7 15 cm of water. COMPOSITION OF CSF Specific gravity: 1.005(1.003- 1.007) at 37degree Centigrade. pH: 7.33 Volume: 120-140 ml Glucose (Fasting): 2.5 4.5 mMOl/L Sodium: 144-152 miliEq/L Calcium: 1.1-1.3 miliEq/L Chloride: 123-128 miliEq/L Bicarbonate: 24-32 miliEq/L Proteins: 200-400 mg/l Urea: 2.0-7.0 miliMOL/L Osmolality: 289 miliMOL/kg of H2O FUNCTIONS OF CSF 1. It acts as a buffer separating the brain and the spinal cord from the hard bony skull and the vertebral canal. 2. Nutrition and oxygen supply to the nerve cells to some extent. 3. Drainage of metabolites. 4. pH changes in CSF, regulates pulmonary ventilation. 5. Reduces effective weight of the brain.

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PHYSIOLOGY OF SPINAL HYPOTENTION 10, 11


Understanding the mechanisms involved in control of arterial pressure in a normal individual and the pathophysiology of hypotension during spinal anaesthesia is the key to safe and appropriate management of the patients.

Control of Arterial Pressure 12: Arterial pressure: is the product of cardiac output and systemic vascular resistance and both these variables are influenced by many other factors. Cardiac output: is determined by venous return according to Frank Starling law. Venous return is influenced by gravity, the calf muscle pump, intrathoracic pressure and the degree of venomotor tone; this is matched to the circulating blood volume. Systemic Vascular Resistance: is determined by sympathetic vasomotor tone and by the influence of hormones such as rennin, angiotensin, aldosterone and antidiuretic hormone. The vasomotor centre in the brain stem controls the degree of sympathetic tone in a feedback loop involving the baroreceptors. Organ Perfusion There are two main mechanisms which control autoregulation and perfusion they are: Myogenic autoregulation: acts via stretch receptors in the vessel walls which cause them to constrict when pressure is decreased. Chemical autoregulation: is mediated by the local concentration of vasoactive metabolites. In the presence of vasodilatation, as produced by sympathetic block, an increase in flow washes out the metabolites and produces reflex vasoconstriction.

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Although it is arterial pressure that we measure and adjust, it is important to remember that organ flow is the vital factor. Compensatory mechanisms mentioned before ensure that the flow to vital organs is maintained over a wide range of pressures. Cerebral blood flow: Autoregulation occurs between 50 to 180mm Hg mean arterial pressure. Since these vessels are devoid of sympathetic nerve supply they autoregulate by myogenic mechanism. The stimulation of vasomotor centre leads to increase sympathetic tone and systemic vascular resistance in an attempt to restore arterial pressure. Coronary blood flow: It is mainly mediated by chemical autoregulation between 60 to 150 mm Hg mean arterial pressure. As the cardia becomes hypoxic, adenosine diphosphate gets accumulated. This gets converted to adenosine, a potent coronary vasodilator, restoring the local blood flow. Renal autoregulation: occurs between 60 to 160mm of Hg mean arterial pressure. The afferent glomerular arteriole has a myogenic response to stretch and constricts with hypertension and dilates with hypotension.

Physiology of Central Neural Blockade. The physiological response to intradural blockade results from autonomic blockade with its major effects on both the vascular beds and cardiac action; from abolition of somatic pain and its reflex mediated response, and blockade of motor fibers. Order of blockade of nerve fibers 5: First to be blocked is autonomic pre ganglionic nerve fibers (B fibers). Second to be blocked are temperature and pain fibers (A and C fibers). Third to be blocked pinprick fibers.

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Fourth to be blocked fibers conveying pain greater than pinprick. Fifth to be blocked touch fibers (A fibers). Sixth to be blocked deep pressure fibers. Seventh to be blocked somatic motor fibers. Eight to be blocked, fibers conveying vibratory sense and proprioception impulses (A fibers). During recovery, return of sensitivity in the reverse order was assumed, but it has

been suggested that sympathetic activity returns before other sensation

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. The most

important physiologic response to spinal anaesthesia involves the cardiovascular system; they include hypotension and bradycardia 13. Primary Mechanisms of Hypotension are 14: (a) Sympathetic preganglionic denervation leading to peripheral venous pooling and decreased venous return. (b) Vasodilatation of arterioles and post arteriolar capillaries (c) Catecholamine depletion due to sympathetic denervation to adrenal medulla (T8 to L1). (d) Splenic venous pooling. (e) Compression of great vessels within abdomen due to muscular paralysis, which is exaggerated by pregnant uterus and abdominal tumors. (f) High blocks lead to sympathetic nerve block to the cardia (T1-T4) leads to decreased contractility.

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Opposing Factors Affecting Heart Rate are 13, 15 I. The decrease in systolic arterial pressure which causes a baroreceptor reflex and an increase in heart rate II. Changes in the preload causing volume receptor reflexes which alter heart rate III. Vagal responses which reduce heart rate. IV. Sympathetic block of Cardio-acceleratory nerves causing a reduction in heart rate. V. The central effect of reduced sensory input to the cortex resulting from subarachnoid block which reduces heart rate. VI. The specific actions on heart rate of the different treatments used in the prevention and treatment of hypotension.

The major factor in the development of hypotension is the level of blockade of sympathetic outflow tract, which is between T1 to L2.Sympathetic preganglionic efferent blockade which extends 2 to 6 dermatomes cephalad to sensory block leads to venous and arteriolar dilation, among which venodilation predominates; this is because of limited amount of smooth muscle in venules and large amount of blood in venous capacitance (approximately 75% of total blood volume). The body senses this fall by the baroreceptors present in carotid sinus and aortic arch and tries to compensate by tachycardia (Mareys law). If the sympathetic blockade extends above fifth thoracic vertebrae level it becomes progressively difficult to compensate as the cardio accelerator fibers arising from T1 to T4 are also blocked. Additionally the heart rate may further decrease as a

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result of fall in right atrial filling. Hypotension usually occurs in the first 10-15 minutes following spinal anaesthesia. Fall in blood pressure is more marked in higher levels of block, geriatric group, pregnancy, hypertensive and hypovolumic states.

Prevention of Hypotension 12: (a) 10 -15 degree lateral tilt or wedge placement under the right buttock in case of supine hypotension syndrome. (b) Adequate preloading with crystalloids (15-20 ml/kg) or colloids (5-7ml/kg). (c) Prophylactic administration of parenteral vasopressors.

Treatment of Hypotension 12: (a) Oxygenation of the patient. (b) Foot end elevation, which should be <20, since extreme trendlenburg leads to increase of internal jugular venous pressure diminishing cerebral perfusion pressure. (c) Rapid infusion of intravenous fluids. (d) Injection of vasopressor with predominant effect on venoconstrictive properties without major undesirable effects on the ratio between myocardial supply and demand. Eg: Ephedrine, Mephentermine. (e) Injection Atropine if bradycardia predominates.

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PHARMACOLOGY
Local anesthetic drugs Local anesthetics are drugs that produce reversible depression of nerve conduction when applied to nerve fiber 16. Local anesthetics consist of a liphophilic group; usually a benzene ring- separated from the hydrophilic group usually a tertiary amine by an intermediate chain that includes an ester or amide linkage. BUPIVACAINE 16, 17, 18: Bupivacaine has probably had the greatest influence on the practice of regional anaesthesia due to the combined properties of an acceptable onset, long duration of action, profound conduction blockade, and significant separation of sensory to motor block. It was synthesized by Ekenstein in 1957 and used in clinical practice by Widman and Telino in 1963. Chemistry: Bupivacaine is 1-n-butyl-DL-piperidine-2-carboxylicacid-2, 6 dimethylanilide hydrochloride. Bupivacaine is a homologie of mepivacaine with molecular formulae of C18 .N2O.H28.Hcl, differing only in a butyl group substituted for a methyl group on the piperidine nitrogen.

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Chemical structure:

Fig.7 Chemical structure of bupivacaine 17. Physiochemical Properties: The base is sparingly soluble, but the hydrochloride salt is readily soluble in water. Bupivacaine is highly stable and can withstand repeated autoclaving. Mechanism of Action: The primary action of local anesthetics is on the cell membrane of the axon. The large transient increase in the permeability to sodium ions, necessary for propagation of impulses is prevented. Thus the resting membrane potential is maintained and depolarization in response to stimulation is inhibited. The mechanism by which local anesthetics block sodium conductance is as follows: (a) Local anesthetics in the cationic form act on the receptors within the sodium channels, on the cell membrane and block it. The local anesthetics can reach the sodium channels either via the lipophilic pathways directly across the lipid membrane or via the axoplasmic opening. The mechanism accounts for 90% of nerve blocking effects of amide local anesthetics. (b) The second mechanism of action is by membrane expansion. This is a nonspecific drug receptor interaction

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Anaesthetic Properties: (a) Potency: Bupivacaine is approximately three to four times more potent than Lidocaine or Mepivacaine and eight times more than Procaine. It appears to have a slow nerve penetrating power leading to slow onset, more prolonged duration of sensory anaesthesia due to its lipid solubility and protein binding properties. Muscle relaxation is not profound with 0.5% as seen with Lidocaine. (b) pKa: is 8.2. (c) pH of saturated solution is 5.2 (d) Anaesthetic Index: It is defined as ratio between potency/toxicity of a local anaesthetic drug. It is 3.0 to 4.0 for Bupivacaine. Pharmacodynamics: Onset of action is between 3 to 4 minutes and complete spinal anaesthesia ensues by 6 to 8 minutes. The duration of spinal anaesthesia varies from 75 to 150 minutes. Pharmacokinetics: Plasma levels of the drug depend on the route, concentration and the total dose administered. The amount of drug absorbed is minimal when administered through subarachnoid route, plasma bupivacaine concentrations within 1 to 2 hours after administration is 1 to 2g/ml. Bupivacaine is distributed throughout all body tissues. T of bupivacaine is 2-7 minutes. T is 28minutes, T is 3-5hrs. Volume of distribution is 72 lts; clearance is 0.47lt/min. The more highly perfused organs show a higher concentration of the drug. The blood concentration of the drug decreases markedly as it passes through the pulmonary vasculature. 23

Plasma Binding: About 90to 95% of the drug is bound to protein, unbound drug is about 1/7 that of Lidocaine and 1/5 that of Mepivacaine. Metabolism and Elimination: Bupivacaine is an amide; liver is the primary site of metabolism. It is metabolized by N-dealkylation and the metabolite, pipecolyloxylidine is excreted in the urine. About 10% of the drug is excreted unchanged in the urine and the remaining is conjugated with glucuronide and excreted Dose: Suggested maximum safe dose of Bupivacaine in a 70kg adult with adrenaline is 5mg that is 2.5 to 3.0mg/kg and without adrenaline 175mg that is 2 to 2.5mg/kg body weight. Type of block Local infiltration Minor nerve block Major nerve block Epidural Spinal 0.75 2-3 15-22.5 Table I. Concentration and doses of Bupivacaine 19. Concentration (In percent %) 0.25-0.5 0.25 0.25-0.5 0.25-0.75 0.5 Dose (in ml) 25-30 5-20 30-50 15-30 3-4 Dose (in mg) 2 12.5-50 400 37.5-225 15-20

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Actions on different systems: a) Central nervous system: An overdose of bupivacaine produces light-headedness and dizziness followed by visual and auditory disturbances such as difficult to focus and tinnitus. Disorientation and drowsiness can also occur. Shivering, tremors of muscles of face and distal part of the extremities can occur. Ultimately generalized convulsions of tonic-clonic nature can occur. Further increase in dose causes respiratory arrest. b) Cardio vascular system: Electrophysiological studies on the effect of local anesthetic have demonstrated that bupivacaine is associated with more pronounced depolarization changes. Bupivacaine blocks cardiac sodium channels and alters mitochondrial function. Its high degree of protein binding makes resuscitation prolonged and difficult. Bupivacaine is highly arrythmogenic. This drug reduces the cardiac contractility. This is done by blocking the calcium transport. Low concentration of bupivacaine produces vasoconstriction while high doses cause vasodilatation. c) Autonomous nervous system: Myelinated preganglionic beta fibers are more sensitive to the action of local anesthetic including bupivacaine. Involvement of preganglionic sympathetic fibers is the cause of widespread vasodilatation and subsequent hypotension that occurs in epidural and paravertebral block. When used for conduction blockade, all local anesthetics particularly bupivacaine produce higher incidence of sensory than motor block.

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d) Respiratory system: Respiratory depression may be caused if excessive plasma level is reached which in turn results in depression of medullary respiratory centers. Respiratory depression may also be caused by paralysis of respiratory muscles as may occur in high spinal or total spinal anesthesia.

e) Neuro-muscular junction: Local anesthetics can affect transmission at neuro-muscular junction and block motor nerve fibers if present in sufficient concentration. TOXICITY: Local anesthetics are relatively safe if administered in appropriate dosage in the correct anatomical location. However accidental intravascular, intrathecal injection or administration of excessive doses results in toxicity. In humans bupivacaine is about 4-5 times more toxic than lidocaine and they manifest by their effects on the CNS and CVS. The CNS effects are characterized by excitation or depression. The first manifestation may be nervousness, dizziness, blurred vision or tremors followed by convulsions, unconsciousness and probably respiratory arrest. Other effects may be nausea, vomiting, chills, constriction of the pupils and tinnitus. The CVS manifestations include myocardial depression, hypotension and cardiac arrest. In obstetrics, fetal bradycardia may occur. Allergic reactions include urticaria, bronchospasm and hypotension. 26

Treatment of toxic reactions: Treatment is mainly symptomatic. Main goal of treatment is to maintain near normal circulation and to support ventilation with oxygen or controlled ventilation if required. Supportive treatment with IV fluids and vasopressors restore the cardiovascular stability, convulsions may be controlled with diazepam or thiopentone sodium and controlled ventilation with oxygen. Corticosteroids may be helpful when allergic reactions are suspected.

