Comparative Study between Volume Preload versus Ephedrine Infusion for Prevention of Hypotension Due to Spinal Anesthesia for Caesarean Section

Abstract

Comparative Study between Volume Preload versus Ephedrine Infusion for Prevention of Hypotension Due to Spinal Anesthesia for Caesarean Section Thesis Submitted for Partial Fulfillment of Master Degree in Anaesthesia By Omnia Samy Mohamed Elkordy M.B.B.Ch., Under Supervision of Prof./ Samia Abdel Mohsen Abdel Latif Professor of Anaesthesia and Intensive Care Faculty of Medicine – Ain Shams University Dr./ Amal Hamed Abdel Hamid Rabie Lecturer of Anaesthesia and Intensive Care Faculty of Medicine – Ain Shams University Dr./ Ahmed Abdel Dayem Abdel Haak Lecturer of Anaesthesia and Intensive Care Faculty of Medicine – Ain Shams University Faculty of Medicine Ain Shams University 2019

بسم الله الرحمن الرحيم وَقُلِ اعْمَلُواْ فَسَيَرَى اللّهُ عَمَلَكُمْ وَرَسُولُهُ وَالْمُؤْمِنُونَ

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Acknowledgments First and foremost, I feel always indebted to Allah the Most Beneficent and Merciful. I wish to express my deepest thanks, gratitude and appreciation to Prof./ Samia Abdel Mohsen Abdel Latif, Professor of Anaesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, for her meticulous supervision, kind guidance, valuable instructions and generous help. Special thanks are due to Dr./ Amal Hamed Abdel Hamid Rabie, Lecturer of Anaesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, for her sincere efforts, fruitful encouragement. I am deeply thankful to Dr./ Ahmed Abdel Dayem Abdel Haak, Lecturer of Anaesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, for his great help, outstanding support, active participation and guidance. I would like to express my hearty thanks to all my family for their support till this work was completed. Omnia Samy Elkordy

List of Contents Title Page No. List of Tables 5 List of Figures 6 Introduction - 1 - Aim of the Work 11 Review of Literature 12 Patients and Methods 34 Results 47 Discussion 55 Summary 61 Conclusion 63 References 64 Arabic Summary

List of Tables Table No. Title Page No. Table (1): Demographic Data of patients included in the study 47 Table (2): Systolic BP 48 Table (3): Heart Rate trends. 50 Table (4): Incidence of Complications: 52 Table (5): Number of ephedrine boluses required to correct hypotension: 53 Table (6): Oxygen saturation: 54

List of Figures Fig. No. Title Page No. Figure (1): Chemical formula of bupivacaine 25 Figure (2): Pharmacological structure of ephedrine. 29 Figure (3): Systolic Blood pressure trends. 49 Figure (4): Heart rate trends. 51 Figure (5): Incidence of complications. 52 Figure (6): Number of ephedrine boluses required to correct hypotension. 53

List of Abbreviations Abb. Full term ABP Arterial blood pressure ACC Aortocaval compression ACTH Adreno cortico tropic hormone AP Arterial pressure ASA American society of anesthesiologists BMI Body mass index BP Blood pressure CO Cardiac output COPD Chronic obstructive pulmonary disease C-section Ceasarean section CSF Cerebrospinal fluid EBP Epidural blood patch ECG Electrocardigraphy FRC Functional residual capacity GA General anesthesia GFR Glomerular filtration rate HR Heart rate IM Intra-muscular INR International normalized ratio IV Intra-venous IVC Inferior venacava L.As Local anesthetics MAP Mean arterial blood pressure NIBP Non-invasive arterial blood pressure PDPH Post dural puncture headache PT Prothrombin time PTT Partial thromboplastin time RR Respiratory rate SPO2 Peripheral oxygen saturation SVR Systemic vascular resistance TNS Transient neurological symptoms

INTRODUCTION A caesarean section (C-section), is a form of childbirth in which a surgical incision is made through a mother's abdomen (laparotomy) and uterus (hysterotomy) to deliver one or more babies. It is usually performed when a vaginal delivery would lead to medical complications. The anesthetic plan for cesarean delivery should take into account the well-being of two patients: the mother and the fetus. Regional anesthesia is the most common method of anesthesia for delivery because it allows the mother to be awake and immediately interact with her baby. It is also safer for the mother than general anesthesia.(1) Spinal anesthesia is often used for genital, urinary tract, or lower body procedures. A successful regional anaesthesia effectively suppresses many of the pain mediated stress responses to surgery such as rise in blood pressure, heart rate and increase in plasma concentrations of catecholamines, cortisol and glucose. Spinal block is also associated with lesser amount of surgical haemorrhage. (2) Spinal anaesthesia produces few adverse effects on the respiratory system as long as unduly high blocks are avoided.(3) As control of the airway is not compromised, there is a reduced risk of airway obstruction or the aspiration of gastric contents. post-operative deep vein thrombosis and pulmonary emboli are less common following spinal anesthesia.(4) Hypotension is the most common complication of spinal anaesthesia for cesarean section. It can cause significant morbidity and mortality. It could be associated with severe nausea and vomiting and serious risk to the mother (unconsciousness and pulmonary aspiration) and baby (hypoxia, acidosis, and neurological injuries). (5) Hypotension is due to sympathetic nervous system blockade which result to decreased systemic vascular resistance and peripheral pooling of blood with decreases cardiac output. Aortocaval compression (ACC) can result in haemodynamic disturbances and uteroplacental hypoperfusion in parturients. The incidence of hypotension and high spinal anaesthesia is higher in cesarean sections (6). Various attempts have been made to reduce the incidence and severity of hypotension including expansion of intravascular volume with up to 2liters of fluids. The use of lateral uterine displacement is a routine procedure to prevent hypotension. intravenous fluid preload has been shown to reduce the risk of hypotension but doesn't eliminate it and many patients still need vasopressor treatment to correct hypotension. parenteral ephedrine may be an effective alternative. (7) Ephedrine is a non-catecholamine sympathomimetic agent that stimulates alpha and beta adrenergic receptors directly and predominantly indirectly, producing its effects by releasing norepinephrine from nerve endings in the autonomous nervous system. Traditionally it is the vasopressor of choice in spinal anesthesia despite the lack of confirmation of its superiority over other vasopressors.(8)

AIM OF THE WORK T he aim of this study is to evaluate the efficacy of intravenous ephedrine versus preload crystalloid administration in reducing the incidence of hypotension during spinal anaesthesia.

REVIEW OF LITERATURE Physiological changes during pregnancy: P regnancy and delivery are associated with vast physiological changes. Those related to pulmonary and cardiovascular systems are of fundamental importance to anaesthesiologist. Respiratory system: To accommodate the increased O2 demand and requirement for carbon dioxide elimination, pregnancy is associated with an increase in the respiratory minute volume and work of breathing. The most impressive change in maternal lung dynamics is a decrease in functional residual capacity (FRC), which at term may have changed by as much as 20% of pr e pregnancy values. Minute ventilation increases by 45% primarily as a result of an increase in the tidal volume because the respiratory rate is essentially unchanged. There is a liability to rapid development of hypoxia as result of decreased FRC and increased oxygen consumption. (9) Capillary engorgement of mucosa and oedema of the orophyranx, larynx, and trachea may result in a difficult intubation. (9)

Cardiovascular system: Cardiac output increases from the fifth week of pregnancy and reaches its maximum levels (approximately 40% of non pregnant values) at 32 weeks. It is due to an increase in the heart rate and the more important factor is the stroke volume. Changes in heart rate are difficult to quantify but it is thought that approximately 20% increase in heart rate present by fourth week of pregnancy. Tachyarrhythmias are more common especially later in pregnancy as a result of both hormonal and autonomic factors. (10) Aortocaval compression by the gravid uterus (supine hypotension syndrome): It occurs in 10-20 % of pregnant females, after 28 weeks of pregnancy. (11) Hematologic system: Maternal blood volume begins to increase early in pregnancy as a result of changes in osmoregulation and the renin- angiotension system causing sodium retention and increasing the total body water by 8.5 litters (L). By term, blood volume increases up to 45% whereas red cell volume increase by only 30%, this differential increase leads to physiological anemia of pregnancy. A state of hypercoaguability exists in pregnancy with an increased level of most coagulation factors mainly fibrinogen and factor VII. (12)

Gastrointestinal system: Although progesterone relaxes smooth muscles, it impairs esophageal and intestinal motility during pregnancy. It has recently been suggested that gastric emptying is not always delayed in pregnant woman, however risk of aspiration remains when caesarean section is done under general anaesthesia. (13) Central nervous system: From early pregnancy, when neuroaxial anaesthesia is administered women require less local anaesthetic than non pregnant women to reach a given dermatomal sensory level because the epidural veins become congested secondary to increase in intra abdominal pressure and epidural space becomes narrower. (14) Renal system: It undergoes many changes in pregnancy, mainly because of the effect of progesterone and the mechanical effects of compression of the gravid uterus. Urea, creatinine and uric acid clearance all increase. Renal plasma flow and glomerular filtration rate (GFR) both also increase rapidly. Glycosuria is common finding in pregnancy. (15)

Physiological changes in anatomy of epidural and subarchnoid spaces in pregnancy: The epidural space in pregnant women might be reduced due to engorgement of veins in the extra-dural space, compression of the subarachnoid space, and reduction in the volume of cerebrospinal fluid. Engorgement of veins in the extra-dural space and increased pressure are secondary to the increased intra-abdominal pressure, which causes compression of the inferior vena cava and consequent reduction in the volume of cerebrospinal fluid. Thus, it is more difficult to predict the extension of the blockade when using the same dose of local anaesthetics in obese and non-obese pregnants. (16) Besides, it is known that the need of local anesthetic in spinal anaesthesia is lower in pregnants especially obese. Mechanisms suggested for this include pregnancy-specific hormonal changes, which affect the action of neurotransmitters in the spinal column, increased permeability of neural membranes. Also, exaggerated lumber lordosis may increase cephaled spread of L.As. (17) Physiological changes during subarachnoid analgesia In pregnancy there are haemodynamic changes in the form of: (18) • Cardiac output rises by 30-40% gradually till the time of delivery. • Blood volume increases by 15-45%, with relative anaemia • Blood pressure slightly decreases as pregnancy progresses. These are accompanied with changes in peripheral blood distribution; the uterus enlarges in size with growth of foetus and placenta. At full term the uterus contains about one-sixth of the mother`s blood volume. The result of such an increase of peripheral blood volume with a concomitant decrease in central blood volume may worsen hypotension during spinal analgesia. (18) Even with the same level of spinal analgesia, hypotension is greater in pregnant than non pregnant women. Moreover, the gravid uterus affects the circulation by its weight compressing the inferior vena cava and partially obstructing the aorta. (19)This will diminish the venous return to the heart, also the arterial blood supply to the pelvic organ and lower extremities are decreased, but the clinical manifestations of compression vary individually according to the degree of the obstruction as well as the degree of compensation. Decreased venous return due to mild to moderate inferior vena cava obstruction can be compensated by an increase in heart rate. (18) Only when such compensatory mechanism is attenuated, cardiac output decreases dramatically and supine hypotension occurs, 10% of women show severe hypotension in supine position in late pregnancy. Pulmonary ventilation mechanisms are little changed even at full term. The elevation of diaphragm during the last trimester tends to decrease the vital capacity but is compensated by widening of the subcostal angle. (18) Effect of spinal anaesthesia on the foetus Spinal anaesthesia has no direct effect on the foetus, but indirectly it impairs maternal circulation to the placenta to an extent causing reduction of oxygen supply across the placenta. But this impairment to the placental circulation does not reach a point that foetal oxygenation is handicapped.(20)

Complications of spinal analgesia in obstetric: 1. Hypotension Hypotension represents incidence of about 55–100%, so it is the most frequent complication. Moreover, hypotension is hazardous for the mother and the baby as it can cause loss of consciousness, aspiration. (21) Hypotension after spinal anaesthesia occurs mainly due to sympathetic block which depend on the height of block. (22) This sympathectomy causes venous and arterial vasodilation, but because of the large amount of blood in the venous system (approximately 75% of the total volume of blood), the venodilation effect predominates as a result of the limited amount of smooth muscle in venules; in contrast, the vascular smooth muscle on the arterial side of the circulation retains a considerable degree of autonomous tone. After neuraxial block–induced sympathectomy, if normal cardiac output is maintained, total peripheral resistance should decrease only 15% to 18% in normovolamic healthy patients. (23) Pregnant women have an elevated resting sympathetic tone and thus increased effects of sympathetic blockade. This also leads to decreased sensitivity to vasopressors, secondary to downregulation of adrenergic receptors and increased synthesis of endothelium-derived vasodilators during pregnancy. Spinal anaesthesia abolishes labor pain, which can decrease maternal blood pressure. (24) Pregnant women have increased sensitivity (i.e. increased peak block height and block duration) to spinal anaesthesia, due to a combination of reduced volume of spinal cerebrospinal fluid (CSF) and enhanced neural susceptibility to local anaesthetics. Aortocaval compression by he gravid uterus,if present, further contributes to hypotension.(24) Aortocaval compression (ACC) occurs when the gravid uterus compresses the maternal abdominal aorta and inferior vena cava (IVC). Compression of the IVC impedes venous return which decreases cardiac output (CO), and compression of the aorta may reduce utero-placental perfusion which may result in fetal acidosis . (25)It is recommended that the ACC be avoided by applying lateral uterine displacement. This can be achieved by tilting the operating table, although the effectiveness of this manoeuvre is unclear and the optimal degree of tilt is unknown. (26) The majority of patients who have ACC are clinically asymptomatic and supine hypotension develops only if ACC is severe, in nearly 8% of the patients. (27) Patients who are asymptomatic with ‘concealed’ ACC are able to maintain their arterial pressure (AP), despite a reduction in CO by compensatory mechanisms such as an increased systemic vascular resistance (SVR). However, these patients may develop severe hypotension as a result of sympathetic blockade during spinal anaesthesia. (28) Treatment of supine hypotension syndrome after 28th week of pregnancy by: 1. Lateral uterine displacement (usually to the left side, >15 degree) by;  Rotating the delivery table to the left.  Placing a pillow or wedge under the right side of the back and buttock. 2. I.v. fluids. 3. I.v. ephedrine (if hypotension occurs). (29) 2. Postdural Puncture Headache (PDPH) PDPH is a common complication of spinal analgesia. Parturient constitutes the highest risk category, the reported incidence in these patients varying between 0 and 30%.The risk of PDPH is less with epidural anaesthesia, but it occurs in up to 50% of young patients following accidental meningeal puncture with large-diameter needles. The headache is characteristically mild or absent when the patient is supine, but head elevation rapidly leads to a severe fronto-occipital headache, which again improves on returning to the supine position. Occasionally, cranial nerve symptoms (e.g., diplopia, tinnitus) and nausea and vomiting are also present. The headache is believed to result from the loss of CSF through the meningeal needle hole, resulting in decreased beyond the support for the brain. In the upright position the brain sags in the cranial vault, putting traction on pain-sensitive structures. Traction on cranial nerves is believed to cause the cranial nerve palsies that are seen occasionally. (30) The incidence of PDPH decreases with increasing age and with the use of small-diameter spinal needles with non cutting tips to less than 3%.(31) Inserting cutting needles with the bevel aligned parallel to the long axis of the meninges has also been shown to decrease the incidence of PDPH. (32) PDPH is usually self-limiting and spontaneous resolution may occur in few days. Therefore, many authors recommend approximately 24 h of conservative therapy. Various pharmacological (e.g. Methylxanthines, ACTH, Caffeine) and interventional measures (e.g., epidural saline/dextran) are available to treat PDPH; epidural blood patch (EBP) has a 96–98% success rate and has been recognized as the definitive treatment for PDPH. (33) 3. Backache Back pain in women during pregnancy is up to 76%. Also, has been cited in one study as the most common reason for patients to refuse future spinal block. (34) The etiology of backache is not clear, although needle trauma, local anaesthetic irritation, and ligamentous strain secondary to muscle relaxation have been offered as explanations. (35)