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EPHEDRINE PHARMACOLOGY20, 21, 22, 23


History 24 Introduction of Ephedrine to western medicine was in 1926 by Chenn and Carl F Schmidt following a visit to china. Used for the first time to counter spinal hypotension in 1927 by Ockerblad and Dillon and by Rudolf and Graham in separate setups, was the greatest boost to spinal analgesia. During this era intravenous infusions were rarely employed to tackle spinal hypotension, and only pressor agents available were adrenaline and Methyl guanidine. They have the adverse effects of severe tachycardia and decrease in ratio of myocardial oxygen need to supply. Since then many pressor agents have come and gone but Ephedrine still remains the preferred drug due to its dual action on both alpha and beta-adrenergic receptors. Chemistry: The active principle of the herb Ma-Huang belonging to the species Ephedra, known to Chinese medicine for a millennia. It was isolated in pure state and named by Nagaun in 1887. Structural formula: C10H15NO.1/2H2O

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Fig.8 Chemical Structure of Ephedrine 23. Chemical Name: (1R, 2S)-2 Methylamino -1 Phenylpropan 1 ol Hemi hydrate Physiochemical properties: It is an alkaloid initially extracted from the Chinese herb Ma-Huang. Now it is synthetically prepared. It is a colourless white crystalline powder or granules with a bitter taste. It is odourless or may have a slight aromatic odour. Melting Point: 217 to 220 Solutions are sterilized by autoclaving or by filtration. It has a self life of 36 months when stored at temperature of 25 or below it, stored in tight containers and protected from light. Mechanism of Action 23, 25, 26: Direct Action: It is a nonselective sympathetomimetic agent acting on both Alpha and beta receptors. Indirect Action: (a) Peripheral postsympathetic norepinephrine release (b) Central nervous stimulation

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(c) Inhibition of norepinephrine reuptake. Pharmacokinetics 23: Ephedrine is resistant to degradation by mono amino oxidase (MAO) in the gastrointestinal tract since it is a Noncatechol Phenylisopropylamine; and resistant to degradation by Catechol-o-methyltransferase (COMT) due to the absence of catecholamine nucleus, this enables the drug to be rapidly and completely absorbed after oral administration. Maximum peak plasma concentrations of 45 to 140 mg/L are obtained after a single dose of 22mg Ephedrine hydrochloride. Peak plasma concentration is achieved within 25 to 30 minutes following oral administration. It is extensively distributed throughout the body; volume of distribution being 122 to 320L. It accumulates in the liver, lungs, kidneys, spleen and brain. The mean plasma half life is 6hours (3 to 11 hours), clearance is 13.6 to 44.3 L/hour. Up to 95% of the drug is excreted in the urine in 24 hours and is pH dependent (since it is slightly alkaline its excretion is increased in acidic urine and a decrease of about 20 to 35% in alkaline urine); 55 to 75 % as unchanged and the rest as metabolites. Renal disease is likely to impair the elimination of the drug. Intra muscular injections of ephedrine are also acceptable since drug induced local vasoconstriction is insufficient to delay systemic absorption. Placental transfer of Ephedrine occurs and fetal blood levels of approximately 70% of maternal blood levels have been reported.

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Action on different systems: (a) Cardiovascular system: It increases the arterial blood pressure by peripheral vasoconstriction and cardiac stimulation (increase in the heart rate and cardiac output). (b) Central nervous system: It is a potent CNS stimulant which can lead to apprehension and tremors. It increases the minimum alveolar concentration of anaesthetic agents. Insomnia is a common side effect of therapeutic doses therefore administration of the drug to be avoided after four in the evening. Amphetamine like psychoses can occur rarely in chronic abuse. (c) Respiratory system: It relaxes bronchial smooth muscles and increases the specific airway conductance within one hour following administration in obstructive airway disease patients. Significant bronchodilatory effects were maintained over 4 to 5 hours. It has a stimulant effect on the respiratory centre. (d) Alimentary and urinary tract: Ephedrine reduces the intestinal tone and motility. Stimulation of the alpha adrenergic receptors of smooth muscle cells in the bladder base and relaxation of the detrusor muscle increases the resistance to the outflow of urine. (e) Uterus: it causes uterine relaxation and preserves the uterine blood flow by its beta adrenergic activity. (f) Musculoskeletal: It stimulates oxygen uptake and thermo genesis. (g) Eyes: It dilates the pupil (mydriasis) but does not alter the light reflexes.

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Therapeutic Uses: (1) As a pressor drug to treat spinal hypotension. (2) Prevention of bronchial spasm in asthma patients. (3) Treatment of narcolepsy. (4) Treating allergic disorders such as hay fever or urticaria. (5) Nasal decongestant. (6) Enuresis. Dosage: Ephedrine in the doses of 15 to 60mg by mouth 3 to 4 times a day is of value in preventing bronchial asthma and narcolepsy. Contraindications: (1) Ischemic heart disease. (2) Hypertensive patients. (3) Benign prostatic hypertrophy patients. (4) Thyrotoxic patients. (5) In lactating mothers and for long durations in pregnant women.

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Drug Interactions 27: a) Hypertensive crises when administered with Mono Amino Oxidase (MAO) inhibitors. b) The plasma half life of dexamethasone was decreased when administered with ephedrine. c) Increase of risk of arrhythmias if patient is on digoxin. d) Increased response in cocaine users. e) Response to indirect effects of Ephedrine may be reduced if patient is on reserpine or guanethidine. f) Decreased response in patients receiving -blockers.

Adverse Effects: In large doses ephedrine gives rise to side effects such as giddiness, headache, nausea, vomiting, sweating, thirst, tachycardia, precordial pain, palpitations, muscular weakness and tremors, anxiety, restlessness and insomnia.

Overdose and Treatment: (1) Protection of patients airway and to support ventilation if required with 100% oxygen. (2) Monitoring and maintaining, within acceptable limits, patients vital signs, blood gases, and serum electrolytes.

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(3) Electrocardiogram to be continuously monitored for supra and ventricular tachyarrhythmia, administration of beta-adrenergic blocker such as Propranalol by slow intravenous infusion; however in asthmatic patients a cardio selective beta-adrenergic blocker (Acebutolol, Atenolol,

Metoprolol) is more appropriate. (4) In alert patients removing Ephedrine from stomach by inducing emesis with Ipecac, followed by activated Charcoal (as long as ileus is not present); in depressed or hyperactive patients it should be done with airway protected gastric lavage. (5) Marked hypertension to be treated with vasodilators. (6) Convulsions to be controlled using Diazepam, Seizures refractory should be treated with Thiopentone and Neuro-muscular blocking agents. (7) Pyrexia controlled by cold intravenous infusion, tepid sponging and dexamethasone.

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REVIEW OF CLINICAL STUDIES


Spinal anaesthesia has celebrated the centennial anniversary and still enjoys the status of being the highest performed anaesthetic procedure since its introduction by August Bier in 1898 due the following reasons 13. (a) Mastering the technique is easier. (b) Quicker in onset no period of waiting. (c) The consequences of multiple drugs avoided. (d) Intubation avoided. (e) Offers high quality sensory and motor block. (f) The patient is awake and will be able to communicate. (g) It is cost effective.

As we are all familiar that none of the technique is ideal, spinal anaesthesia also has a set of disadvantages. The most common serious side effects being hypotension and bradycardia, Methods developed in due course to combat are (1) Physical methods used to increase venous return 12, 29: Foot end elevation
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wrapping of patients legs with elastocrit bandage 28, inflatable boots application, left uterine displacement are the various physicals methods used, they are less successful in combating hypotension.

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(2) Volume Expansion 29: Are achieved either by infusing crystalloids or colloids, crystalloids comparatively are cheaper, they improve peripheral circulation and decreases hypotension to a certain extent by virtue of filling up the venous capacitance vessels. They have disadvantages like haemodilution which can hamper oxygen supply, they lead to abnormal rise in central venous pressure
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and the problem is further increased as the need for catheterization arises as a result of urinary retention when combined with spinal block. Colloid like Albumin has eliminated hypotension in various studies but the major set back is they are very expensive for daily use in all patients. Hetastarch 6% or haemaccel do not have better results in comparison to crystalloids in preventing hypotension, added to this are the side effects like anaphylactic reaction, disturbance in coagulation cascade and interference in blood group cross matching. (3) Vasoconstrictors 31: The spinal hypotension was initially thought due to anterior abdominal wall paralysis causing decreased intra thoracic pressure during inspiration. Later it was confirmed that the cause was due to blockade of sympathetic preganglionic fibers, this lead to treatment of spinal hypotension with vasopressors. Epinephrine was the vasopressor initially used, due its cardiac side effects it was replaced by Ephedrine on its introduction into clinical practice by Ockerland and Dillon, and by Rudolf and Graham in 1927
24

. Since then it has

remained the vasopressor of choice to combat spinal hypotension. 36

Datta et al in 1982 32 assessed the effectiveness of intravenous Ephedrine in prevention of hypotension, nausea alone, or with vomiting. Method: Sixty healthy parturients, scheduled for caesarean section at term were studied. They were assigned into three groups according to the blood pressure levels after spinal anaesthesia. In group A (n=22), there was no change of blood pressure so none received Ephedrine, group B (n=18) due to hypotension received Inj. Ephedrine 10mg intravenously, it was repeated until blood pressure rose to at least 100mm Hg. In group C (n=20), Ephedrine was administered (10-30mg) intravenously as soon as any fall of blood pressure from base line. Result: The incidence of nausea or with vomiting was clearly correlated with the development of maternal hypotension. None of the parturients in group A complained of nausea alone or with vomiting, two mothers (10%) had these symptoms in Group C, where as two-thirds of patients (66%) in group B developed nausea or both nausea and vomiting (P<0.01). They concluded that prompt intravenous administration of Ephedrine as soon as fall in base line blood pressure was detected prevents further fall in blood pressure and markedly reduces the incidence of nausea alone or with vomiting.

Kang et al in 1982

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assessed whether prophylactic intravenous infusion of Ephedrine

can effectively maintain maternal blood pressure without adversely affecting the mother or fetus. Method: Forty four healthy parturients undergoing elective caesarean section under spinal anesthesia were randomly assigned into two groups. Twenty patients received

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Ephedrine infusion (5mg/min, 0.01% solution) and twenty four patients (control group) received 20mg of Ephedrine as an intravenous bolus. Results: In patients given the infusion, systolic blood pressure did not change significantly from the baseline and reactive hypertension did not occur. Nausea and/ or vomiting occurred in nine women in the control group and one patient in the infusion group (p<0.001). They concluded that prophylactic intravenous infusion of Ephedrine was safe and effective in healthy parturients undergoing cesarean section under spinal anaesthesia, without causing significant maternal tachycardia, hypertension, nausea and vomiting, or fetal compromise.

Hemmingsen .C et al in 1989

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conducted a study to determine the clinical use of

prophylactic Ephedrine before spinal anaesthesia. Method: Forty eight patients scheduled to undergo surgical procedures on the lower extremities/ limb under spinal anaesthesia were allocated into three groups of 16 each according to American Society of anesthesiologists (ASA) classification of I-II-III
rd

grade. Each patient received a fluid load of 7ml/kg and either

Ephedrine 12.5mg I.V and 37.5mg I.M or placebo. Result: They found twelve patients in the placebo group development a maximal decrease in mean arterial blood pressure exceeding 20%, five of them developed a decrease exceeding 33% and required treatment. In ASA III, all patients in placebo group had a decrease in mean arterial blood pressure exceeding 33%. They concluded that it is

38

appropriate to administer prophylactic Ephedrine I.V and I.M. routinely at induction of spinal anaethesia especially in ASA class III patients to prevent hypotension.

Gajraj et al in 1993

35

designed a study to compare the efficacy of Ephedrine infusion

with crystalloid administration for reducing the incidence of hypotension during spinal anesthesia. Method: Fifty four ASA grade I patients undergoing postpartum tubal ligation were randomly allocated to two groups. Group 1 received lactated ringers solution, 15ml/kg. Group 2 did not receive any crystalloid before the spinal anesthesia, but received Ephedrine infusion (50mg in 50ml of lactated ringers solution) using syringe pump. Result: they found the incidence of hypotension was 55% in the crystalloid group and 22% in the infusion group. They concluded that Ephedrine infusion was found more effective than crystalloid administration in preventing hypotension in this patient population, and did so without unwanted side effects such as hypertension or tachycardia.

Kafle .S.K, Malla .S.M and Lekhak in 1994

36

conducted a study to demonstrate the

efficacy of oral ephedrine in preventing hypotension following subarachnoid block. Method: Two hundred female patients of ASA I and II scheduled to undergo elective lower abdominal surgery (abdominal hysterectomy, tuboplasty, ovarian tumor) were randomly divided into two groups. Group I patients in addition to routine premedication were given Ephedrine 30mg PO, thirty minutes before subarachnoid block. Both group of patients received preload of 10ml/kg crystalloid solution.

39

Result: they deducted that the total dose of Ephedrine supplemented in group I was 4.3 4.8mg compared with 11.6 9.4mg in group II (P<0.01). Also 55 patients in group I required intraoperative inotrope supplement compared to 83 in group II (P<0.01). They concluded that oral Ephedrine given 30-45 minutes before surgery is a simple and effective method of reducing the incidence of hypotension during spinal anaesthesia. They suggested that it is an acceptable alternative to other techniques used for this purpose in ASA I or II patients.

Critchley et al in 1995

37

compared the haemodynamic effects of Ephedrine alone with

Ephedrine and colloid for the treatment of spinal hypotension. Method: 30 ASA II-III patients aged 60-90 years with fracture of the neck of femur were divided into two groups. Group one received Ephedrine as an initial bolus dose of 0.2mg/kg followed by an infusion of 0.5mg/kg/hour. Group two received Ephedrine and colloid (polygeline, haemaccel) 8ml/kg. If necessary, up to three rescue bolus doses of Ephedrine (0.1mg/kg) and then colloid solution (8ml/kg) were given to maintain systolic pressure above 75% of baseline. Result: in patients receiving Ephedrine only central venous pressure, and stroke index decreased and heart rate increased (P<0.0001). Five patients in the same group required colloid, the effect of which was to restore central venous pressure, increase cardiac index and stroke index. In patients receiving Ephedrine and colloid solution , systemic vascular resistance index decreased and cardiac index, stroke index and heart rate increased(P<0.0001). They concluded that Ephedrine in the doses used in the study had

40

limited action on peripheral vasoconstriction and relied on its ability to increase cardiac output in order to maintain systolic arterial pressure.

Sterno et al in 1995

38

conducted a study to investigate the efficacy of intramuscular

Ephedrine in elderly patients undergoing hip arthroplasty under spinal anaesthesia. Method: Ninety eight patients with age group ranging from 37-89 years and belonging to the entire ASA grade were included in the study. Fifty patients received Ephedrine 0.6mg/kg body weight, deep in the paravertebral muscles immediately after spinal anaesthesia; the remaining forty eight received an equal volume of saline. Patients in both groups were given the same volume of fluid before spinal blockade. Result: They found systolic arterial pressure during the first 60 minutes after anaesthesia remained significantly more stable in the Ephedrine group, and there were also a significantly smaller number of patients in this group who had decreases of pressure of more than 30% preblock levels, and fewer required rescue I.V. Ephedrine. They concluded that Ephedrine 0.6 mg/kg body weight administered in the paravertebral muscles immediately after plain Bupivacaine spinal anaesthesia is a simple and effective means of reducing the incidence of hypotensive episodes in elderly patients. Chan .W.S et al in 1997
39

compared the efficacy of prophylactic ephedrine infusion

over fluid preloading in prevention of maternal hypotension during spinal anaesthesia for caesarean section.

41

Method: Forty six women scheduled to undergo elective caesarean section at term were allocated randomly to receive either Hartman solution preloading 20ml/kg (fluid group) or prophylactic intravenous Ephedrine 0.25mg/kg (ephedrine group). Result: There was lower incidence of severe hypotension in the Ephedrine group when compared to fluid group (35% vs. 65%, P=0.04). Mean umbilical venous pH was higher in the Ephedrine group than in fluid group (7.33 vs. 7.29, p=0.02) and the number of patients shivering was lower in the ephedrine group (2 vs. 9, P=0.02). They concluded that prophylactic Ephedrine infusion is a quick and simple technique which also confers the advantages of reducing the incidence of severe hypotension and neonatal acidosis. They further questioned the need for intravenous fluid preloading.

Webb and Shipton in 1998

40

assessed the safety and efficacy of 37.5 mg Ephedrine

I.M. in preventing hypotension associated with spinal anaesthesia for caesarean section. Method: Double-blind randomized study, 40 patients (20 in each group) were given either 37.5mg Ephedrine (study group) or 1.5ml Normal saline (control group) I.M. into the left deltoid. Result: Incidence of hypertension was 30% in study group compared with 20% for the control group. Incidence of hypotension was lower in study group (50%) than in the control group (80%) and the incidence of delayed hypotension was only 10% in the study group patients compared with 50% (P<0.05) in the control group patients. They concluded that 37.5mg Ephedrine I.M. (10 minutes) prior to spinal anaesthesia was not

42

associated with reactive hypertension or tachycardia. Intramuscular Ephedrine provided more sustained cardiovascular support than intravenous Ephedrine.

Marcel. P.Vercauteren et al in 2000

41

evaluated the effectiveness of prophylactic

Ephedrine for the prevention of hypotension associated with spinal anesthesia in patients undergoing cesarean section. Method: Fifty parturients were divided into equal groups and received either Ephedrine 5mg or Saline I.V. immediately after induction of spinal anaesthesia. Result: More number of patients in the saline group were found to develop hypotension (58% vs. 25%, P<0.05).Only two patients (8%) in the Ephedrine group developed Systolic blood pressure values <90mm hg, whereas 10 patients (42%) in the saline group experienced hypotension of this severity (p<0.05). In addition incidence of nausea was also higher in the saline group. They suggested that the incidence and severity of hypotension are significantly reduced by the I.V. administration of prophylactic dose of 5mg Ephedrine in patients receiving small-dose spinal anesthesia for cesarean delivery.

Ngan Kee et al in 2000 42 designed a randomized, double blinded study to determine the efficacy and optimal dose of I.V. Ephedrine for prevention of hypotension during spinal anesthesia for cesarean delivery. Method: Eight women who received an I.V. crystalloid preload preceding spinal anesthesia for elective cesarean section. One minute after the intrathecal injection, patients were given saline control, or Ephedrine 10, 20 or 30mg I.V.

43

Result: They found that systolic arterial pressure in the first 12 minutes was greater in 30mg group when compared to other groups. Hypotension occurred in 7 patients (35%) in the 30mg group compared with 19 (95%), 17(85%) and 16(80%) patients in the control and 10. 20mg groups respectively. Reactive hypertension occurred in 9 patients (45%) in the 30mg group compared with 2(10%), 1(5%) and 5(25%) patients in the other groups. Heart rate changes, total Ephedrine requirement, incidence of nausea and vomiting, and neonatal outcome were similar among all groups. They concluded that in patients having spinal anesthesia for cesarean section after I.V. Crystalloid preload, the minimum

effective dose of I.V. Ephedrine given one minute after the spinal anesthesia to reduce the incidence of hypotension was 30mg and it caused reactive hypertension in some patients. Further investigation of other methods of reducing the incidence of hypotension during spinal anesthesia for cesarean delivery was indicated.

Loughrey et al in 2002

43

evaluated the efficacy and optimal dose of prophylactic

intravenous Ephedrine for prevention of hypotension associated with spinal anaesthesia for caesarean section. Method: Sixty six patients were randomized into three groups according to which they received a bolus of 0.9% saline I.V. (Group C, n=20), Ephedrine 6mg (Group E-6, n=24) Or ephedrine 12mg (Group E-12, n=22) simultaneously with the subarachnoid block. Result: There was a significantly higher incidence of hypotension in Group C compared with Group E-12 (60% vs. 27.3%, P<0.05). Less rescue doses of ephedrine were required in Group E-12 compared with the control group (1.8 1.2 vs. 3.3 2.1, p<0.05). They

44

concluded that prophylactic bolus of Ephedrine 12mg I.V. is safe and efficacious in reducing the incidence of maternal hypotension compared to I.V. rescue boluses alone.

Erogulu et al in 2003 44 investigated the prophylactic effects of systemic oral Ephedrine in spinal anesthesia induced hypotension during transurethral prostatectomy. Method: Sixty ASA grade II and III patients were randomized into two groups. Patients in Group I (n=30) received oral Ephedrine 50mg in addition to routine premedication, whilst those in Group II (n=30) received only premedication 30 min before spinal anaesthesia. Result: Systolic arterial pressure values were significantly lower in Group II during the spinal anesthesia, post-spinal and intraoperative periods (p<0.0001). The incidence of hypotension was halved in Group I compared to Group II (23.33% vs. 50%, P=0.003). Six patients in Group II also received Inj. Atropine I.V. because of severe bradycardia. They concluded that a prophylactic oral dose of Ephedrine 50mg is effective for minimizing and managing spinal anesthesia-induced hypotension during transurethral prostatectomy.

Loughrey et al in 2005

45

evaluated the hypothesis that an I.V. bolus of Phenylephrine

combined with Ephedrine, when compared to Ephedrine alone, could reduce the incidence and severity of hypotension during spinal anesthesia for cesarean delivery.

45

Method: Forty three ASA grade I & II non-laboring patients were randomized into two groups. Group E (n=20) received bolus I.V. Ephedrine 10mg and Group EP (n=20) received Ephedrine 10mg and Phenylephrine 40g I.V. Result: The overall hypotension was 80% in Group E vs. 95% in Group EP. They concluded that combination of Ephedrine and Phenylephrine given as intravenous bolus at the doses mentioned is not superior to Ephedrine alone in preventing or treating hypotension in healthy parturients undergoing cesarean delivery.

46

MATERIALS AND METHODS


This is a randomized, prospective study performed over a period of one year from June 2004 to June 2005.The study was carried out in one hundred patients between the age group of 20-60 years belonging to American society of Anesthesiologist (ASA) grade I and II who were scheduled for elective surgery being performed over the lower abdomen or the lower limbs under spinal anaesthesia. After institutional Ethical committee approval and informed consent from each patient, the study was conducted at Sree Siddartha Medical College Hospital and Government District hospital (General Hospital), Tumkur. Inclusion Criteria: 1. Patients belonging to ASA grade I and II posted for elective surgery on the lower abdomen or lower limbs under spinal anaesthesia. 2. Patients between the age group 20-60 years of both sexes 3. Patients weighing between 40 to 80kgs.

Exclusion Criteria: 1. Patient refusal. 2. Patients having systemic cardiovascular, respiratory, hepatic, renal or central nervous system disorders. 3. Patients on MAO-inhibitor antidepressants and -blockers.

47

4. Patients with haemorrhagic disorders or patients who are on anticoagulant therapy. 5. Disease and deformities of spinal cord or vertebral column. 6. Patients with haemoglobin less than 10gm/dl. 7. A patient in whom more than 10% blood loss is anticipated or occurs on table during the study. 8. Patients who were chronic smokers and alcohol dependent. The selection of patients was carried out randomly. Patients were explained in there own language the anaesthetic procedure they are going to undergo the next day, following which an informed written consent was obtained from each patient. Pre- anesthetic examination was done the previous day to surgery which included patients height and weight, general examination, systemic examination of cardio vascular system, respiratory system, CNS and examination of spine. Basic investigations like heamoglobin percentage, total blood count, differential blood count, urine routine, bleeding and clotting time, blood Sugars (if urine sugar positive). Blood urea, serum creatinine and electrocardiogram were carried out before taking up for surgery in patients aged above 40 years. All patients were pre-medicated with Tab. Ranitidine 150mg Po the night before surgery and 2hrs before surgery. Tab. Diazepam 10mg Po was administered the night before surgery. All patients were kept nil orally before surgery.

48

The baseline Heart rates (HR), Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were recorded for all patients using the L. & T. monitor. Patients then were randomly allocated into two groups. Group A (n=50) were given Tab. Ephedrine 30mg orally with a sip of water 30 minutes before surgery. Group B (n=50) were given a placebo to be taken orally with a sip of water 30 minute before surgery. Patients were shifted to the operation theatre, intravenous access was obtained using a 18 gauge canula, an infusion of ringer lactate was started. The pre subarachnoid block Heart rates (HR), Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were recorded for all patients and continuous monitoring done with L. & T. monitor. Patient was then put to left lateral position. Under strict aseptic precaution lumbar puncture was performed using 25-gauge disposable Quincke type of spinal needle at L3-L4 spinal intervertebral space by midline approach. After the free flow of cerebrospinal fluid, 3ml of Bupivacaine Hydrochloride was injected intrathecally and the time noted. The patients were repositioned, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) were recorded in all patients at every 2 minutes interval for 10 minutes, then at every 10 minutes interval up to 45minutes and then at every 15 minutes till the end of surgery. Level of sensory blockade was checked using a 23G hypodermic needle, Success of the block was defined as pinprick analgesia extending cranially at least to the T8 dermatome. Following subarachnoid block the following vitals were monitored during

49

Fig: 9 Oral Ephedrine Tablets.

Fig: 10

Intravenous Ephedrine and Other Essential Drugs.

50

Fig: 11

Spinal Puncture Being Performed.

Fig: 12

C.S.F Flow through Spinal Needle.

51

Peri-operative period. They included hypotension, Nausea, vomiting, desaturation or hypoxemia (SpO2<90%) and blood loss during the surgical procedure.

Hypotension was defined as a decrease in systolic blood pressure (SBP) more than 20% from the base line. If hypotension occurred in any of the patients they were treated first with foot end elevation, then infusion of ringer lactate was increased. If hypotension continued following these measures finally they were treated with Inj. Ephedrine administered intravenously in 5mg boluses at 2 minute interval until the SBP returned to within 20% of the base line values. Inj. Atropine 0.6mg was administered intravenously to any patient if the heart rate decreased below 60 beats/minute. Statistical analysis: The observations are expressed as Mean one standard deviation. The baseline haemodynamic values and the postspinal haemodynamic changes at various time intervals were compared using Unpaired t and Chi-square tests. The values of p<0.05 were considered statistically significant.

52

RESULTS AND ANALYSIS


Age distribution of the patients Age (years) 21-30 31-40 41-50 51-60 Group A Number 19 22 9 0 Group B Number 14 21 13 2

% 38 44 18 0

% 28 42 26 4

Table: II. Age distribution of the two groups of patients The age range was 21-48 years in group A and 20-56 years in group B.
Age Distribution of Patients
25 20 15 10 5 0 21-30 31-40 41-50 51-60 Age(years) Group A Group B

Number of Patients

Graph: 1 Age Distribution of Patients

Sex distribution of the patients SEX


MALE FEMALE

Group A Number %
23 27 46 54

Group B Number %
24 26 48 52

Table: III. Sex distribution of the two groups of patients. There were 23 males and 27 females in Group A and 24 males and 26 females in Group B. The two groups are thus almost perfectly matched.

53

Sex Distribution

27 26 25 Number of 24 Patients 23 22 21 MALE FEMALE Group A Group B

Graph: 2 Sex Distribution. Height distribution of the patients Height Group A Group B (cm) Number % Number % 141-150 3 6 5 10 151-160 28 56 27 54 161-170 18 36 17 34 171-180 1 2 1 2 Table: IV. Height distribution of the two groups of patients. In group A, the height range was 148-172 cm and in the other group, 146-172 cm.
Height Distribution of Patients
30 25 20 Number of 15 Patients 10 5 0 141-150 151-160 161-170 171-180 Height(Cms) Group A Group B

Graph: 3 Height Distribution

54

Weight distribution of the patients Group A Group B Weight Number % Number % (kg) 40-45 2 4 2 4 46-50 9 18 4 8 51-55 8 16 11 22 56-60 15 30 22 44 61-65 10 20 9 18 66-70 6 12 2 4 Table V. Weight distribution of the two groups of patients The range of weight in group A was 44-79 kg and in group B, it was 43-70 kg.
Weight Distrbution of Patients
25 20 15 10 5 0 40-45 46-50 51-55 56-60 61-65 66-70 Weight(Kgs) Group A Group B

Number of Patients

Graph 4 Weight Distribution

55

Statistical comparison of age, height and weight of the two groups of patients

t p Group A Group B Mean S.D. Mean S.D. value value Age (years) 33.54 8.14 36.68 8.87 1.844 0.0682 Height (cm) 159.00 5.44 158.96 5.64 0.0361 0.9713 Weight (kg) 57.32 7.32 56.52 5.57 0.6150 0.5400 Table VI. Statistical comparison of age, height and weight of the two groups of patients In Table VI the mean, the standard deviation (S.D) and the unpairedt test value of age, height and weight of the two groups of patients are presented. It is seen that the groups are matched in respect of these parameters. Type of surgery Presents the kind of surgical interventions carried out on the patients in both the groups Type of surgery Group Group A B Appendicectomy 12 11 Herniorraphy 8 8 Fissurectomy & 7 5 Lords dilatation Haemorrhoidectomy 6 3 Hydrocele excision 3 3 Hysterectomy, 3 2 vaginal Anatomical repair 2 2 Curettage & skin 1 3 grafting Venous stripping 1 2 Fistulectomy Multiple subfacial ligation Ovariectomy Drainage Excision Mesh repair Varicocelectomy K wire fixation 1 1 1 1 1 0 1 1 4 2 0 1 2 2 0 0

Parameter

Table VII. Type of surgery carried out on the two groups of patients

56

14 12 10 8 6 4 2 0 Ovariectomy Anatomical repair Multiple subfacial Lords dilatation Venous stripping Haemorroidectomy Curettage & skin Appendicectomy Hysterectomy, Varicocelectomy Fissurectomy & K wire fixation Herniorraphy Fistulectomy Mesh repair Hydrocele Drainage Excision Group A Group B

Graph 5 Type of surgery carried out on the two groups of patients

Appendicectomy, herniorraphy, fissurectomy and Lords dilatation (A/H/F) constituted 54% of all operations in Group A and 48% of operations in the other group of patients. The next common cluster of surgeries comprised haemorrhoidectomy, hydrocele excision and hysterectomy vaginal (H/H/H); they accounted for 24% of cases in Group A and 16%, in Group B. The frequency based cluster-wise distribution of operations is shown in Table VIII. The difference in the surgeries between groups is statistically not significant.

Surgery clusters Group A Group B A/H/F 27 24 H/H/H 12 8 Others 11 18 Table VIII. The cluster-wise distribution of surgeries in the two groups of patients x2 = 2.666, p= 0.2637

57

Level of sensory block The level of anaesthesia in the two groups of patients is given in Table IX and Graph 6

Level of Group A Group B anesthesia Number % Number % T6 16 32 20 40 T8 34 68 29 58 T10 0 0 1 2 Table IX. Level of anaesthesia in the two groups of patients

35 30 25 Num ber of 20 Patients 15 10 5 0 T6 T8 Level of Block T10

Group A Group B

Graph 6 Level of Spinal anaesthesia

Blood pressure Baseline status Systolic Blood Pressure (SBP) Systolic BP Group A Group B (mmHg) Number % Number % 100-110 4 8 12 24 111-120 20 40 11 22 121-130 21 42 10 20 131-140 5 10 17 34 Table X. Baseline systolic blood pressure in the two groups of patients The range of SBP was 110-136 mmHg in group A and 104-140 mmHg in group B. 58

Diastolic Blood Pressure (DBP) Diastolic BP Group A Group B (mmHg) Number % Number % 61-70 2 4 8 16 71-80 30 60 20 40 81-90 18 36 22 44 Table XI. Baseline diastolic blood pressure in the two groups of patients The range of DBP was 70-92 mmHg in group A and 68-90 mmHg in group B. Mean Arterial Pressure (MAP)

Meal arterial pressure Group A Group B (mmHg) Number % Number % < 86 0 0 5 10 86-90 13 26 14 28 91-95 27 54 11 22 96-100 8 16 9 18 > 101 2 4 11 22 Table XII. Baseline mean arterial pressure in the two groups of patients The range of MAP was 87.33-105.33 mmHg in group A and 82-106.66 in the other group.