4. Needle breakage, infection, haematoma and oedema. Infections such as epidural abscess or meningitis are extremely rare. Infection may be exogenous in origin and be caused by the contamination of equipment or pharmacologic agents or by colonization of the catheter. Endogenous spread may occur from a site of infection elsewhere in the body. (36) The incidence of neurologic injury resulting from haematoma associated with neuraxial anaesthesia is very low, with estimates of 1 in 150,000 and 1 in 220,000 for epidural and spinal anaesthesia, respectively. A review of 61 cases of spinal haematoma associated with spinal or epidural anaesthesia reported evidence of haemostatic abnormality in 68% of patients and difficult or bloody placement of needles and catheters in 25% of cases. In 15 of the reported cases the patients received spinal anaesthesia, with the remaining 46 receiving epidural anaesthesia. (37) 5. Systemic Toxicity Toxicity occurs due to overdosage or intravascular injection of the local anaesthetic. The signs are excitement, disorientation, twitches, convulsions and perhaps apnea with severe cardiac depression. (38)

6. Total Spinal Anaesthesia Total spinal anaesthesia occurs when local anaesthetic spreads high enough to block the entire spinal cord and occasionally the brainstem during either spinal or epidural analgesia. Profound hypotension and bradycardia are common secondary to complete sympathetic blockade. Respiratory arrest may occur as a result of respiratory muscle paralysis or dysfunction of brainstem respiratory control centers. Management includes vasopressors, atropine, and fluids as necessary to support the cardiovascular system, plus oxygen and controlled ventilation. If the cardiovascular and respiratory consequences are managed appropriately, total spinal block will resolve without sequelae. (39,40) 7. Neurologic Injury Persistent parasthesias and limited motor weakness are the most common injuries, although paraplegia and diffuse injury to cauda equina roots (cauda equina syndrome) do occur rarely. Injury may result from direct needle trauma to the spinal cord or spinal nerves, from spinal cord ischemia, from accidental injection of neurotoxic drugs or chemicals, from introduction of bacteria into the subarachnoid or epidural space, or very rarely from epidural haematoma. (41)

9. Nausea and vomiting Nausea and vomiting are common side effects in parturients undergoing caesarean delivery performed under spinal anaesthesia can be very unpleasant to the patients. The reported incidence of nausea and vomiting during caesarean performed under regional anaesthesia varies from 50% to 80% when no prophylactic antiemetic is given. (42) Nausea and vomiting are commonly associated with hypotension, bradycardia and high sensory block (T5 and above). It is usually corrected as the blood pressure is restored to normal. Persistent nausea and vomiting are treated by antiemetics. (43) 10. Urine retention Not more common after spinal than after general anaesthesia and usually yields to neostigmine 0.5 mg. IM. (44) 11. Shivering Shivering-like tremor in patients given neuraxial anaesthesia is always preceded by core hypothermia and vasoconstriction (above the level of the block). The local anaesthetic blocks the inhibitory pathways in the brain and thus produce excitatory signs such as shivering, It is uncomfortable for the patients and may interfere with monitoring of electrocardiogram, blood pressure (BP) and oxygen saturation.(45) Pharmacological considerations A. Pharmacology of Bupivacaine Bupivacaine hydrochloride is a local anesthetic that is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. It contains an amide linkage between the aromatic nucleus and the piperidine group. (46)

Figure (1): Chemical formula of bupivacaine.(46) Bupivacaine is present in a hyperbaric or plain form. The hyperbaric one is prepared by the addition of glucose and is suitable for spinal anesthesia. Its specific gravity is between 1.030 and 1.035. (47) Levobupivacaine hydrochloride is the S (-) - stereoisomer of bupivacaine that is less cardiotoxic than the later on a per milligram basis. Also, levobupivacaine provides sensory block that is more intense than that of bupivacaine although motor block is greater for the later. This could be explained by the ability of levobupivacaine to widen the sensory-motor dissociation. (48) Pharmacokinetics: 1- Absorption: The rate of systemic absorption of bupivacaine, as other local anesthetics, is dependent upon: (49) • The total dose and concentration of bupivacaine administered. • Route of administration. • Vascularity of the administration site. • The presence or absence of epinephrine in the anesthetic solution. 2- Distribution: Bupivacaine has a high binding capacity to non-albumin proteins (95%). It crosses the placenta by passive diffusion. After injection for caudal, epidural or peripheral nerve blocks, peak levels in blood are reached in 30 to 45 minutes, followed by decline to insignificant levels during the next three to six hours. The half life in adults is approximately 2.7 hours.(50) 3- Metabolism: Bupivacaine is metabolized in the liver via conjugation with glucuronic acid. Pipecoloxylidine is its major metabolite.(50) 4- Excretion: Bupivacaine is excreted through the kidney. Only 6 to 7% are excreted unchanged in the urine.(50) 5- Duration of action: The duration following spinal administration is about 90 to 120 minutes. The duration of two segments regression following epidural administration is approximately 2.5 hours.(50) Mechanism of action: Bupivacaine acts by binding to sodium channels in the inactivated state, preventing subsequent channel activation and the large transient sodium influx associated with membrane depolarization. (51) Contraindication: The drug is contraindicated in case of known hypersensitivity to any local anesthetic of the amide type. Also, it is not used for obstetrical paracervical block anesthesia as it may cause fetal bradycardia and death (52) Special conditions: Geriatric patients: elderly patients may require lower doses of bupivacaine hydrochloride. They also may be at increased risk for developing hypotension particularly those with hypertension. (53) Patients with severe hepatic disease: may be more susceptible to the potential toxicity. Adverse reactions: These reactions are related to excessive plasma levels due to overdosage (maximum safe dose is 3 mg/kg)(54), unintentional intravascular injection or slow metabolic degradation. One of the specific features of bupivacaine is that its toxic effects on the cardiovascular system appear earlier than on the central nervous system. This is due to the fact that bupivacaine is highly protein bound, the free concentration of the drug in plasma remains low until all the protein binding sites are fully occupied, after which, it increases rapidly and toxicity occurs without patients exhibiting signs of central nervous system toxicity. (55) This cardiotoxic effect is much less with levobupivacaine.(56) CNS reactions:  Excitation and/or depression.  Restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors and finally convulsions.  Drowsiness merging into unconsciousness and respiratory arrest. (57) CVS reactions: Decreased cardiac output, heart block, hypotension and bradycardia. Ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation and cardiac arrest. (57) B. Pharmacology of ephedrine: Description: • Ephedrine is a sympathomimetic drug. • Chemically designated α-[1-(methylamino) ethyl] benzenemethanol sulfate (2:1) (salt). It has the following structural formula. Figure 3 (58)

Figure (2): Pharmacological structure of ephedrine.