59

Heart Rate (HR)

Heart rate Group A Group B (beats/min) Number % Number % 61-70 7 14 8 16 71-80 25 50 12 24 81-90 12 24 26 52 91-100 6 12 4 8 Table XIII. Baseline heart rate in the two groups of patients In group A, HR range was 64-100 beats/minute, and in group B, it was 62-96 beats/minute.

SBP and DBP in the same group of patients The SBP and DBP patients at different time periods of Group A are shown in Graph 7 and those of Group B in Graph 8.

135 125 115

mmHg

105 95 85 75 65 Baseline At SAB 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes

Systolic BP Diastolic BP

Time

Graph 7. The SBP and DBP of patients in Group A at different time Intervals.

60

130 120 110

mmHg

100 90 80 70 60 Baseline At SAB 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes

SBP DBP

Time

Graph 8. The SBP and DBP of group B patients at different time Intervals.

The two blood pressure curves of Group A (Graph 7) are almost of similar shape. They first rise slightly and then show a gradual and steady decline. The two curves of Group B (Graph 8) are more or less similar. At first they are horizontal and then they dip down to form concavities. The concavity of the curve for SBP is deeper than that for DBP.

61

Comparison of BP in the two groups The SBP of the patients at different times is presented in Graph 9 and Table XIV. In group A the lowest SBP was 115.6 mmHg at 60 minutes; and in group B the lowest SBP was 100.1 at 8 minutes.

140 130

mm Hg

120 110 100 90 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes Baseline At SAB

Group A Group B

Time

Graph 9. The SBP of the two groups of patients at different time intervals Group A Group B t value p value Significant Mean S.D. Mean S.D. Baseline 121.98 7.36 123.85 11.45 0.9715 No 0.3337 At SAB 127.14 7.36 123.96 10.47 No 1.757 0.820 2 minutes 128.74 8.18 116.2 10.95 Yes 6.487 <0.0001 4 minutes 126.84 7.90 107.72 9.73 10.787 <0.0001 Yes 6 minutes 121.94 10.10 102.52 9.56 Yes 9.874 <0.0001 8 minutes 120.34 11.84 100.1 11.09 Yes 8.822 <0.0001 10 minutes 118.7 11.44 100.78 8.91 Yes 8.739 <0.0001 20 minutes 118.6 9.10 101.18 7.87 10.238 <0.0001 Yes 30 minutes 119.92 8.14 104.18 7.44 Yes 9.695 <0.0001 40 minutes 118.84 6.60 107.46 7.28 Yes 8.189 <0.0001 50 minutes 117.74 6.90 109.72 6.76 Yes 5.871 <0.0001 60 minutes 115.6 7.53 118.33 10.41 No 1.503 0.1364 Table XIV. Statistical comparison of SBP (mmHg) in the two groups The differences are highly significant except at baseline, at SAB and at 60 minutes. 62 Period

The DBP of the two groups of patients at different time intervals are presented in Graph 10 and Table XV. The lowest DBP was 73. 2 mmHg at 60 minutes in group A, and 66.4 mmHg at 10 minutes in the other group.

85 80

mmHg

75 70 65 60 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes Baseline At SAB

Group A Group B

Time

Graph 10. The DBP of the two groups of patients at different time intervals

Group A Group B t value p value Significant Mean S.D. Mean S.D. Baseline 79.32 4.97 79.0 6.73 No 0.271 0.7874 At SAB 81.7 5.95 78.82 6.60 No 1.496 0.1379 2 minutes 81.72 7.59 75.66 6.25 Yes 4.358 <0.0001 4 minutes 80.44 7.69 71.76 5.54 Yes 6.476 <0.0001 6 minutes 77.78 7.58 68.46 6.4 Yes 6.643 <0.0001 8 minutes 76.5 7.40 67.38 7.92 Yes 5.590 <0.0001 10 minutes 75.54 7.49 66.4 6.53 Yes 6.504 <0.0001 20 minutes 75.44 6.01 67.6 6.01 Yes 6.522 <0.0001 30 minutes 75.78 5.20 67.62 4.25 Yes 8.592 <0.0001 40 minutes 75.76 6.10 70.1 5.19 Yes 4.997 <0.0001 50 minutes 75.48 5.76 70.96 4.88 Yes 4.234 <0.0001 60 minutes 73.2 3.27 76.66 6.66 Yes 3.298 0.0014 Table XV. Statistical comparison of DBP (mmHg) in the two groups The differences are highly significant except at baseline and at SAB.

Period

63

The MAP of the two groups of patients at different time intervals is presented in Graph 11 and Table XVI. In group A, the lowest MAP was 87.33 mmHg at 60 minutes, and the highest was 97.39 mmHg at 2 minutes. In group B, the lowest was 78.88 mmHg at 6 minutes, and the highest was 103.44 mmHg at 60 minutes

110

100

mmHg

90

Group A GroupB

80

70 Baseline At SAB 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes 2 minutes 4 minutes 6 minutes 8 minutes

Time

Graph 11. The MAP of the two groups of patients at different time intervals Period Baseline At SAB 2 minutes 4 minutes 6 minutes 8 minutes 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes Table XVI. Group A Group B T value P value Significant Mean S.D. Mean S.D. 93.54 5.19 93.95 7.27 No 0.325 0.7458 96.84 6.01 93.80 7.26 Yes 2.281 0.0247 97.39 7.17 89.17 7.13 Yes 5.748 <0.0001 95.91 7.36 83.75 6.33 Yes 8.857 <0.0001 92.5 8.05 78.88 8.01 Yes 8.481 <0.0001 91.11 9.29 94.87 5.51 Yes 2.462 0.0156 89.92 8.25 94.99 5.31 Yes 3.654 0.0042 89.82 6.45 95.90 5.12 Yes 5.221 <0.0001 90.49 5.23 96.11 5.31 Yes 5.332 <0.0001 89.21 8.66 96.11 5.06 Yes 4.864 <0.0001 89.57 5.70 96.31 5.07 Yes 6.247 <0.0001 87.33 4.52 103.44 5.7 Yes 15.659 <0.0001 Statistical comparison of MAP (mmHg) in the two groups

The differences are highly significant except at baseline

64

The HR of the two groups of patients at different time intervals is presented in Graph 12 and Table XVII.

Graph 12. The HR of the two groups of patients at different time intervals

Group A Group B t value p value Significant Mean S.D. Mean S.D. Baseline 78.34 7.97 81.14 8.05 No 1.748 0.0836 At SAB 81.98 8.29 83.2 6.77 No 0.806 0.4222 2 minutes 83.08 8.33 85.26 7.35 No 1.388 0.1684 4 minutes 83.2 8.76 88.32 8.3 Yes 3.000 0.0034 6 minutes 83.3 8.27 89.58 8.66 Yes 3.708 0.0003 8 minutes 82.56 8.11 92.26 9.07 Yes 5.637 <0.0001 10 minutes 82.62 8.04 92.1 8.41 Yes 5.761 <0.0001 20 minutes 81.84 6.48 93.26 7.63 Yes 8.067 <0.0001 30 minutes 81.6 6.56 92.08 7.87 Yes 7.233 <0.0001 40 minutes 80.56 5.95 90.44 6.96 Yes 7.826 <0.0001 50 minutes 81.26 5.53 89.6 6.59 Yes 6.855 <0.0001 60 minutes 79.2 4.55 96.0 12.49 Yes 8.937 <0.0001 Table XVII. Statistical comparison of HR (beats/minute) in the two groups The differences are highly significant from 4th minute onwards.

Period

65

Intra-group comparison at selected periods The comparison of SBP, DBP and heart rate at baseline with the corresponding values at SAB, at 8 minutes and at 60 minutes is presented in Tables XVIII, XIX and XX. Time Group A
Mean (mm Hg) S.D (mm Hg)

T value

p value

Group B
Mean (mm Hg) S.D. (mm Hg)

t value

p value

Baseline 122 7.36 3.505 0.0007 123.9 11.45 0.05 0.9601 SAB 127.1 7.36 124 10.47 Baseline 122 7.36 0.832 0.4075 123.9 11.45 10.54 <0.0001 8 min 120.3 11.84 100.1 11.09 Baseline 122 7.36 4.284 <0.0001 123.9 11.45 2.522 0.0133 60 min 115.6 7.53 118.3 10.41 Table XVIII. Comparison of SBP at baseline with SBP at SAB, at 8 minutes and at 60 minutes

Time

Group A
Mean (mmHg) S.D (mmHg)

t value

p value

Group B
Mean (mmHg) S.D. (mmHg)

t value

p value

Baseline SAB Baseline 8 min Baseline 60 min

79.32 81.7 79.32 76.5 79.32 73.3

4.97 5.95 4.97 7.4 7.36 3.27

2..171 2..237

0.0324 0.0276

7.274 <0.0001

79.06 78.82 79.06 67.38 79.06 76.66

6.73 6.6 6.73 7.92 6.73 6.66

0.135

0.8929

7.906 <0.0001 1.748 0.0897

Table XIX. Comparison of DBP at baseline with DBP at SAB, at 8 minutes and at 60minutes

66

Time

Group A
Mean (beats / min) S.D (beats/ min)

t value

p value

Group B
Mean (beats/ min) S.D (beats / min).

t value

p value

2..624 0.0101 6.484 <0.0001 8 min 82.56 8.11 92.26 9.07 Baseline 78.34 7.97 8.05 0.662 0.5091 81.14 7.071 <0.0001 60 min 79.2 4.55 96 12.49 Table XX. Comparison of heart rate at baseline with heart rate at SAB, at 8 minutes and at 60 minutes

Baseline SAB Baseline

78.34 81.98 78.34

7.97 8.29 7.97

2..238

0.0275

81.14 83.2 81.14

8.05 6.77 8.05

1.385

0.1692

The Haemodynamic variations pertaining specifically to spinal anaesthesia occur during the first 30minutes following the block 10. In intra group comparison of Group A even though SBP at 60 minutes and DBP at 8 and at 60 minutes were statistically significant none of the values are less than 80% of the baseline. In Group B values are statistically significant and the values are less than 80% of the baseline values. . In my Study its been proved beyond doubt that prophylactic Oral Ephedrine is effective in preventing spinal induced hypotension during this period.

The heart rate at SAB and at 8 minutes differed significantly from the baseline value in Group A; in group B, the heart rate at 8 minutes and at 60 minutes differed significantly from the baseline value.

67

Hypotension There were 4 cases of hypotension in Group A, and 20 in Group B. This difference is statistically highly significant (x2 = 12.336, p = < 0.0001) Of the 20 cases of hypotension in Group B, 6 were noted at the 4th minute, another 6 at the 6th minute, 4 at the 8th minute, 2 at the 10th minute and the remaining 2 at the 20th minute (see Graph 13).

2 2 6
4 minutes 6 minutes 8 minutes 10 minutes

20 minutes

Graph 13. Time of onset of hypotension in 20 cases of group B

In 4 patients the hypotension was controlled in less than 6 minutes. In another 4 patients, normal blood pressure was restored in 7- 24 minutes. Ten patients needed 25-48 minutes before regaining normotensive status.

68

Two cases had hypotension lasting for more than 48 minutes. These are shown diagrammatically in Graph 14 and Graph 15.

150 140 130 mmHg Case 1 80% baseline value 120 110 100 90 80 sab 2 4 6 Baseline 8 10 20 30 40 50
50

Time (minutes)

Graph 14. First protracted cases of hypotension

140 120 100 80 10 20 30 40 Baseline sab 60 2 4 6 8

Case 2 80% baseline value

Graph 15. Second protracted case of hypotension. Non-haemodynamic side-effects There was one case of nausea and vomiting in Group A and eight cases in Group B. This difference is statistically significant (x2 = 0.4396, p = 0.036).

60

69

DISCUSSION
Anaesthesiologists master spinal anaesthesia early during there training with achievement of competence (>90% technical success rate) after only 40-70 supervised attempts 13. The ease and long history of success has made Subarachnoid block the anaesthetic procedure of choice for surgeries involving the lower abdomen / lower limbs. Though spinal anaesthesia has a wide range of advantages like the simplicity of technique, its rapid onset of action, economical and minimal postoperative complications, it is not without the risk of physiological side effects on the various systems 46. The most common serious side effects from spinal anaesthesia are hypotension and bradycardia
47

. Large surveillance studies typically observed incidence of

hypotension around 33% and bradycardia around 13% in non-obstetric patient group 13. Hypotension is due to the combined effects of autonomic denervation and the added effect of vagal nerve predominance 10. These lead to: Peripheral venous pooling causing decrease in preload. Arteriolar vasodilatation leading to decrease in afterload. Blockade of cardio-accelerator fibers (T1-T4) leading to bradycardia and decrease in contractility further reducing the blood pressure.

70

Risk factors for hypotension include 13: Spinal block height. Age of 40years and above Baseline systolic blood pressure <120mm of Hg. Spinal puncture above L3-4 intervertebral space. Inferior venacaval vein compression in obstetric patients leading to hindrance to venous return from lower part of the body.

Spinal anaesthesia induced hypotension is treated physiologically by improving the venous return so as to increase the preload thereby restoring the cardiac output. Mechanical methods like head down or leg elevation (10-15) or leg wrapping with elastocrit bandages and splints does not abolish the incidence of hypotension 28, 48. Volume preloading studies have proved beyond doubt that colloids are no better than crystalloids in preventing the incidence of hypotension 49 and has the added set of draw backs like : Increased cost in comparison to crystalloids 50. Anaphylactic reactions 50, 51. Interference with the clotting cascade 52. Interference to Blood Grouping and cross matching studies 53.

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Crystalloids on the other hand are required in great volumes (>15ml/kg) to decrease the incidence of hypotension effects like : Increased central venous pressure 55, 56. Blood dilution leading to decrease in oxygen carrying capacity 57. Release of atrial natriuretic peptide initiating diuresis, thereby attenuating the effect of volume load on blood pressure 58. In due consideration to the above statements it seems appropriate that prophylactic administration of a pharmacologic agent is more effective than prehydration for prevention of hypotension 56, 59, 60. Among the Vasopressors a mixed adrenergic agonist such as Ephedrine more ideally corrects the non cardiac circulatory sequelae of spinal anaesthesia than does either a pure -or -adrenergic agonist 31. There are mixed results to prophylactic administration of I.M. Ephedrine as to its postoperative incidences of hypertensive episodes and alleged unpredictable absorption from the site of injection 61. The belief that a relative overdose may result in hypertension, tachycardia or both postoperatively, and may therefore be detrimental 62. Nevertheless, administration of Ephedrine 37.5mg I.M. was not associated with reactive hypertension or tachycardia in women undergoing caesarean section 40. In other studies patients aged >60years received I.M. Ephedrine for prevention of hypotension. Although the incidence of hypotensive episodes was effectively reduced, all patients experienced a significant decrease in systolic pressure after spinal anesthesia 38.
54

. These huge volumes have detrimental

72

Studies related to prophylactic bolus or infusions of I.V. Ephedrine have proved their efficacy in preventing the episodes of hypotension without unwanted side effects 41, 42, 43. Studies relating to Oral route of prophylactic Ephedrine are sparse. So we conducted this study to determine the safety and efficacy of prophylactic Oral Ephedrine in reducing the incidence of hypotension after subarachnoid block. Changes in Respiratory rate and Oxygen saturation: In the present study all patients were monitored clinically in the intra operative. It was recorded that none of the patients in both the groups had changes in respiratory rate or oxygen saturation.

Incidence of Hypotension: In our study, incidence of hypotension is 8% in Group A patients and 40% in patients of Group B. All these patients who developed hypotension showed a fall in systolic arterial pressure of more than 20% of the base line value within the first 20minutes of intrathecal block. The incidence of hypotension is greater in Group B when compared to Group A which is statistically highly significant (x2 = 12.336, p = < 0.0001) Kafle et al 1994 36 in there study found the incidence of hypotension to be 55% in Group I (ephedrine group) and 83% in Group II (control group). These high incidences of hypotension may be attributed to the high level of sensory block T3-T4 level, higher doses of bupivacaine heavy 0.5% (3.2 to 3.6ml) used and non exclusion of patients who had intraoperative bleeding above 10% in both the groups.

73

Eroglu et al 2003

44

in there study found the incidence of hypotension to be

23.33% in Group I (ephedrine group) and 50% in Group II (control group). These values differ in comparison to my values as the patients enrolled into there study were aged >60years (range 60-87) and belonged to ASA Grades II and III. Both the studies have shown that the incidence of hypotension is statistically lower in patients who have received prophylactic Oral Ephedrine before Subarachnoid block; this is in support to my finding. Intraoperative Supplemental Pressor Agent: In our study patients in whom we noticed a fall in blood pressure, we adopted active measures like head down position, increasing the rate of infusion and oxygenation. If the hypotension continued despite the above measures Inj. Ephedrine hydrochloride 5mg bolus were administered I.V. at 2 minute interval until the blood pressure returned to within 80% of baseline values. In our study 18% of patients in Group B required vasopressors therapy and larger volumes of additional intravenous fluid. In Group A none of the patients received vasopressors and the 8% of patients who had hypotensive episodes were rectified by application of active measures. Kafle et al 1994
36

in there study supplemented Inj. Ephedrine I.V. as soon as

there was a fall in blood pressure and did not use any form of measures used in my study. Patients in Group I (ephedrine group) received 4.34.8mg I.V. Ephedrine and Group II (control group) received 11.69.4mg I.V. Ephedrine which was statistically significant (p<0.01).

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Eroglu et al 2003 44 in there study supplemented Inj. Ephedrine I.V. as soon as there was a fall in blood pressure and did not use any form of measures used in my study. Patients in Group I (ephedrine group) received 3.420.97mg I.V. Ephedrine and Group II (control group) received 8.861.24mg I.V. Ephedrine which was statistically highly significant (p<0.0001). In both the above mentioned studies there is a statistically significant reduction in the supplemental doses of intraoperative I.V. Ephedrine in patients who received prophylactic oral Ephedrine which is consistent with my study. Heart rate: In our study even though both the groups had a statistically non significant variation in the heart rate up to the 2nd minute, there was a steady rise in the heart rate of Group B patients from 4th minute onwards when compared with Group A patients who had none. This can be explained by the intravenous supplements of Ephedrine boluses and increased infusion of Ringer solution in Group B patients who had blood pressure < 80% of baseline values. Kafle et al 1994
36

found in there study that tachycardia did occur in patients

given intravenous Ephedrine to treat the hypotension and none of the patients who received oral Ephedrine prophylactically had tachycardia. This finding is consistent with my study. Eroglu et al 2003 44 recoded six cases of bradycardia in Group II (control group) who responded to Inj. Atropine Intraoperatively. These cases of bradycardia were

75

attributed to the high level of sensory block (T4 level). None of there patients who received Oral Ephedrine had episodes of tachycardia which is consistent with my study. Non-Haemodynamic side effects: The incidence of nausea alone or with vomiting during spinal anaesthesia in our study was 16% in Group B and 2% in Group A which is statistically significant (x2 = 0.4396, p = 0.036). Major causes of nausea and vomiting has been ascribed in part to a reduction in medullary blood flow to the chemoreceptor trigger zone, and therefore Ephedrine is commonly employed to increase mean arterial pressure and presumably improve medullary blood flow. An increase in gastric peristalsis due to preganglionic sympathetic denervation of the stomach may also provoke nausea and vomiting during spinal anesthesia, but whether Ephedrine could mitigate this mechanism remains unknown. Sanjay Datta et al 1982
32

conducted a study on Sixty healthy parturients

scheduled for caesarean section and assessed the effectiveness of intravenous Ephedrine in prevention of hypotension, nausea alone, or with vomiting. They concluded that prompt intravenous administration of Ephedrine as soon as fall in base line blood pressure was detected prevents further fall in blood pressure and markedly reduces the incidence of nausea alone or with vomiting. Kang et al 1982 33 Rothenberg et al 1991 63 designed a study to determine the antiemetic effect of ephedrine in a prospective, randomized, and double blind fashion in patients under going outpatient gynecologic laparoscopy. Before reversal of neuromuscular blockade

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patients either received placebo (0.9% saline I.M.), 0.04mg/kg I.M. Droperidol, or 0.5mg/kg I.M. Ephedrine. They concluded that Ephedrine is an effective prophylactic antiemetic agent in patients having general anaesthesia for outpatient laparoscopy. Gajraj et al 1993 35 Vercauteren et al 2000
41

in there study have shown lower incidence of

nausea in patients who received prophylactic 5mg Inj. Ephedrine I.M. this is consistent with my study. In all the above mentioned studies have demonstrated lower incidence of nausea alone or with vomiting which is in accordance to my study. Central nervous system stimulation and Arrhythmias. In our study group none of the patients who received prophylactic oral Ephedrine had episode of excitability, restlessness or arrhythmias. Kafle et al 1994 36 Eroglu et al 2003 44 Both the above studies did not show any form of central nervous system stimulation or arrhythmias which is consistent with my study. In the present study prophylactic administration of Oral Ephedrine 30mg 30minutes before spinal anaesthesia not only reduced the incidence of hypotension effectively in patients undergoing various elective lower abdomen / lower limb surgeries involving blood loss <10% but also reduces the incidence of Intraoperative nausea and vomiting considerably without any unwanted side effects like central nervous system stimulation, tachycardia or arrhythmias. 77

SUMMARY
This prospective randomized comparative study was designed to know the efficacy and safety of prophylactic oral Ephedrine in prevention of spinal anesthesia induced hypotension. Patients belonging to ASA Grade I & II undergoing elective surgeries on the lower abdomen / lower limb under spinal anaesthesia were randomly allocated into two groups of 50 each. Group A: Received prophylactic Oral Ephedrine 30mg with a sip of water 30minutes before SAB with 3ml of 0.5% hyperbaric bupivacaine hydrochloride. Group B: Received a Placebo (control) with a sip of water 30minutes before SAB with 3ml of 0.5% hyperbaric bupivacaine hydrochloride.

Intraoperatively and postoperatively no significant changes were noted in respiratory rate and oxygen saturation levels in any of the patients in both the groups. Incidence of hypotension was 8% in Group A patients and 40% in Group B patients respectively. Among the hypotensive patients in Group B 12% were recorded at 4th minute, another 12% at 6th minute, 8% at 8th minute, 4% at 10th minute and the remaining 4% at the 20th minute. The numbers of patients receiving vasopressor therapy intraoperatively were higher among Group B (18%) in comparison to Group A which received none. 78

There was incidence of tachycardia in Group B when compared with Group A after the 4th minute of SAB, which was statistically significant (p<0.005) Incidence of non-haemodynamic side effects like Intraoperative nausea and vomiting was 16% in Group B and 2% in Group A respectively. Which is statistically significant (x2 = 0.4396, p = 0.036).

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CONCLUSION
The prophylactic administration of oral Ephedrine in ASA Grade I & II patients undergoing elective surgery under spinal anaesthesia is an effective measure in preventing hypotension without causing untoward side effects like central nervous system stimulation, tachycardia or arrhythmias. To conclude, this study demonstrates that prophylactic Oral Ephedrine is a simple, easy, economical, effective and reliable method not only in preventing the incidence of hypotension but also reduces the incidence of intraoperative nausea and vomiting considerably.

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Anesthesiology.2001; 94:5:888-907. 14. Rout C.C and Rocke D.A. Prevention of Hypotension Following Spinal Anesthesia for Cesarean Section. International Anesthesiology Clinics. 1994; 32:117-135. 15. Critchley L.A.H. Hypotension, Subarachnoid block and the elderly patient. Anaesthesia. 1996; 51, 1139-1143. 16. Margaret W. Local anesthetic agents. In: Wood M and Wood JJA Edt. Drugs and anesthesia. Pharmacology for Anaesthesiologist. 2nd ed, London: Williams and Wilkins. 319-345. 82

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25. Foex. P. Drugs acting on the cardiovascular system. In: Hialy. T. E. J, Knight.P.R Edt: Wylie and Churchill- Davidsons. A Practice of Anesthesia, 7th ed, London, Arnold Publications. 2003:145-166. 26. Aitkenhead RA, Rowbotham JD and Smith G Edt.Drugs acting on the Cardiovascular and autonomic nervous system. In: Text book of anesthesia. 4th ed, London: Churchill Livingstone. 2001; 65-100. 27. Jacobsohn.E. Ephedrine. In: Roizen.M. F, Fleisher. L.A. Edt: Essence of Anesthesia practice, Philadelphia, W.B. Saunders Company 1997:498. 28. Rout C.C, Rocke D.A, Gouws E. Leg elevation and wrapping in the prevention of hypotension following spinal anaesthesia for elective Caesarean section.

Anaesthesia. 1993; 48:304-308. 29. Morgan P. The role of Vasopressors in the management of hypotension induced by spinal and epidural anaesthesia. Can. J. Anaesth. 1994; 41:5:404-13. 30. Wouman.S. B, Marx. G. F. Acute hydration for prevention of hypotension of Spinal anesthesia in parturients. Anesthesiology 1967:29:374-380. 31. Butterworth J.F, Piccione W, Berrizbeitia L.D, Dance. G, Shemin. R. J and Cohn. L. H. Augmentation of Venous Return by Adrenergic Agonists during Spinal Anesthesia. Anesth Analg. 1986; 65:612-6. 32. Datta S, Alpher M.H, Ostheimer G.W, Weiss J.B. Method of Ephedrine Administration and Nausea and Hypotension during Spinal Anesthesia for Cesarean Section. Anesthesiology.1982; 56:68-70.

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British J. Anaesth.1989; 63:340-342. 35. Gajraj N.M, Victory R.A, Pace N.A, Van Elstraete. A. C and Wallace. D. H. Comparison of an Ephedrine infusion with Crystalloid Administration for Prevention of Hypotension during Spinal Anesthesia .Anesth Analg.1993; 76:1023-6. 36. Kafle S.K, Malla S.M, Lekhak B.D. Prophylactic Oral Ephedrine reduces the incidence of hypotension after subarachnoid block.

Can. J. Anaesth.1994; 41:11: 1091-3. 37. Critchley L.A.H, Stuart J.C, Conway.F, Short.T. G. Hypotension during Subarachnoid anaesthesia: Haemodynamic effects of Ephedrine.

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41. Vercauteren M.P, Copejans H.C, Hoffmann V.H, Adriaensen.H. A. Prevention of Hypotension by Single 5-mg Dose of Ephedrine during Small-Dose Spinal Anesthesia in Prehydrated Cesarean Delivery Patients. Anesth Analg. 2000; 90:324-7. 42. Ngan Kee W.D, Khaw K.S, Lee B.B, Lau. T. K, Gin. T. A Dose-Response Study of Prophylactic Intravenous Ephedrine for the Prevention of Hypotension during Spinal Anesthesia for Cesarean Delivery. Anesth Analg.2000; 90:1390-5. 43. Loughrey J.P.R, Walsh F, Gardiner J. Prophylactic intravenous bolus ephedrine for elective Caesarean Section under spinal anaesthesia.

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Prostatectomy. Scand. J. Urol Nephrol, 2003; 37, 145-150. 45. Loughery J.P.R, Yao N, Datta S. Hemodynamic effects of spinal anesthesia and simultaneous intravenous bolus of combined phenylephrine and ephedrine versus ephedrine for cesarean delivery.

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48. Morgan P.J, Halpern S.H, Tarshis J. The Effects of an Increase of Central Blood Volume before Spinal Anesthesia for Cesarean Delivery: A Qualitative Systematic Review. Anesth Analg. 2001; 92:997-1005. 49. Murray A.M, Moragan M, Whitwam J.G. Crystalloid versus Colloid for circulatory preload for epidural Caesarean Section. Anaesthesia. 1989; 44:463-466. 50. Ngan Kee W.D, Khaw K.S, Lee B.B, Wong. M. M. S. Randomized controlled study of Colloid preload before spinal anaesthesia for Caesarean section.

British J. Anaesth. 2001; 87:772-4. 51. McHugh G.J. Anaphylactoid reaction to pentastarch.Can.J.Anaesth.1998; 45:3:270-2. 52. Caruso. J. L, Kirby. R.R. Fluid, Electrolytes, Blood, and Blood substitutes. In: Kirby. R. R, Gravenstein. N, Lobato. E. B, Gravenstein. J. S. Edt: Clinical Anaesthesia Practice, 2nd edition, Philadelphia, W.B.Saunders Company 2002; 770-789. 53. Mc Daniel. L. B, Prough. D. S. Fluid therapy during and after anaesthesia. In: Prys-Roberts. C and Brown Jr. B. R. Edt: International practice of Anaesthesia. Oxford, Butterworth- Heinemann 1996, Volume 1/ Chapter 47/ 1-17. 54. Coe. A.J, Revanas. U.B, Centrallaserettet. K. A. Is Crystalloid preloading useful in spinal anaesthesia in the elderly? Anaesthesia 1990; 45:241-243. 55. Rout C.C, Akoojee S.S, Rocke D.A, Gouws. E. Rapid Administration of Crystalloid Preload does not Decrease the Incidence of Hypotension after Spinal Anaesthesia for Elective Caesarean Section. British J. Anaesth. 1992; 68:394-397. 56. Jackson R, Reid J.A, Thorburn J. Volume preloading is not essential to prevent spinal-induced hypotension at Caesarean section .British J. Anaesth.1995;75:262-265. 87

57. Veyama. H, Yan-lung He, Tanigami. H, Mashimo. T. Effects of Crystalloid and colloid preload on blood volume in the parturient undergoing Spinal anesthesia for elective Cesarean Section. Anesthesiology 1999; 91:6:1571-76. 58. Pouta A.M, Karinen J, Vuolteenaho O.J. Effect of intravenous fluid preload on vasoactive peptide secretion during Caesarean Section under spinal anaesthesia. Anaesthesia. 1996; 51:128-132. 59. Buggy D. Higgins P, Moran C, OBrien. D McCarroll. M. Prevention of Spinal Anesthesia-Induced Hypotension in the Elderly: Comparison between Preanesthetic administration of Crystalloids, Colloids, and No Prehydration.