Mechanism of Action: Two mechanisms of action direct and indirect: • Indirect sympathomimetic effect: ephedrine releases endogenous norepinephrine from its storage sites. Norepinephrine, in turn, stimulates various alpha and beta-receptors. • Direct effect: by stimulate beta-receptors directly, particularly in bronchiolar smooth muscle. Beta-adrenergic effects result from the production of cyclic-AMP by activation of the enzyme adenylate cyclase .(59) • Up to 40% of a single dose of ephedrine is excreted unchanged in the urine. Some ephedrine is deanimated by MAO in the liver, and conjugation also occurs.(60) Pharmacokinetic data • Metabolism: minimal liver • Onset of action: IV (seconds), IM (10 min to 20 min) • Elimination half-life: 3 h to 6 h • Duration of action: IV/IM (60 min) • Excretion: 22% to 99% (urine) • Dose: Initial dose: 5-10 mg IV bolus (must dilute) Administer additional boluses as needed, not to exceed a total cumulative dosage of 50 mg.(61) Cardiovascular effects of ephedrine: The cardiovascular effects of ephedrine resemble epinephrine, but its blood pressure-elevating response is less intense and lasts approximately 10 times longer. It requires approximately 250 times more ephedrine than epinephrine to produce equivalent blood pressure responses. Intravenous administration of ephedrine results in increases in systolic and diastolic blood pressure, heart rate, and cardiac output. Renal and splanchnic blood flows are decreased, whereas coronary and skeletal muscle blood flows are increased.(62) Systemic vascular resistance may be altered minimally because vasoconstriction in some vascular beds is offset by vasodilation (beta-2 stimulation) in other areas. These cardiovascular effects are due, in part, to alpha receptor-mediated peripheral arterial and venous constriction.(63) The principal mechanism, however, for cardiovascular effects produced by ephedrine is increased myocardial contractility owing to activation of beta-1 receptors. In the presence of preexisting beta blockade, the cardiovascular effects of ephedrine may resemble responses more typical of alpha-receptor stimulation.(63) A second dose of ephedrine produces a less intense blood pressure response than the first dose. This phenomenon, known as tachyphylaxis, occurs with many sympathomimetics and is related to the duration of action of these drugs. Tachyphylaxis probably represents a persistent blockade of adrenergic receptors. For example, ephedrine-induced activation of adrenergic receptors persists even after blood pressure has returned to near predrug levels by virtue of compensatory cardiovascular changes. When ephedrine is administered at this time, the receptors still occupied by ephedrine limit available sites and the blood pressure response is less. Alternatively, tachyphylaxis may be due to depletion of norepinephrine stores.(64) Pharmacology of Ringer's solution Ringer's solution may be considered as normal saline solution. Modified by the substitution of potassium and calcium for some of the sodium, in concentrations approximately those of plasma.(65)

Composition Sodium chloride 0.86gm/100ml Potassium chloride 0.030gm/100ml Calcium chloride 0.033gm/100ml Indications  Dehydration following reduced water intake or increased water loss (vomiting, diarrhea, fistulous drainage),  Ringer's solution can be used to treat mild alkalosis and hypochloremia.(66) Contraindications Addison's disease. Dosage and administration The usual dose for adults is 1-2 litres per day, may be given as rapidly as 30 ml per kg per body weight per hour unless there are cardiac or other contraindications to rapid infusion.(66)

PATIENTS AND METHODS T his study was conducted in the obstetric department of Al Matarya Teaching Hospital on fifty parturient undergoing elective caesarean section after the approval of the ethical medical committee. A written consent was taken from all patients who were either class I or II according to the classification of the American society of Anesthesiologists ASA I, II. This study was a prospective double blind randomized controlled study where the patients were allocated into two equal groups twenty five patients each: Group F & Group E (by closed envelope method):  Group F: those who received crystalloid preloading.  Group E: those who received prophylactic ephedrine intravenously after spinal anesthesia. Inclusion criteria:  The patient selected according to ASA status (ASA I, II).  prime gravida  Normal coagulation profile.  Age range between 20 till 45 years old.  BMI not more than 35  Height 160 to 170 cm. Exclusion criteria:  Patient refusal.  Hypertensive and Diabetic patients.  Pre-eclampsia and eclampsia.  Patients having any coagulopathy disorder or receiving any anticoagulant drugs.  Patients with signs suggesting cardiac or respiratory system failure.  Infection at site of the injection.  Patients with known history of allergy to local anaesthetics’ drugs.  Any pre-existing neurological or psychological disease. Anesthetic management: I. Preoperative management: 1- Preoperative assessment: a) History for: • Cardiac problems, hypertension, ischemic heart disease. • Diabetes mellitus or any endocrinal disorders. • Bronchial asthma, COPD (chronic obstructive pulmonary disease) and smoking. • Bleeding tendency, antiplatelet drugs or anticoagulants. • Hepatic or renal impairments. • Convulsions or any neurological disease. • History of drug intake, history of allergy and sensitivity to any drug and previous anesthetic experiences. b) Examination: • Clinical examination of the chest and heart. • Vital data (HR, RR, ABP, Body Temperature). • Examination of spines. • Examination for jaundice, anemia, cyanosis, clubbing and edema. • Airway examination. c) Investigations: • Complete blood count. • Coagulation profile (PT, PTT, INR, bleeding time) • Liver and kidney function tests. • Random blood sugar. • ECG. 2- Preoperative preparation: a) Preparation of the patient: • Patient consent was taken for spinal anesthesia. • Zantac ampoule the last evening and the morning of operation 75mg and sodium citrate 30ml/ oral. • No premedication was taken before the procedure. b) Preparation of equipments and drugs: I. Equipment: • Spinal needle (pencan, 25 gauge with introducer). • Intravenous cannulas 18 gauge its trade name is (venocath). • Ringer solution, its trade name (Ringer). • Sterilized gown, towels and gauze. • Povidine iodine 10% for sterilization. • Syringes (5cc, 3cc, insulin) and adhesive tape. • Intravenous line. • Disposable face mask. • GA equipment (tubes size 6.5 / 7, laryngoscope) must be available; if needed. II. Drugs: • Lidocaine available as vial containing 20 ml of xylocaine 2%; each 1 ml contains 20mg. • Hyperbaric bupivacaine available as an ampoule containing 4ml. • Fentanyl citrate available as an ampoule containing 100mcg/2ml. • GA drugs (propofol, succinylcholine, atracurium) must be available, if needed. III. Emergency drugs: • Atropine sulphate available as an ampoule 1 mg/ml, diluted with normal saline to a concentrateion of 0.1 mg/ml in a 10 ml syringe, Atropine was only used if needed for bradycardia. • Ephedrine hydrochloride available as an ampoule 30mg/ml, diluted with normal saline to a consaneatetion of 3mg/ml in a 10 ml syringe, Ephedrine was only used if needed for hypotension.

II. Intraoperative management: a) Anesthetic technique: 1. On the day of surgery, the patient was admitted to the operating room earlier than the expected time of surgery by about 10 min. 2. On arrival to the operation room, two 18 gauge intervenous cannula were inserted. Group F (fluid group) will receive crystalloid preloading 15ml/kg (Ringer solution) over 20 minutes before spinal anesthesia and group E (ephedrine group) will receive 8 ml/kg of Ringer solution as preload (500-1000ml). 3. Anti-aspiration measures as Ranitidine (Zantac) were given IV slowly on the previous infusion evening and morning and sodium citrate. 4. Standard monitoring was applied; electrocardiography (ECG), non-invasive arterial blood pressure (NIBP) and peripheral oxygen saturation (SPO2) was monitored via datex Ohmeda monitor. 5. After fluid preload, all patients received spinal anesthesia by spinal needle. 6. Patients were placed in sitting position. 7. Sterilization of the back was done with povidone iodine solution in a circular manner with covering the back by sterilized towels just exposing the spinal segments to be injected. 8. Identification of the level using intercrestal line (Tuffier`s line) which passes through L4-L5 intervertebral space. 9. The skin and subcutaneous tissue were infiltrated with 3ml of xylocaine 2%. 10. A 25G spinal needle pencil point was placed through distal port facing laterally at L4-L5 inter-space. After penetration of ligamentum flavum, dura and arachnoid matter, correct needle placement was identified by free flow of cerebrospinal fluid. 11. A local anesthetic solution {2ml of 0.5% heavy Bupivacaine + fentanyl (25 µg)} was injected over 10-15 seconds. 12. The patients were placed supine immediately after injection with elevation of the head by a pillow and left uterine tilt. 13. Oxygen was supplied to the patient 4L/min via disposable face mask. 14. Group E: will receive prophylactic ephedrine intravenously (30 mg in 60ml saline) by infusion pump, 5mg (10ml) over 2 minute provided 1mg/2ml and 1mg at every minute thereafter for 15 minutes after spinal anesthesia.

b) Patient assessment: I. Intraoperative assessment: 1. Spinal anesthesia parameters: a) Sensory block assessment:  Onset of sensory block: The onset is the time between injection of intrathecal local anesthetic till the absence of pain at specified dermatome. Sensory block was tested in a caudal to cephald caudal direction with a pin prick test using the needle of 3ml syringe. The upper spread of sensory block was determined bilaterally using pin prick test to identify affected dermatomes.  Duration of sensory block: Duration oh the block is the time between intrathecal injection of local anesthetic till analgesics are required or till normal sensation is regained. b) Motor block assessment:  Density of motor block: The degree of motor block was assessed at the same time points as sensory block using a modified Bromage scale. Modified Bromage Scale: 0= full leg movement 1= inability to rise extended leg, can flex knee 2= inability to flex the knee, can flex ankle. 3= no movement  Duration of motor block: Duration of motor block is the time between intrathecal injections of local anesthesia till normal function is regained. 2. Hemodynamic and respiratory parameters:  Non invasive mean arterial blood pressure (MAP): Mean arterial blood pressure (MAP) was measured with an autonomic cycling device. It was recorded preoperatively (before the subarachnoid injection), after induction of spinal anesthesia, during surgery at 3 min intervals until the end of the procedure and postoperatively every 15 min for 24 hour. If MAP decreased more than 30% below the preanesthetic value or to less than 90 mmHg it was considered to be significant hypotension and ephedrine 5 mg increments were given intravenously together with additional 500 ml ringer solution.  Heart rate (HR): Heart rate (HR) was continuously monitored from the electrocardiogram and recorded before the subarachnoid injection, after induction of spinal anesthesia, during surgery at 5 min intervals till the end of procedure and postoperative for 2 hours. Significant bradycardia affecting hemodynamic (HR<50 beats/min) was treated with atropine sulphate 0.5 mg intravenously.  Respiratory rate (RR): Continuously monitored and recorded before subarachnoid injection, after induction of spinal anesthesia, during surgery at 5 minutes interval until the end of procedures and postoperative every 2 hours for 24 hours.  Peripheral oxygen saturation(SPO2): Using pulse oximeter, SPO2 was continuously monitored and recorded before the subarachnoid injection, after induction of spinal anesthesia, every 5 min till the end of the procedure. II. Post-operative assessment: Postoperative assessment was done every 1 hour and continued till spinal effect till off and includes: 1. Hemodynamic and respiratory parameters:  MAP  HR  RR  SPO2 2. Incidence of complications: The incidence of intraoperative complications as (vomiting, hypotension, pruritus, bradycardia, total spinal) as well as postoperative complications as (respiratory depression, backache, post dural puncture headache (PDPH), and transient neurological symptoms (TNS). Patients were notified to contact the emergency room team if any remote complication appears for days postoperative as PDPH or TNS in the form of pain or dysesthesias on back, buttocks or legs irradiating to lower extrimities or any other complication. Evaluation criteria: 1. Hemodynamic parameters:  MAP  HR  RR  SPO2  Need for extra fluid or extra ephedrine 2. Incidence of complication:  Hypotension  Bradycardia  Vomiting  Respiratory depression  PDPH  TNS  Hypoxia  Backache  Pruritus Statistical Analysis A prospective power study showed that a sample size of 25 per study group will have 80% power at the 5%signficance level to detect a difference of 50%in the incidence of hypotension in the E group compared with F group assuming a baseline incidence of 80% as reported by a published study of a similar patient group. Statistical analysis will be done with mixed ANOVA design to compare inter-groupal& intra-groupal results. Obtained data will be presented as mean ± standard deviation or median, interquartile range (IQR) or count &percentage as appropriate. Comparisons will be performed using student t-test, Chi square test, or analysis of variance according to type of variance data. Data will be analyzed using computer package SPSS (version 20, 2012) and Microsoft Excel 2013. P value ≤ 0.05 will be considered statistically significant.

Data collection form Patient Name: Date: / /2018 MR/Unit: / Age: ASA: □ I □II □III □IV CS: □Elective Anesthetist Experience: □RY1 □RY2 □RY3 □Others Bundle therapy Check list: Position: □ Sitting □ Lateral preload 15 ml/kg □ Yes □NO Approach: □Midline □Para median ephedrine IV □ Yes □NO Interspace: □ L2-3 □L3-4 □L4-5 □Others Supine wedged position □ Yes □NO Needle: G Type: CSF: □ Clear □ Blood stained CSF Flow: □ Acceptable □ Fair □ Poor. Barbotage during technique: □ Yes □NO. Local anesthetic solution: □ Hyperbaric Bupivacaine 0.5% □Others Please state: Dose: mg Adjuvant: □ Fentanyl Dose µg □ others Type: Dose T0 (Base) T1 T2 T3 T4 (End) Bromage Scale: □0 □1 □2 □3 MAP mmHg Sensory:□>T4 □ T4-6 □T7-9 □ Failed HR (Beat/min) Nausea: □YES □NO SPO2 (%) Vomiting: □YES □NO Hypotensive episode: □ Yes □ NO Number of episodes: Additional ephedrine total dose: mg Bradycardia: □ Yes □ NO Number of episodes: Total atropine dose: mg Intraoperative anesthetic events and Medications (sedatives, oxytocic, antiemetics, antacid) List Event/Medication Remarks (management, dose, etc) 1 2 3 4 5 Total volume (including 15 ml/kg bundle therapy): ml Urine output: ml Surgeon: □ Resident □ AL/specialist □ Lecturer/consultant Duration of surgery: (min) □ Successful spinal anesthesia □ Inadequate spinal anesthesia (requires heavy sedation/analgesia) □ Failed (GA) Ry:-residency-years

RESULTS Fifty patients were recruited for this study and randomly allocated into 2 groups, F group (fluid) and E group(ephedrine). 1) Demographic Data: They showed no significant differences as regard age, BMI, height and parity (table 1). Table (1): Demographic Data of patients included in the study P value E Group F Group 0.21 27 (20-40) 27 (20-39) Age 0.40 35.3±1.7 35.2±1.7 BMI 0.24 163.3±3.7 162.7±2.9 Height 0.44 1(0-5) 2 (0-4) Parity Data represented as Mean ± SD or Median (Range) 2) Blood Pressure: SBP was generally higher in E group when compared to F group, however the results were statistically unsignificant except at 4 and 22 min. post spinal. (table 2)(figure 4). Incidence of hypotension was significantly lower in E group 6/25 (24%) when compared to F group12/25 (38%), P value(0.03).

Table (2): Systolic BP P value E Group F Group 0.09 119 ±9.9 122.6±7.8 Baseline 0.48 116.4±12.3 116.3±12.3 1 min 0.04* 110.2±15.5 103.9±8.8 4 min 0.4 111.7±13.7 110.6±12.8 7 min 0.4 112.4±13.2 111.7±10.1 10 min 0.3 110.4±12.0 108.7±6.6 13min 0.08 115.6±10.9 111.4±10.2 16 min 0.3 113.7±13.5 111.9±10.9 19 min 0.04* 117.8±10.8 112.1±11.8 22 min 0.1 116.4±9.7 113.3±8.6 25 min 0.08 117.5±11.9 113.3±12.5 28 min 0.0 118.1±9.7 114.3±8.3 31 min 0.0 116±9 112.4±9.7 36 min 0.3 116.2±6.0 115.1±6.1 41 min 0.1 116.4±9.8 113.4±6.8 46 min 0.3 118±6.7 117.0±5.4 51 min 0.4 119.7±6.2 119.1±9 56 min 0.4 122.9±5.2 122.5±6.2 61 min 0.3 121.4±7.59 120.5±6.5 90 min Data represented as Mean ± SD *= P value ≤ 0.05

Figure (3): Systolic Blood pressure trends. 3) Heart rate: The heart rate was generally higher in E group when compared to F group, In (F Group) mean pulse rate changed from baseline of 90.1 ± 8.5 to a maximum of 92.6 ± 11.7 at 28 minute. In (E Group) mean pulse rate increased from baseline of 92.5 ± 5 to maximum of 95.6 ± 8 at 7 minute after spinal block, however it was not statistically significant (table 3) (figure 5).