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PROFORMA
Name: Age: Ward: Anaesthesiologist: Diagnosis: Surgery Performed: IP No. Sex: M / F ASA Grade: I / II Surgeon:

General Physical Examination Height: Built & Nourishment: Weight: Heart Rate: BP:

Pallor/Icterus/Cyanosis/Clubbing/Edema

Systemic Examination Cardiovascular System: Central Nervous System: Respiratory System: Gastrointestinal System: Investigations Hb%: Differential Leukocyte count: Blood Grouping: HIV (ELISA): Total Leukocyte Count: Urine routine: B.T & C.T: Hb-S Ag:

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If Patient above 40years: Blood Urea: Serum Creatinine: ECG:

Blood Sugars (if urine sugars positive):

Pre-Medication: Tab. Ranitidine 150mg 1 H.S Tab. Diazepam 10mg 1 H.S Night before surgery for Both the Groups

Group A. Tab Ranitidine 150mg 2hours before surgery. Tab. Ephedrine 30mg with sip of water 30minutes before SAB. Group B. Tab Ranitidine 150mg 2hours before surgery. Placebo with sip of water 30minutes before SAB. Baseline Values: Heart rate: Respiratory rate: Regional Anaesthesia: Procedure: SAB Posture: Lateral position Right / Left Site of Injection: L3-L4 intervertebral space. Drug: Inj. Bupivacaine heavy 3ml. Level of Blockade: SBP: Spo2: DBP: MAP:

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Parameters Recorded:

Time At SAB 2 min 4 min 6 min 8 min 10 min 20 min 30 min 40 min 50 min 60 min 75 min 90 min

SBP

DBP

MAP

HR

RR

Spo2

Drugs used

Side Effects

I.V. Fluids used: IF BP falls > 20% baseline (1) Head low: (3) Total Inj. Ephedrine Dose Used: (2) Increase I.V. Fluids:

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92

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A RANDOMISED CLINICAL TRIAL OF COMPARISON BETWEEN PROPHYLACTIC ORAL EPHEDRINE AND CONTROL (WITHOUT ORAL EPHEDRINE) IN REDUCING THE INCIDENCE OF HYPOTENSION FOLLOWING SUBARACHNOID BLOCK

By

Dr. RAGHAVENDRA.R., M.B.B.S.


Dissertation Submitted to the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore In partial fulfillment of the requirements for the degree of

M.D. DEGREE IN ANAESTHESIOLOGY


Under the guidance of

Dr. PREMKUMAR.B., D.A, M.D.


Professor, Department of Anaesthesiology

DEPARTMENT OF ANAESTHESIOLOGY

SREE SIDDHARTHA MEDICAL COLLEGE


TUMKUR SEPTEMBER 2006

DECLARATION BY THE CANDIDATE


I hereby declare that this dissertation/thesis entitled A randomized clinical trial of comparison between prophylactic oral Ephedrine and control (without oral ephedrine) in reducing the incidence of hypotension following subarachnoid block is a bonafide and genuine research work carried out by me under the guidance of Dr. Prem Kumar. B.

Date: Place: Tumkur Dr.RAGHAVENDRA.R. Postgraduate in Anaesthesiology, Sree Siddhartha Medical College, Tumkur

- ii -

CERTIFICATE BY THE GUIDE

This is to certify that this dissertation entitled A randomized clinical trial of comparison between prophylactic oral Ephedrine and control (without oral ephedrine) in reducing the incidence of hypotension following subarachnoid block is a bonafide research work done by

Dr.RAGHAVENDRA.R. in partial fulfillment of requirement for the degree of Master of Medicine in Anaesthesiology.

Date: Place: Tumkur Dr.PREMKUMAR.B. , DA, MD. Professor, Dept. of Anaesthesiology Sree Siddhartha Medical College, Tumkur

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ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE INSTITUTION


This is to certify that the dissertation entitled A randomized clinical trial of comparison between prophylactic oral Ephedrine and control (without oral ephedrine) in reducing the incidence of hypotension following subarachnoid block is a bonafide research work done by

Dr.RAGHAVENDRA.R. under the guidance of Dr.PREMKUMAR.B.

Seal & Signature of the HOD Name Date:

Seal & Signature of the Principal Name Date:

Place:

Place:

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INTRODUCTION
Spinal anaesthesia was introduced into clinical practice by August Bier in 1898 even before the break-through of orotracheal intubation by Franz Kuhn in 1901. The only anaesthetic techniques to precede it were topical anaesthesia of the eye by Carl Koller and infiltration anaesthesia by Carl-Ludwig Schleich in 1892 1. Spinal anaesthesia has enjoyed a long history of success and recently celebrated a centennial anniversary.

Regional techniques are the preferred Anaesthetic procedure for surgeries involving abdomen and lower extremities. The various advantages include 2: 1. Blunting of stress response to surgery 2. Avoidance of intubation 3. Decrease in intraoperative blood loss 4. Earlier return of gastrointestinal function 5. Lower incidence of postoperative throboembolic events.

The unavoidable sequence of spinal anaesthesia is blockade of sympathetic preganglionic efferents leading to peripheral venous pooling causing hypotension. Therapies are primarily aimed at reducing the severity of hypotension, they include prophylactic leg elevation and wrapping, use of inflatable boots, preloading of the patient with crystalloids and colloids, lateral uterine displacement in Obstetric patients, and vasopressors used as last resort with varying results.

Ephedrine the most commonly used among vasopressors to treat spinal induced hypotension
2, 3

. Studies in relation to prophylactic parenteral Ephedrine have been

described earlier in plenty compared to oral Ephedrine studies which are sparse. So this prospective randomized study is performed to determine the efficacy of prophylactic oral Ephedrine in preventing spinal hypotension following subarachnoid block in our patient group.

AIMS OF STUDY

To determine the safety and efficacy of prophylactic oral Ephedrine in reducing the incidence of hypotension following subarachnoid block.

REVIEW OF LITERATURE
HISTORY OF SPINAL ANAESTHESIA 3, 4, 5. The concept of local analgesia began with demonstration of anaesthetic properties of cocaine eye drops by Koller in 1884 and neural blockade by Halsted in 1885. The term Spinal anaesthesia was introduced by Corning in1885. Corning with the aim of injecting Cocaine between the spinal processes for means of managing neurologic disorders instead accidentally injected it epidurally in 1885. The present day spinal anaesthesia and technique of lumbar puncture was described by Quincke in 1891. The first two publications on spinal anaesthesia for surgical procedures were made in 1899 by Bier in the first paper later on by Tuffier. Bier had used it for surgeries on the lower limbs and Tuffier to relieve pain of sarcoma of the leg in a young man. Kries in 1900 used spinal analgesia for caesarean section, during the same year W.S.Bainbridge reported his first successful case of paediatric spinal analgesia. Dowitz in 1903 added adrenaline to prolong the anaesthetic effect, substitutes to cocaine emerged due to its toxic effects with Procaine (Novocaine) by Einhorn and Stovaine by Fourneau in 1905. Next series of studies were aimed at achieving higher levels of spinal blockade, formulation of alcohol mixture with local anaesthetic to make it lighter than cerebrospinal fluid.

Group A

Sl.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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

Age Sex Height Weight Cms Kgs LAKSHAMMA 1350/3905 40 F 158 52 AMZAD KHAN 1150/3704 21 M 164 50 MANJAIAH 1359/3913 25 M 158 61 ANAND SWAMY 364/4375 35 M 162 68 SUMANTH 466/4477 40 F 148 55 JAYALAKSHMI 1322/5333 21 F 152 44 PRADEEP KUMAR 1146/5157 24 M 158 56 TAHEERA BANU 421/5817 32 F 160 50 GOVINDARAJU 474/5870 45 M 164 64 LAKKAMMA 779/7577 45 F 158 50 SANNAPUTTAMMA 1017/7815 48 M 150 46 RENUKAMMA 979/7777 32 F 157 55 PATHLINGAPPA 1340/8138 40 F 159 62 YASHODA 96749 22 F 156 56 NAGESH 96652 23 M 164 50 SHETTALAMMA 1344/8142 46 F 153 54 GANGAMMA 1355/8153 38 F 156 52 HANUMANTHIAH 73/8399 26 M 152 48 SUMA 96774 28 F 151 54 PANCHAKSHARIAH 96125 36 M 159 60 LALITHAMMA 1157/7955 30 F 156 61 BANUPRAKASH 97425 35 M 155 56 NARASIMHARAJU 50/8376 26 M 157 58 RAVINAYAK 197/8523 34 M 162 64 LOHITH 2458 23 M 157 56 DODDANANIAH 97428 46 M 160 66 RAFFULLA 651/8977 24 M 162 47 BETTAIAH 800/9136 21 M 169 53 UMESH 926/9252 28 M 153 59 RAMANJANAPPA 96270 30 M 161 64 RANGAPPA 97267 40 M 162 62 ARUN KUMAR 96432 30 M 165 64 PUTTAGANGAMMA 96393 45 F 158 59 MUNIYAPPA 96210 36 M 170 65 SOWBAGYA 97277 25 F 160 58 SACHIN 97069 32 M 156 52 ASHWATHAMMA 97294 38 F 161 67 RADHAMMA 1786 35 F 158 60 NARASIMHA 1827 40 M 161 59 JULABEE 94459 45 F 155 50 JAYAMMA 1110/8214 46 F 166 56 RANGAMMA 98134 35 F 163 62 VIJAYA 1158 22 F 156 44 DORESWAMY 1914 40 M 155 56 RANGIAH 99658 38 M 170 66 RADHAMMA 1786 35 F 162 60 PUTTASWAMY 1174 32 M 149 58 GANGAMMA 800/10957 35 F 166 79 SIDDARAJU 1189/11396 42 M 172 72 SUSHEELA 1171/11434 22 F 156 46

Patient Name

I.P.NO.

Diagnosis III UV Prolapse Rt sided inguinal hernia # Rt Patella Recurrent Appendicitis Acute appendicitis Acute appendicitis Recurrent appendicitis III Heamorroids III Heamorroids III UV Prolapse Recurrent Appendicitis Chronic Fissure Rt sided inguinal hernia Chronic Fissure Acute appendicitis Incisional Hernia Chronic Fissure Lt Sided Varicose Veins Acute appendicitis Rt Sided Hydrocele Rt Inguinal Hernia II Haemorroids Acute appendicitis Lt Sided Inguinal Hernia Congenital Hydrocele Rt Sided Inguinal Hernia Chronic Fissure Acute appendicitis Acute appendicitis II Haemorroids Rt sided inguinal hernia # Lt Patella Rt Varicose Veins Perianal Abscess Recurrent Appendicitis Bilateral Varicocele Incisional Hernia Chronic Fissure Non Healing Ulcer Rt Leg Rt Sided Ovarian Mass III UV Prolapse Chronic Fissure Fistula in Ano' II Haemorroids III Haemorroids Chronic Fissure Rt Hydrocele Incisional Hernia Rt Sided Inguinal Hernia Recurrent Appendicitis

Procedure Vaginal hysterectomy Herniorraphy Herniorraphy Appendicectomy Appendicectomy Appendicectomy Appendicectomy Haemorroidectomy Haemorroidectomy Vaginal Hysterectomy Appendicectomy Fissurectomy & Lords Dilatation Herniorraphy Fissurectomy & Lords Dilatation Appendicectomy Herniorraphy Fissurectomy & Lords Dilatation Multiple Subfascial Ligation Appendicectomy Hydrocele Excision Herniorraphy Haemorroidectomy Appendicectomy Herniorraphy Hydrocele Excision Herniorraphy Fissurectomy & Lords Dilatation Appendicectomy Appendicectomy Haemorroidectomy Herniorraphy Patella Excision Venous Stripping Drainage Appendicectomy Varicocelectomy Anatomical Repair Fissurectomy & Lords Dilatation Skin Grafting Ovariectomy Vaginal Hysterectomy Fissurectomy & Lords Dilatation Fistulectomy Haemorroidectomy Haemorroidectomy Fissurectomy & Lords Dilatation Hydrocele Excision Anatomical Repair Herniorraphy Appendicectomy

Group A

Sl.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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 SBP 116 126 124 135 120 136 118 131 126 122 120 126 124 128 110 112 120 110 126 114 128 120 112 116 122 128 123 118 126 122 126 112 116 126 120 118 120 128 130 110 120 130 114 118 132 115 123 128 136 118

Basal Reading DBP MAP HR 78 90.667 72 86 99.333 92 84 97.333 84 80 98.333 74 79 92.667 82 90 105.33 92 76 90 66 92 105 92 82 96.667 84 83 96 88 76 90.667 84 84 98 76 72 89.333 76 80 96 84 76 87.333 78 72 85.333 92 80 93.333 80 76 87.333 78 84 98 80 72 86 78 84 98.667 76 76 90.667 72 78 89.333 82 78 90.667 72 83 96 74 88 101.33 64 76 91.667 76 78 91.333 76 78 94 73 82 95.333 78 79 94.667 76 70 84 82 72 86.667 72 82 96.667 88 80 93.333 76 80 92.667 74 78 92 70 84 98.667 84 86 100.67 81 70 83.333 72 80 93.333 76 82 98 72 76 88.667 70 77 90.667 64 82 98.667 83 74 87.667 70 72 89 68 76 93.333 100 84 101.33 92 79 92 72

SBP 126 134 129 137 124 140 117 138 130 120 124 128 132 124 120 116 128 118 138 118 136 124 111 121 128 134 130 126 131 132 131 116 115 132 128 124 126 134 133 114 126 138 122 128 138 122 126 132 138 120

AT SAB DBP MAP 82 96.667 91 105.33 86 100.33 90 105.67 82 96 92 108 82 93.667 88 104.67 84 99.333 82 94.667 80 94.667 90 102.67 76 94.667 70 88 79 92.667 74 88 82 97.333 74 88.667 82 100.67 71 86.667 86 102.67 80 94.667 76 87.667 68 85.667 85 99.333 91 105.33 78 95.333 77 93.333 80 97 82 98.667 82 98.333 73 87.333 70 85 86 101.33 85 99.333 82 96 84 98 88 103.33 90 104.33 74 87.333 84 98 84 102 81 94.667 82 97.333 89 105.33 78 92.667 80 95.333 82 98.667 89 105.33 82 94.667

HR 82 92 80 76 78 98 62 96 84 86 90 80 82 84 80 92 74 72 83 88 82 78 88 74 84 71 86 76 70 82 82 86 90 98 92 90 86 89 96 70 78 70 76 74 86 76 76 70 90 74

SBP 126 132 131 140 117 141 126 124 124 127 122 131 130 130 120 117 126 119 133 116 137 126 114 130 128 132 123 128 136 126 140 120 114 130 130 125 118 138 138 114 132 144 134 136 144 126 132 138 144 128

2 MINUTES DBP MAP 83 97.3333 94 106.667 84 99.6667 88 105.333 83 94.3333 86 104.333 81 96 84 97.3333 70 88 74 91.6667 70 87.3333 95 107 72 91.3333 80 96.6667 80 93.3333 71 86.3333 81 96 73 88.3333 75 94.3333 77 90 90 105.667 73 90.6667 70 84.6667 69 89.3333 82 97.3333 86 101.333 78 93 76 93.3333 83 100.667 78 94 80 100 82 94.6667 72 86 82 98 88 102 88 100.333 78 91.3333 88 104.667 92 107.333 70 84.6667 86 101.333 88 106.667 80 98 84 101.333 94 110.667 80 95.3333 90 104 90 106 100 114.667 88 101.333

HR 82 82 96 78 76 84 96 64 92 78 82 91 87 79 82 80 94 76 71 85 86 89 88 92 86 88 72 72 77 72 79 89 86 96 92 90 90 90 94 72 84 70 76 72 100 78 82 71 88 80

SBP 125 134 125 142 130 137 117 133 119 125 122 127 127 128 122 115 124 117 124 120 133 127 108 126 126 125 117 126 127 129 136 124 111 127 129 125 112 136 137 120 140 122 136 136 142 122 134 136 134 126

4 MINUTES DBP MAP 81 95.67 94 107.3 79 94.33 92 108.7 86 100.7 85 102.3 73 87.67 78 96.33 65 83 82 96.33 74 90 77 93.67 73 91 76 93.33 80 94 70 85 72 89.33 71 86.33 77 92.67 76 90.67 86 101.7 86 99.67 68 81.33 71 89.33 86 99.33 86 99 70 85.67 74 91.33 84 98.33 75 93 82 100 82 96 70 83.67 83 97.67 85 99.67 86 99 70 84 89 104.7 92 107 70 86.67 88 105.3 80 94 82 100 80 98.67 94 110 82 95.33 92 106 90 105.3 92 106 86 99.33

HR 84 98 82 68 78 92 60 90 78 89 88 78 81 84 76 90 78 80 91 84 92 90 94 84 94 72 74 77 76 82 81 86 86 93 94 94 88 88 96 72 82 69 76 74 104 76 78 74 86 79

SBP 118 131 120 132 127 132 114 134 117 101 119 120 128 120 122 112 128 120 118 124 134 127 78 122 124 124 113 125 122 127 125 116 114 128 133 130 100 130 133 116 126 120 112 118 136 120 122 133 130 122

6 MINUTES DBP MAP 68 84.667 84 99.667 75 90 86 101.33 85 99 82 98.667 74 87.333 84 100.67 72 87 68 79 80 93 75 90 76 93.333 80 93.333 80 94 65 80.667 78 94.667 75 90 73 88 74 90.667 87 102.67 86 99.667 56 63.333 64 83.333 80 94.667 83 96.667 72 85.667 73 90.333 82 95.333 75 92.333 79 94.333 74 88 71 85.333 86 100 85 101 86 100.67 68 78.667 84 99.333 92 105.67 68 84 78 94 72 88 70 84 78 91.333 92 106.67 76 90.667 86 98 86 101.67 86 100.67 80 94

HR 86 89 84 75 74 90 62 88 80 80 93 73 76 80 79 94 80 70 88 86 96 89 90 98 94 73 72 74 84 79 83 88 78 92 92 94 94 83 95 72 88 78 78 80 100 78 82 76 82 80

Group A

Sl.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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 SBP 111 124 116 129 131 130 118 137 124 88 112 124 140 118 120 110 132 116 114 116 135 120 86 119 127 120 112 125 126 123 126 114 100 142 127 128 88 130 130 114 126 122 114 113 132 116 116 130 126 120

8 MINUTES DBP MAP 68 82.333 78 93.333 76 89.333 82 97.667 84 99.667 85 100 74 88.667 85 102.33 69 87.333 62 70.667 72 85.333 70 88 71 94 86 96.667 80 93.333 64 79.333 78 96 74 88 71 85.333 74 88 86 102.33 70 86.667 61 69.333 78 91.667 85 99 82 94.667 70 84 72 89.667 83 97.333 71 88.333 82 96.667 71 85.333 68 78.667 80 100.67 84 98.333 86 100 60 69.333 84 99.333 90 103.33 71 85.333 74 91.333 76 91.333 75 88 76 88.333 90 104 78 90.667 78 90.667 84 99.333 78 94 79 92.667

HR 88 90 88 80 70 90 62 92 82 92 86 72 77 81 74 92 100 78 72 88 92 86 92 72 88 76 72 81 87 77 80 85 86 88 92 90 88 83 96 74 90 76 78 82 98 80 76 74 79 76

SBP 114 123 121 124 130 131 120 112 116 92 118 120 137 122 122 111 130 117 112 118 131 113 88 119 117 119 113 116 129 122 122 110 81 137 126 124 93 132 131 112 120 119 118 114 134 117 118 132 122 116

10 MINUTES DBP MAP 70 84.667 80 94.333 83 95.667 84 97.333 83 98.667 84 99.667 72 88 68 82.667 68 84 65 74 77 90.667 79 92.667 70 92.333 75 90.667 80 94 65 80.333 76 94 73 87.667 65 80.667 75 89.333 84 99.667 70 84.333 64 72 68 85 78 91 80 93 69 83.667 72 86.667 85 99.667 70 87.333 80 94 66 80.667 59 66.333 80 99 80 95.333 82 96 66 75 86 101.33 90 103.67 70 84 72 88 76 90.333 72 87.333 84 94 92 106 76 89.667 80 92.667 86 101.33 76 91.333 72 86.667

HR 84 88 86 82 68 88 60 94 76 90 90 76 78 75 82 94 90 72 79 88 94 90 88 78 84 74 74 85 84 82 76 90 94 86 96 90 88 85 91 73 86 78 80 80 102 82 74 68 82 82

SBP 122 121 117 116 128 123 116 120 123 104 123 119 136 124 118 108 130 114 114 115 130 114 94 106 118 122 115 105 127 120 116 108 96 136 125 124 106 130 128 110 119 118 126 113 130 116 116 130 123 118

20 MINUTES DBP MAP 73 89.333 71 87.667 73 87.667 72 86.667 79 95.333 80 94.333 82 93.333 72 88 71 88.333 68 80 71 88.333 80 93 72 93.333 72 89.333 78 91.333 66 80 78 95.333 74 87.333 70 84.667 66 82.333 89 102.67 72 86 66 75.333 75 85.333 77 90.667 78 92.667 73 87 71 82.333 86 99.667 72 88 78 90.667 70 82.667 68 77.333 82 100 78 93.667 80 94.667 70 82 86 100.67 90 102.67 70 83.333 78 91.667 76 90 77 93.333 70 84.333 90 103.33 76 89.333 72 86.667 80 96.667 78 93 76 90

HR 80 86 84 80 70 88 64 86 82 94 86 74 78 73 79 90 94 78 82 90 92 86 83 72 86 78 74 84 83 79 82 83 88 84 93 86 88 85 88 76 82 76 80 78 96 76 76 72 80 86

SBP 125 125 126 114 120 129 124 118 117 106 124 126 117 139 120 120 110 132 120 116 114 130 102 112 118 114 117 116 120 125 125 112 100 139 120 124 108 128 130 106 116 121 120 119 128 120 120 128 118 118

30 MINUTES DBP MAP 75 91.667 77 93 74 91.333 72 86 82 94.667 78 95 82 96 73 88 72 87 70 82 80 94.667 76 92.667 75 89 72 94.333 80 93.333 65 83.333 76 87.333 72 92 76 90.667 71 86 88 96.667 70 90 67 78.667 75 87.333 72 87.333 80 91.333 79 91.667 72 86.667 82 94.667 77 93 75 91.667 68 82.667 70 80 82 101 76 90.667 80 94.667 71 83.333 87 100.67 86 100.67 68 80.667 75 88.667 74 89.667 79 92.667 72 87.667 86 100 74 89.333 76 90.667 78 94.667 76 90 76 90

HR 74 88 83 79 69 86 66 88 84 86 80 80 75 79 78 88 94 74 80 88 90 93 86 76 86 81 73 84 78 74 81 76 82 84 96 86 86 87 89 76 78 76 76 83 94 78 82 77 82 84

SBP 120 118 116 118 125 120 114 118 125 112 117 122 126 125 123 112 128 124 115 110 124 113 109 117 112 116 115 119 125 118 114 110 104 136 120 124 111 128 130 108 116 120 118 120 130 118 116 129 122 112

40 MINUTES DBP MAP 68 90 75 94 82 88 74 92 79 88.333 70 89.333 74 87.333 74 90.667 77 89.667 72 92.667 83 85.667 70 95.333 82 93.333 77 96.333 82 84.333 65 92 82 98.667 84 91.333 75 82.333 66 95.333 88 89.333 72 79.667 63 87 76 87 72 88.667 77 86 71 90.333 78 95.667 84 91 74 90 76 83.333 68 83.333 70 88 80 96 76 93.333 80 88 70 95 87 100 86 88.667 68 86 75 86.667 72 90.667 76 88.667 74 100 90 91.333 72 88.667 74 92 80 92.333 74 90 74 37.333

HR 84 84 86 82 76 82 62 86 76 83 84 79 76 74 77 90 86 80 82 92 86 86 82 73 88 79 76 80 76 78 82 78 81 80 94 86 86 80 84 78 78 72 76 73 94 76 77 77 80 80

Group A

Sl.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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 SBP 120 116 116 112 120 121 110 126 120 114 115 118 127 125 122 110 132 120 113 108 129 110 114 116 113 117 116 107 119 121 116 110 104 134 108 120 117 126 130 106 115 120 118 116 132 118 114 120 116 120

50 MINUTES DBP MAP 75 90 76 89.33 78 90.67 68 82.67 75 90 71 87.67 80 90 81 96 72 88 72 86 70 85 73 88 77 93.67 82 96.33 75 90.67 66 80.67 86 101.3 70 86.67 76 88.33 70 82.67 85 99.67 72 84.67 68 83.33 76 89.33 74 87 77 90.33 79 91.33 75 85.67 72 87.67 73 89 70 85.33 69 82.67 68 80 80 98 72 84 79 92.67 80 92.33 86 99.33 86 100.7 68 80.67 73 87 72 88 77 90.67 70 85.33 94 106.7 72 87.33 78 90 82 94.67 78 90.67 76 90.67

HR 83 88 90 88 92 81 82 84 79 78 86 83 74 79 75 92 88 82 79 86 92 88 84 80 82 78 74 78 79 70 79 70 83 80 80 86 83 80 82 76 80 74 76 76 92 82 80 80 76 78

SBP 109 118 109 114

60 MINUTES DBP MAP 68 81.67 73 88 74 85.67 70 84.67

110 71 118 77 123 79

84 90.67 93.67

106 68 121 71 112 127 116 112 108 117 114 68 86 70 66 70 77 72

80.67 87.67 82.67 99.67 85.33 81.33 82.67 90.33 86

123 70 116 72 102 65 110 70 104 66 113 74 118 84 128 80 104 66 114 72 107 70

87.67 86.67 77.33 83.33 78.67 87 95.33 96 78.67 86 82.33

104 116 124 114 120

68 76 76 73 73

80 89.33 92 86.67 88.67

75 MINUTES 90 MINUTES Level of Side HR SBP DBP MAP HR SBP DBP MAP HR block Effects 78 101 65 77 81 T8 76 T8 92 T8 83 102 66 78 88 T8 T8 T8 T6 T6 T8 78 112 70 84 76 110 69 82.67 79 T8 N&V 83 113 71 85 80 T8 T6 73 T8 T8 T6 90 108 65 79.33 87 T6 T8 82 120 73 88.67 80 T8 T8 90 T8 94 T8 86 T6 84 T8 76 T8 79 T8 76 T8 T6 T6 70 T8 T6 76 T8 70 99 66 77 72 T8 76 112 70 84 73 112 72 85.33 74 T8 T8 82 T8 88 T6 86 T6 T8 70 125 76 92.33 69 T8 76 T6 76 100 68 78.67 80 T6 T8 84 T8 T8 T8 84 T8 82 T6 81 T8 73 T6 76 T6

Group B

Sl.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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

Patient Name RAMANJANAPPA RATHNAMMA PARVATHAMMA ERAPPA THIMMAIAH ASHWATHAMMA DODDANIAH SIDDAGANGAMMA BASAVARAJU SRIRANGAPPA RATHNAMMA RAJU RANGAMMA RAGHUNATH CICILY VINCENT MUBARAK BORELINGIAH MASTAN VENKATARAMIAH SRINIDHI VIJAYALAKSHMI MADHUMATHI KRISHNA RAHEENA SHIVAMMA JULABEE SIDDAREDDY NAZERBEE RESHMA RANGANATH KAVERAMMA PUTTASWAMY SEETHAMMA VIJAYALAKSHMI ERANNA SHABANA RASHMI SHARADHA NARASIMHA JAYARAJ UMESH DODANARSIAH KESHAVA GOWRAMMA LOHITH ASMA KADREGOWDA MARAMMA NAGRAJU UMADEVI

I.P.NO. 96270 96550 97090 96962 7288 97294 97428 97395 97403 97525 97942 98193 98134 98360 97103 98689 99023 98762 98671 99106 99275 99360 99468 98112 99459 99476 35 213 526 733 1129 1174 1236 1716 1894 436/7218 1764 1884 1827 534/7316 1857 676/7458 2416 2534 2458 436/7218 2432 534/7316 864/11021 2562

Age Sex Height Weight Diagnosis Procedure Cms Kgs 30 M 158 59 II Haemorroids Haemorroidectomy 34 F 155 60 Recurrent Appendicitis Appendicectomy 44 F 157 59 Cronic Fissure in Ano Fissurectomy & lords Dilatation 36 M 162 57 Rt Sided Inguinal Hernia Herniorraphy Acute Appendicitis Appendicectomy 35 M 164 62 38 F 156 56 Incisional Hernia Mesh Repair 46 M 168 64 Rt Sided Inguinal Hernia Herniorraphy 34 F 155 48 Acute Appendicitis Appendicectomy 40 M 160 63 Rt Sided Inguinal Hernia Herniorraphy 46 M 158 58 Lt Sided Inguinal Hernia Herniorraphy 35 F 155 46 Incisional hernia Anatomical Repair 30 M 156 54 III Haemorroids Haemorroidectomy 35 F 160 51 Fissure in Ano Fissurectomy & lords Dilatation 25 M 156 56 Rt Sided Inguinal Hernia Herniorraphy 46 F 159 49 Ulcer on left leg Curretage & Skin Graft 20 M 161 52 Lt Sided Inguinal Hernia Herniorraphy Appendicectomy 24 M 156 53 Recurrent Appendicitis Acute Appendicitis Appendicectomy 36 M 170 59 40 M 165 61 Varicose veins Lt leg Multiple Subfascial Ligation Acute Appendicitis Appendicectomy 38 M 162 64 Acute Appendicitis Appendicectomy 26 F 153 56 38 F 164 63 II Haemorroids Haemorroidectomy 38 M 148 52 Acute Appendicitis Appendicectomy 45 F 146 59 Rt Sided Inguinal Hernia Herniorraphy 36 F 150 53 Fissure in Ano Fissurectomy & lords Dilatation 49 F 162 66 III U V Prolapse Vaginal Hysterectomy 43 M 160 53 Varicose veins Rt leg Venous Stipping 27 F 154 44 Perinial Abscess Drainage 32 F 157 56 Fistula in Ano Fistulectomy 28 M 161 58 Lt Sided Inguinal Hernia Herniorraphy 42 F 156 57 Paraumbilical Hernia Anatomical Repair 35 M 158 58 Rt Sided Hydrocele Hydrocele Excision 46 F 160 60 Fistula in Ano Fistulectomy 38 F 148 55 Incisional Hernia Mesh Repair 28 M 172 70 Fistula in Ano Fistulectomy 36 F 150 54 Fissure in Ano Fissurectomy & lords Dilatation Appendicectomy 26 F 155 51 Recurrent Appendicitis 50 F 158 58 III U V Prolapse Vaginal Hysterectomy 40 M 163 61 Non Healing Ulcer Rt leg Skin Grafting 56 M 156 56 Varicose Veins Rt leg Multiple Subfascial Ligation Skin Grafting 30 M 169 62 Ulcer on Rt foot 49 M 165 58 Rt Sided Hydrocele Hydrocele Excision 24 M 163 55 Fistula in Ano Fistulectomy 50 F 160 57 Lipoma Thigh Excision 21 M 158 43 Rt Sided Hydrocele Hydrocele Excision 23 F 159 46 Acute Appendicitis Appendicectomy 32 M 161 57 Fissure in Ano Fissurectomy & lords Dilatation 52 F 158 58 Lt Ovarian Mass Excision 49 M 170 63 Varicose Veins Venous Stipping Appendicectomy 33 F 161 56 Recurrent Appendicitis