Table (3): Heart Rate trends. P value E Group F Group 0.1 92.5 ±5 90.1±8.5 Baseline 0.35 93.9±7.4 92.7±13.4 1 min 0.32 92.2±9.1 90.5±16.5 4 min 0.11 95.6±8 91.9±13 7 min 0.17 94.7±9.5 92±10.6 10 min 0.15 94.7±10.6 91.5±11.3 13min 0.11 95±10.4 91.6±8.8 16 min 0.11 93.2±8.4 90±10.5 19 min 0.11 91.6±7.5 87.9±13.6 22 min 0.27 92.6±9.2 90.6±14.2 25 min 0.3 94.2±9.6 92.6±11.7 28 min 0.10 94.5±8.9 91.2±9.4 31 min 0.2 93.4±8.4 91±10.9 36 min 0.42 91.2±6.5 90.7±12 41 min 0.10 91.4±7.2 88.7±10.9 46 min 0.10 91.4±7.2 88.4±9.4 51 min 0.10 90.5±5.6 87.9±8.7 56 min 0.10 91±5.9 88.3±9 61 min 0.17 87.7±6.3 85.6±9.5 90 min Data represented as Mean ± SD

Figure (4): Heart rate trends. 4) Incidence of complications: Regarding incidence of complications; incidence of hypotension was significantly higher in F group when compared to E group, incidence of nausea and vomiting was higher in F group when compared to E group but it was not statistically significant, and there was no chest symptoms in both groups (table 4)(figure 6).

Table (4): Incidence of Complications: P value E Group F Group 0.03 * 6/25(24%) 12/25(48%) Hypotension 0.23 3/25(12%) 5/25(20%) Nausea& Vomiting 0 0/25(0%) 0/25(0%) Chest symptoms Data represented as Number of positive cases /total number of patients (%) *= P value ≤ 0.05

Figure (5): Incidence of complications.

5) Number of ephedrine boluses: Number of boluses of ephedrine required to correct hypotension were significantly lower in ephedrine group when compared to fluid group (f group) 0.6±0.8 and (E group) 0.3±0.54 with a p value 0.046 (table 5)(figure 7). Table (5): Number of ephedrine boluses required to correct hypotension: P value E Group F Group 0.046* 0.3±0.54 0.6±0.8 Number of boluses Data represented as Mean ± SD *= P value ≤ 0.05

Figure (6): Number of ephedrine boluses required to correct hypotension. 6) Oxygen saturation: Regarding oxygen saturation there was no significant differences between the 2 groups (table 6). Table (6): Oxygen saturation: P value E Group F Group 0.23 98.3±0.7 98.5±0.8 Baseline 0.26 99.8±0.4 99.7±0.5 30 min 0.5 99.8±0.4 99.8±0.4 60 min 0.11 98.7±0.6 98.9±0.5 90 min (Post) Data represented as Mean ± SD

DISCUSSION S pinal anaesthesia is considered to be safe as compared to general anaesthesia for caesarean section.General anesthesia is associated with higher mortality rate in comparison to regional anesthesia. However spinal anesthesia is not without risk, Hypotension during caesarean section under spinal anaesthesia is very frequent and if not prevented, it can induce complication for the mother and/ or the fetus(67). Untreated, severe hypotension can pose serious risks to both mother (unconsciousness, pulmonary aspiration, apnoea or even cardiac arrest) and baby (impaired placental perfusion leading to hypoxia, fetal acidosis and neurological injury) .Even mild hypotension can reduce the uteroplacental blood flow and can contribute to fetal acidosis(68). Intravenous preloading is the most popular non-pharmacological method. Early studies had impressive results and it became established as an accepted standard of care. However, more recent controlled studies have questioned the efficacy of preloading. Some had shown that it reduced the severity of hypotension, and some showed that preloading have minimal effect on the incidence of hypotension (69). Vercauteren et al. (2000) stated that ephedrine is the vasopressor of choice for hypotension associated with spinal anesthesia in the parturient because of its ability to maintain uteroplacental blood flow since Ephedrine’s action is considered to be mainly indirect, via stimulating release of norepinephrine from sympathetic nerve terminals; and the uteroplacental circulation is largely devoid of direct sympathetic innervation, so it is relatively resistant to the vasoconstrictive effects of ephedrine .The appropriate route and dose of ephedrine that should be used to prevent hypotension after spinal anaesthesia during caesarean section still remains controversial.(70) In this study we compared the efficacy of fluid preloading with 15ml/Kg ringer (F group) versus prophylactic IV ephedrine infusion without fluid preload(E group) for prevention of hypotension after spinal anesthesia for cesarean section. The changes in blood pressure are related to the level of block, and the risk of hypotension increase with height of block due to higher level of sympathetic block. (71) In this study, there was no significant difference in the distributions by dermatome levels for patients of both groups ranged between T4 – T5 upper sensory level block, so patients treated was having similar degrees of sympathetic block. Therefore, the differences in the incidence of hypotension observed between the two groups to were due to presence or absence of preventive measures only. Our findings showed that SBP was generally higher in ephedrine group when compared to fluid group and it was high statistically significant difference found between two groups from 4min till 28min post spinal, statistically significant difference found between two groups from 33min till 38min post spinal. The heart rate was generally higher in E group when compared to F group, In (F Group) mean pulse rate changed from baseline 89.68 ± 0.48to a maximum of 92.64 ± 1.21at 16 minute. In (E Group) mean pulse rate increased from baseline of 92.40 ± 0.71to maximum of 95.12 ± 1.33at 7 minute after spinal block. Number of boluses of ephedrine required to correct hypotension were significantly lower in ephedrine group (E group) 1.60±0.71 when compared to fluid group (f group) 2.20±0.96 and with a p value 0.015. Also the incidence of nausea and vomiting was lower in the E group when compared with F group. Gajraj et al. (1993)(72) compared the efficacy of an ephedrine infusion with crystalloid administration for reducing the incidence of hypotension during spinal anesthesia for patients scheduled for postpartum tubal ligations under spinal anesthesia, the patients were randomly allocated to receive either 15 mL/kg of crystalloid (crystalloid group) or ephedrine infusion (infusion group). Spinal anesthesia was performed using 70-90 mg of hyperbaric 5% lidocaine. Patients in the infusion group immediately thereafter received an ephedrine infusion at the same rate as in our study. He found that the incidence of hypotension was significantly higher in the crystalloid group compared to the infusion group (P < 0.05). There was no significant difference between the groups in relation to the level of anesthesia or maximal heart rate, and hypertension did not occur in either group which is similar to our results but there was no difference in the incidence of nausea and vomiting in contrast with our study, which may be due different type of patient (pregnant versus non pregnant) and different type of surgical procedure(cesarean section versus postpartum tubal ligation). Bhovi et al. (2014)(73), studied the efficacy of ephedrine for preventing hypotension in patients undergoing caesarean section under spinal anesthesia. The patients were randomly allocated to receive either ephedrine infusion 50mg in 500ml of Ringer’s Lactate immediately after administration of spinal anesthesia at rate of 50ml/min for first 2 minutes, and 10ml/min for next 18 min. or 20ml/kg of Ringer’s Lactate solution as preloading solution prior to subarachnoid block. The study revealed that the incidence of hypotension was significantly higher in the patient group who received fluid preload (60%) compared with (12%) in the patients group who received ephedrine infusion. The incidence of hypotension in the ephedrine group in this study was(12%)in comparison with our study the incidence of hypotension in the ephedrine group was (24%), this difference may be due to different doses of ephedrine used and different volume of infusion. In contrast to this study; Thiangtham et al. (2009)(74) performed a concealed randomized study, 96 parturients were divided into two groups, the study group received ephedrine 18 mg (3 ml) added to 100 ml normal saline, while the control group received 3 ml of normal saline instead of ephedrine given by intravenous continuous infusion over 10 minutes. All patients had preloading fluid with lactated Ringer's solution 20 ml/kg 10 minutes before spinal block was done with 0.5% hyperbaric bupivacaine mixed with preservative free morphine. He found that there was no statistically significant difference in the incidence of hypotension between the two groups, the incidence of hypotension was 93.8% in the control group and 85.4% in the study group, this may be due to the small dose of ephedrine used and different infusion rate. In contrast to this study; Iclal et al. (2009)(75) designed a randomized, double-blinded study to determine the efficacy and safety of 0.5 mg/kg intravenous ephedrine for the prevention of hypotension during spinal anesthesia for cesarean delivery, and its effect on neonatal outcome and umblical artery PH. Patients were randomly allocated into two groups: ephedrine group and control group. All patients received preloading with 15ml/kg lactated ringer before spinal block, patients of the ephedrine group were injected with 0.5mg/kg ephedrine intravenously over 60 seconds while patients of control group were injected with saline. He found that there were significant lower incidences of hypotension and nausea and vomiting in the ephedrine group compared with the control group. In consistence with our results, Minj et al. (2018) (76) comparing the incidence of hypotension and the need for vasopressors in patients submitted to caesarean section under spinal anaesthesia following preload crystalloid with vasopressors conclude that the combined use of volume preloading to compensate for vasodilatation and vasopressor to counteract arterial dilatation is a very effective method in reducing the incidence, severity and duration of spiral hypotension. The combination group with decreased volume of preload and reduced dose of vasoconstrictor provides better haemodynamic stability when compared to preloading of vasoconstrictors alone. It differ from our study by different method (combined preload and vasopressor group and preloading of vasoconstrictors alone group) Limitations in our study; the umbilical artery PH and neonatal APGAR score were not measured to demonstrate the effect of ephedrine on acid base status of the fetus and whether it is clinically significant or not. Recommendations for further studies; to compare neonatal APGAR score and fetal acid base status in both groups ephedrine and phenylephrine.

SUMMARY A caesarean section (C-section), is a form of childbirth in which a surgical incision is made through a mother's abdomen (laparotomy) and uterus (hysterotomy) to deliver one or more babies. It is usually performed when a vaginal delivery would lead to medical complications. The anesthetic plan for cesarean delivery should take into account the well-being of two patients: the mother and the fetus. Regional anesthesia is the most common method of anesthesia for delivery because it allows the mother to be awake and immediately interact with her baby. It is also safer for the mother than general anesthesia. Regional anesthesia is used for 95 percent of planned cesarean deliveries in the United States. The aim of this study is to evaluate the efficacy of ephedrine infusion versus preload crystalloid administration in reducing the incidence of hypotension during spinal anaesthesia. This study was conducted in the obstetric department of Al Matarya Teaching Hospital on fifty parturient undergoing elective caesarean section after the approval of the ethical medical committee. A written consent was taken from all patients who were either class II according to the classification of the American society of Anesthesiologists ASA II. This study was a prospective double blind randomized controlled study where the patients were allocated into 2 equal groups 25 patients each. We concluded that prophylactic IV Ephedrine infusion is more effective than fluid preload in prevention of hypotension due to spinal anesthesia for cesarean section without causing significant tachycardia or hypertension.

CONCLUSION W e concluded that prophylactic IV Ephedrine infusion is more effective than fluid preload in prevention of hypotension due to spinal anesthesia for cesarean section without causing significant tachycardia or hypertension.