Group B

Sl.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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

Basal Reading SBP DBP MAP HR 114 72 86 80 126 70 88.67 86 110 78 88.67 70 132 82 98.67 76 140 84 102.7 70 129 78 95 88 130 68 88.67 90 120 80 93.33 82 123 76 91.67 86 138 90 106 90 132 80 97.33 82 108 76 86.67 86 120 84 96 72 116 70 85.33 68 140 88 105.3 82 118 76 90 78 138 84 102 90 132 82 98.67 82 139 88 105 86 112 73 86 73 106 68 80.67 66 120 70 86.67 94 133 87 102.3 84 130 90 103.3 82 110 70 83.33 80 140 80 100 86 134 86 102 74 106 86 92.67 96 128 78 94.67 84 120 82 94.67 80 110 76 87.33 86 104 77 86 76 140 87 104.7 83 136 82 100 80 126 70 88.67 90 138 86 103.3 83 130 72 91.33 84 110 86 94 82 114 72 86 70 110 86 94 68 132 74 93.33 82 110 72 84.67 90 108 68 81.33 62 120 80 93.33 74 128 86 100 90 130 82 98 68 110 74 86 92 120 72 88 76 140 90 106.7 92 132 82 98.67 86

SBP 113 126 116 132 140 130 130 121 120 136 130 110 120 120 136 120 140 130 136 116 108 120 130 130 112 140 130 106 128 120 110 110 142 140 120 140 130 116 110 114 130 106 110 116 130 126 116 120 136 130

AT SAB 2 MINUTES 4 MINUTES 6 MINUTES DBP MAP HR SBP DBP MAP HR SBP DBP MAP HR SBP DBP MAP HR 70 84.33 82 110 70 83.333 84 108 69 82 83 100 70 74.67 90 74 91.33 72 113 70 84.333 86 100 68 78.67 88 100 62 77.33 86 72 86.67 76 100 73 82 77 98 70 79.33 76 92 66 81.33 84 86 101.3 80 130 84 99.333 76 123 79 93.67 78 112 76 90.67 73 80 100 73 136 79 98 74 126 82 96.67 76 110 80 80 75 76 94 86 122 70 87.333 83 108 68 81.33 88 100 65 74.67 90 70 90 84 118 68 84.667 88 98 60 72.67 93 94 62 78 100 82 95 86 114 78 90 82 110 76 87.33 88 100 70 80 86 82 94.67 82 116 78 90.667 84 109 74 85.67 89 98 70 80.67 86 92 106.7 92 126 84 98 88 117 76 89.67 84 104 72 77.33 90 84 99.33 86 123 80 94.333 82 112 70 84 90 103 64 77 96 70 83.33 83 103 68 79.667 86 100 70 80 84 98 64 79.33 100 80 93.33 78 122 84 96.667 88 110 80 90 88 96 70 72 90 78 92 76 114 76 88.667 80 108 70 82.67 82 93 60 79 88 90 105.3 80 128 82 97.333 79 114 78 90 86 106 72 82 94 82 94.67 84 120 80 93.333 94 110 76 87.33 78 107 70 83.67 74 80 100 96 132 76 94.667 93 126 74 91.33 98 116 72 84 96 78 95.33 86 120 76 90.667 92 104 70 81.33 100 94 68 78 104 86 102.7 82 130 82 98 80 118 76 90 90 112 70 82 93 76 89.33 82 115 73 87 85 107 70 82.33 84 100 67 72 90 70 82.67 68 108 71 83.333 70 96 64 74.67 84 90 58 78 92 70 86.67 90 118 68 84.667 92 110 72 84.67 76 106 72 87.33 70 84 99.33 80 110 70 83.333 88 110 76 87.33 86 112 78 77.33 82 88 102 83 121 79 93 84 100 69 79.33 90 93 60 72.33 72 68 82.67 82 100 68 78.667 83 90 60 70 98 106 62 82 89 76 97.33 88 130 78 95.333 86 126 76 92.67 85 121 70 89.67 88 80 96.67 84 120 80 93.333 78 118 72 87.33 74 108 74 88 76 80 88.67 100 100 80 86.667 88 100 78 85.33 92 110 78 86 94 80 96 86 108 76 86.667 88 100 76 84 93 102 74 80.67 90 78 92 82 120 70 86.667 84 110 75 86.67 84 90 70 71.33 93 74 86 93 106 70 82 96 100 66 77.33 102 96 62 80.67 100 73 85.33 80 100 74 82.667 76 102 76 84.67 88 108 73 82.67 90 84 103.3 86 126 80 95.333 84 115 78 90.33 89 110 70 80.67 84 86 104 84 118 78 91.333 90 108 70 82.67 96 102 66 80.67 98 80 93.33 84 116 80 92 84 100 70 80 84 103 70 85 86 88 105.3 80 130 80 96.667 82 120 76 90.67 88 108 76 86 89 86 100.7 86 120 84 96 82 110 73 85.33 84 105 75 73.67 84 80 92 84 98 60 72.667 90 94 58 70 88 90 58 71.33 102 68 82 83 97 68 77.667 86 90 62 71.33 89 94 62 78 93 82 92.67 74 109 70 83 100 104 68 80 101 103 70 69 96 80 96.67 86 120 88 98.667 88 98 60 72.67 100 82 52 73.33 96 66 79.33 87 100 68 78.667 84 105 70 81.67 82 102 69 86 86 68 82 66 104 64 77.333 72 116 73 87.33 74 114 78 87.33 78 74 88 76 110 76 87.333 88 100 76 84 102 108 74 82.67 96 88 102 94 120 80 93.333 100 110 74 86 106 100 70 80 98 80 95.33 75 140 88 105.33 68 120 72 88 76 122 70 82 80 70 85.33 96 100 74 82.667 92 90 70 76.67 96 86 62 64.67 98 80 93.33 83 113 76 88.333 86 96 72 80 88 82 54 79.33 90 88 104 90 130 82 98 87 122 80 94 90 122 78 86 94 79 96 84 126 72 90 106 120 70 86.67 108 116 68 38.67 110

Group B

Sl.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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 SBP 96 100 96 100 102 94 96 104 106 96 106 100 94 82 110 102 108 98 106 96 72 108 106 94 104 124 102 106 100 104 92 106 98 98 100 102 106 86 92 98 76 102 118 106 106 122 72 82 126 105

8 MINUTES DBP MAP 64 100 66 88 69 92 74 88 76 95.333 64 98 66 96 68 96 73 95.333 68 90.667 68 90 68 97.333 72 88.667 52 90 69 96 70 86 76 102.67 70 100.67 68 99.333 62 94.667 52 94.667 72 89.333 70 92.667 62 86 62 97.333 74 103.33 73 86 78 96.667 74 93.333 70 92 60 94.667 77 96.667 70 90 72 96.667 66 93.333 73 91.333 72 91.333 53 99.333 64 90.667 66 99.333 48 98.667 66 88.667 80 88.667 72 103.33 72 102.67 72 92.667 50 94.667 46 96.667 78 108.67 62 109.67

HR 102 82 90 82 92 100 96 92 90 88 82 96 86 94 89 78 100 102 96 94 106 80 86 82 94 93 78 92 90 86 96 92 86 96 90 86 84 106 90 100 110 82 74 102 101 78 106 104 100 112

SBP 100 92 100 106 104 94 102 106 102 94 98 98 104 90 102 94 100 106 96 88 84 110 94 92 106 110 100 100 118 100 76 110 116 100 93 110 96 92 106 86 104 96 105 118 100 110 96 105 120 110

10 MINUTES DBP MAP 68 97.33 63 100 70 90.67 70 88.67 77 94 62 94 70 92.67 70 91.33 68 91.33 66 94 62 94 63 95.33 66 90.67 62 95.33 68 91.33 70 87.33 68 97.33 64 98 60 93.33 54 100 56 94.67 70 88.67 62 94 65 89.33 60 99.33 70 102.7 69 90.67 76 88.67 68 90 69 95.33 52 94.67 73 94 72 105.3 69 104 63 96.33 70 91.33 64 88 52 100 62 96.67 58 88 70 101.3 60 99.33 74 89.67 76 98.67 69 98.67 80 84.67 62 93.33 60 103 82 104 66 108.7

HR 96 104 86 80 89 94 88 84 86 94 92 94 84 98 86 84 96 94 92 106 100 78 94 88 96 99 86 83 76 93 104 86 100 106 98 82 84 104 92 89 100 101 82 89 98 72 92 102 96 108

SBP 102 96 100 100 106 96 100 103 80 100 98 103 110 98 100 86 108 105 98 76 98 116 106 103 108 110 86 104 110 100 112 103 106 100 98 106 93 100 103 94 102 98 106 101 105 103 98 100 121 104

20 MINUTES DBP MAP 66 98 66 100 73 88.67 70 86.67 76 94 66 96 70 92 72 94.33 54 88.67 68 95.33 66 94.67 70 94.33 72 91.33 64 99.33 63 93.33 58 91.33 60 97.33 68 97 68 91.33 52 94.67 62 96.67 70 90.67 60 106 62 101 60 100 72 98.67 63 100.7 71 92 73 96.67 76 92 72 109.3 76 93 70 103.3 69 102.7 62 96.67 60 90 68 93 60 101.3 65 94.33 70 88.67 69 101.3 68 95.33 76 92.67 78 88.33 74 101.7 76 89.67 70 94 68 100 76 101.7 62 105.3

HR 96 102 83 80 88 96 88 90 93 93 93 90 82 100 90 94 92 93 88 104 96 78 106 100 96 93 108 86 90 88 108 88 102 104 96 82 93 102 90 86 101 94 86 82 100 83 92 100 92 106

SBP 102 100 104 106 110 100 103 100 90 100 96 109 100 108 103 94 106 103 106 108 116 118 100 101 103 118 90 110 113 94 110 112 109 102 100 103 110 94 104 100 102 100 103 110 96 94 104 106 129 110

30 MINUTES DBP MAP 68 92.67 69 100 70 88 72 91.33 69 96.67 70 88 68 91.67 74 94.67 56 96.67 70 92 64 92 68 95 76 90.67 68 105.3 68 90.33 60 99.33 66 99.33 66 94.33 64 92.67 68 100 69 104 66 91.33 67 102 64 103.7 70 91.67 68 96.67 66 99.33 76 94 71 97.67 78 90 70 105.3 78 98.67 76 103 68 102 65 94.67 65 91.67 65 96.67 65 102 65 93.33 65 89.33 65 104.7 65 93.33 65 87.67 65 92.67 65 93.33 65 91.33 65 98.67 65 94.67 65 103 65 108.7

HR 88 100 80 84 90 82 86 92 100 88 90 88 86 104 84 102 96 90 86 96 98 78 103 105 86 86 104 86 90 88 103 92 100 102 92 86 90 106 88 84 106 90 80 84 92 90 96 89 90 108

SBP 104 102 106 104 96 99 100 107 100 106 109 110 104 106 110 100 103 110 109 112 116 112 106 101 106 110 100 110 116 102 116 110 112 100 100 112 114 120 100 103 113 102 116 113 103 100 110 103 139 111

40 MINUTES DBP MAP 66 92 70 95.333 69 90.667 68 92 63 93.333 65 90.333 70 88 70 97 60 101.33 72 91.333 68 99 70 95.333 72 90.667 64 106 68 95.333 66 102.67 65 97 70 92 66 96.333 72 94 70 97.333 74 90.667 68 100.67 63 104.33 70 94 72 91.333 63 100 76 91.333 68 100 69 91.333 72 102.67 76 96 68 105.33 70 97.333 64 96 76 97.333 73 95.333 84 104 68 90 76 90.333 72 89.667 64 95.333 80 98.667 69 95 70 94.333 70 90.667 82 100 72 93 84 107.67 68 106.33

HR 86 92 83 86 92 86 82 92 102 84 94 88 84 106 88 104 94 83 90 85 88 80 98 106 88 82 100 82 92 86 96 89 102 96 94 90 86 96 85 84 78 92 90 86 90 86 95 88 92 104

Group B

Sl.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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 SBP 101 103 106 108 102 110 96 111 116 100 110 107 108 112 100 110 102 110 105 114 112 104 110 112 104 114 113 110 105 112 116 113 108 100 110 116 115 124 102 103 110 112 116 110 113 109 114 118 136 114

50 MINUTES DBP MAP 65 89.67 68 95.67 65 88.67 67 101.3 70 98 66 102 68 90.67 74 93 66 98.67 66 95.33 70 97.33 69 95.67 70 94.67 66 104 72 89.33 69 103.3 64 96.67 70 92.67 68 93.67 74 94.67 66 98.67 70 92 65 96.67 68 102.7 68 85.33 70 99.33 73 101.7 71 94 65 97.67 73 93.33 71 98.67 74 95 70 98 76 96 68 100.7 74 96 76 102.3 90 104 70 91.33 75 89.67 76 86 70 92.67 73 95.33 76 88.67 71 99 74 94.33 80 100.7 76 99.33 82 101.3 70 110

HR 84 92 80 98 96 98 88 84 90 93 91 90 88 100 84 100 94 84 88 85 92 86 90 98 76 92 96 86 94 84 90 86 93 94 96 86 96 94 86 83 74 83 85 78 92 87 94 90 84 108

60 MINUTES 75 MINUTES SBP DBP MAP HR SBP DBP MAP HR 104 66 88 80 101 103 112 108 64 84.33 76 70 101 100 65 99.33 93 70 99.33 95 108 70 99.33

95

110 72 94 86 106 68 96.67 92 108 70 96 90

107 103 104 100

63 99.67 96 68 91 85 71 96 92 106 72 83.33 72 102.7 104

90

107 70 95.67 90 110 70 94 86 103 67 91.67 86 106 110 116 112 108 116 112 107 110 114 110 118 114 117 107 100 108 110 112 114 113 68 104.7 104 69 91.33 82 72 100 92 110 70 83.33 74 96 88 118 72 87.33 68 75 70 80 72 75 68 76 74 86 69 70 78 72 76 70 73 96 97.33 94.67 94.33 96.67 102 96.67 100.7 101.3 101 94.33 92.67 84 90.67 92.67 91.33 97.67 90 88 86 88 90 96 90 92 95 93 88 89 72 81 83 80 90 100 75 83.33 114 79 90.67 101 69 79.6

91 86 92 94 82

115 82 111 71 103 70

93 84.3 81

90 86 83

115 75 99.67 92 116 72 86.66 130 84 100.7 86 110 71 110 110

90

Level of 90 MINUTES SBP DBP MAP HR block T6 T6 T8 T8 T6 T6 T8 T6 T8 T8 T6 T8 T8 T6 T8 T6 T6 T6 T8 T6 T6 T8 T6 T6 T8 112 71 84.6 88 T8 T8 T10 T8 T8 110 72 84.6 83 T6 T8 T8 T8 T8 T8 T6 116 81 93.7 86 T8 T8 T8 T8 T8 T8 T6 T8 T6 T8 T6 T8 T6

Side Effects

N&V

N&V

N&V

N&V

N&V

N&V N&V

N&V