REFERENCES 1. Bucklin BA, Hawkins JL, Anderson JR, Ullrich FA. Obstetric anesthesia workforce survey: twenty-year update. Anesthesiology 2005; 103:645. 2. Park GE, Hauch MA, Curlin F, Datta S, Bader AM. The effects of varying volumes of crystalloid administration before cesarean delivery on maternal hemodynamics and colloid osmotic pressure. Anesth Analg. 1996; 83:299–303. 3. Hossain N, Tayab S, Mahmood T. Spinal anaesthesia for caesarean section. J Surg Pak 2002; 7: 19-21 4. Ismail S, Huda A. An observational study of anaesthesia and surgical time in elective caesarean section: spinal compared with general anaesthesia. Int J Obstet Anesth. 2009; 18(4):352-5 5. Kuczkopwski KM, Reisner LS, Lin D. Anesthesia for cesarean section. In:Chestnut DH, Polley LS, Tsen LC, Wong CA, editors. Chestnut’s ObstetricAnesthesia: Principles and Practice. 4th ed. Philadelphia: Mosby; 2009. p. 422-5. 6. Cyna AM, Andrew M, Emmett RS, Middleton P, Simmons SW. Techniques for preventing hypotension during spinal anaesthesia for caesarean section. Cochrane Database Syst Rev 2006;18(4) 7. Bhagat H, Malohtra K, Ghildyal SK, Srivastava PC. Evaluation of preloading and vasoconstrictors as a combined prophylaxis for hypotension during subarachnoid anaesthesia. Indian J Anaesth 2004; 48 (4): 299-303 8. Rout CC, Rocke DA. Prophylactic intramuscular ephedrine prior to cesarean section. Anaesthesia and intensive care1992;20:448.52 9. Rout CC, Rocke DA, Levin J et al. — A reevaluation of the role of crystalloid preload in the prevention of hypotension associated with spinal anesthesia for elective cesarean section. Anesthesiology, 1993;79:262-269 10. Tsen LC. What's new and novel in obstetric anaesthesia? contributions from the 2003 scientific literature. Int J Obstet Anaesth 2005; 14(2):126- 46. 11. McKenzie AG. Researches on supine hypotension in pregnancy, Int Congress Series, 2002; 1242: 597-601. 12. Dyer RA, James MF. Maternal hemodynamic monitoring in obstetric anaesthesia. Anesthesiology 2008; 109(5):765- 7. 13. Parker JA, Barroso F, Stanworth SJ, Spiby H, Hopewell S, Doree CJ, et al. Gaps in the evidence for prevention and treatment of maternal anaemia: a review of systematic reviews. BMC Pregnancy Childbirth 2012; 12: 56. 14. Wong CA, Loffredi M, Ganchiff JN, Zhao J, Wang Z, Avram MJ. Gastric emptying of water in term pregnancy. Anesthesiology 2002; 96(6):1395- 400. 15. Karaman S, Akercan F, Akarsu T, Firat V. Comparison of the maternal and neonatal effects of epidural block and of combined spinal-epidural block for cesarean section. Eur J Obstet Gynecol Reprod Biol 2005; 121:18- 23. 16. Saravanakumar K, Rao SG, Cooper GM. Obesity and obstetric anaesthesia. Anaethesia 2006; 61: 36- 48. 17. Andreasen KR, Andersen ML, Schantz AL. Obesity and pregnancy. Acta Obstet Gynecol Scand 2004; 83:1022-9. 18. Karaman S, Akercan F, Akarsu T, Firat V. Comparison of the maternal and neonatal effects of epidural block and of combined spinal-epidural block for cesarean section. Eur J Obstet Gynecol Reprod Biol 2005; 121:18- 23. 19. Dyer RA, James MF. Maternal hemodynamic monitoring in obstetric anaesthesia. Anesthesiology 2008; 109(5):765- 7. 20. Pollard JB. Cardiac arrest during spinal anesthesia:Common mechanisms and strategies for prevention. Anesth Analg 2001; 92:252–6. 21. Edward MG, Maged SM, John ET. Spinal, Eipdural and caudal blocks. 2nd ed. Clinical Anesthesiology 1996; 1: 211-244. 22. Hartmann B, Junger A, Klasen J, Benson M, Jost A, Banzhaf A, et al. The incidence and risk factors for hypotension after spinal anesthesia induction: an analysis with automated data collection. Anesth Analg 2002; 94(6):1521-9. 23. Ellis H, Feldman SJ, Harrop-Griffiths W. Anatomy for anaesthetists. 8thed. Oxford, London: Blackwell Scientific Publication; 2004. 24. Brown DL. Spinal, epidural and caudal anaesthesia. In: Miller ED (ed). Miller’s anesthesia. 7thed. Philadelphia: Churchill Livingstone; 2010. 1611- 39. 25. Clark SL, Cotton DB, Lee W, et al. Central hemodynamic assessment of normal term pregnancy, Am J of Obstet Gynecol, 1989; 161: 1439-42. 26. Bamber JH, Dresner M. Aortocaval compression in pregnancy: the effect of changing the degree and direction of lateral tilt on maternal cardiac output, Anesth Analg , 2003; 97: 256-8. 27. Kinsella SM, Lohmann G. Supine hypotensive syndrome, Obstet Gynecol, 1994; 83: 774-88. 28. McKenzie AG. Researches on supine hypotension in pregnancy, Int Congress Series, 2002; 1242: 597-601. 29. Baysinger CL, Pope JE, Lockhart EM, Mercaldo ND. The management of accidental dural puncture and postdural puncture headache: a North American survey. J Clin Anesth 2011; 23:349. 30. Darvish B, Gupta A, Alahuhta S, Dahl V, Thorsteinsson A, Irestedt L, et al. Management of accidental dural puncture and post-dural puncture headache after labour: a Nordic survey. Acta Anaesthesiol Scand 2011; 55: 46-53. 31. Dahl JB, Jeppesen IS, Jorgensen H. Intraoperative and postoperative analgesic efficacy and adverse effects of intrathecal opioids in patients undergoing cesarean section. Anesthesiology 1999; 91: 1919- 27. 32. Traore M, Diallo A, Coulibaly Y, Guinto C, Timbo S, Thomas J. Cauda equina syndrome and profound hearing loss after spinal anesthesia with isobaric bupivacaine. Anesth Analg 2006; 102:1863- 4. 33. Bromage PR. Neurologic complications of regional anaesthesia for obstetrics. In: Hughes SC, Levinson G, Rosen MA (eds). Shnider and Levinson’s anaesthesia for obstetrics. 4thed. Philadelphia: Lippincott Williams and Wilkins; 2002. 409–16. 34. Kwak KH. Postdural puncture headache. Korean Journal of Anesthesiology. 2017; 70(2):136. 35. Shaikh J, Memon A, Memon M, Khan M. Post dural puncture headache after spinal anaesthesia for caesarean section: a comparison of 25 g Quincke, 27 g Quincke and 27 g Whitacre spinal needles. Ayub Med Coll Abbottabad 2008; 20: 10- 3. 36. Srivastava V, Jindal P, Sharma P. Study of post dural puncture headache with 27G Quincke & Whitacre needles in obstetrics/non obstet. Middle East J 2010; 20: 709- 17. 37. Wong CA, Scavone BM, Dugan S, Smith JC, Prather H, Ganchiff JN, et al. Incidence of postpartum lumbosacral spine and lower extremity nerve injuries. Obstet Gynecol 2003; 101: 279-88. 38. Colc CD, MC Morland GH, Axelson JE. Epidural blockede for cesarean section comparing lidocaine hydrobonated and lidocaine hydrochloride. Anesthesiology 1985; 83: 348- 50. 39. Viitanen H, Porthan L, Viitanen M, Heula AL, Heikkila M. Postpartum neurologic symptoms following single-shot spinal block for labour analgesia. Acta Anaesthesiol Scand 2005; 49: 1015– 22. 40. Bursell B, Ratzan RM, Smally A. Lidocaine toxicity misinterpreted as a stroke. West J Emerg Med 2009; 10: 292- 4. 41. Kitagawa N, Oda M, Totoki T. Possible mechanism of irreversible nerve injury caused by local anesthetics: detergent properties of local anesthetics and membrane disruption. Anesthesiology 2004; 100: 962. 42. Johnson ME, Saenz JA, DaSilva AD. Effect of local anesthetic on neuronal cytoplasmic calcium and plasma membrane lysis (necrosis) in a cell culture model. Anesthesiology 2002; 97: 1466-76. 43. Gozdemir M, Muslu B, Usta B, Sert H, Karatas F, Surgit O. Transient neurological symptoms after spinal anaesthesia with levobupivacaine 5 mg/ml or lidocaine 20 mg/ml. Acta Anaesthesiol Scand 2010; 54: 59- 64. 44. Kovac AL. Prevention and treatment of postoperative nausea and vomiting. Drugs 2000; 59: 213-43. 45. Kamphuis ET, Ionescu TI, Kuipers PW, de Gier J, van Venrooij GE, Boon TA. Recovery of storage and emptying functions of the urinary bladder after spinal anesthesia with lidocaine and with bupivacaine in men. Anesthesiology 1998; 88: 310– 6. 46. Piper SN, Fent MT, Rohm KD. Vrapidil does not prevent postanesthetic shivering: a dose-ranging study. Can J Anaesth 2001; 48: 742-7. 47. Suzuki S, Gerner P, Lirk P. Local anesthetics. InPharmacology and Physiology for Anesthesia 2019 Jan 1 (pp. 390-411). Elsevier. 48. Chen MQ, Chen C, Li L. Effect of Baricity of Bupivacaine on Median Effective Doses for Motor Block. Medical science monitor: international medical journal of experimental and clinical research. 2017; 23:4699. 49. Camorcia M, Capogna G, Berritta C. The relative potencies for motor block after intrathecal ropivacaine, levobupivacaine and bupivacaine. Anesth Analg 2007; 104: 904-7. 50. Muchhal M, Maheshwari RC. Evaluation of Different Local Anesthetic Solutions for Extradural Anaesthesia in Elective Caesarean Section-A Comparative Study. Journal of Advanced Medical and Dental Sciences Research. 2018; 6(2):82-5. 51. Ruiz-Tovar J, Muñoz JL, Gonzalez J, Zubiaga L, García A, Jimenez M, Ferrigni C, Durán M. Postoperative pain after laparoscopic sleeve gastrectomy: comparison of three analgesic schemes (isolated intravenous analgesia, epidural analgesia associated with intravenous analgesia and port-sites infiltration with bupivacaine associated with intravenous analgesia). Surgical endoscopy. 2017; 31(1):231-6. 52. Bay-Nielson L, Klarskov B, Bech K. Levobupivacaine vs bupivacaine as infiltration anaesthesia in inguinal herniorrhaphy. Br J Anaesth 1999; 82: 280-2. 53. Bar-Oz B, Bulkowstein M, Benyamini L. Use of antibiotic and analgesic drugs during lactation. Drug Saf 2003; 26: 925-35. 54. Veering BT, Burm AG, Vletter AA. The effect of age on systemic absorption and systemic disposition of bupivacaine after subarachnoid administration. Anesthesiology 1991; 74: 250-7. 55. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth pain med 2004; 29: 564-75. 56. Desai N, Gardner A, Carvalho B. Labor Epidural Analgesia to Cesarean Section Anesthetic Conversion Failure: A National Survey. Anesthesiology Research and Practice. 2019; 2019. 57. Ohmura S, Kawada M, Ohta T. Systemic toxicity and resuscitation in bupivacaine-, levobupivacaine- or ropivacaine-infused rats. Anesth Analg 2001; 93: 743-8. 58. Autory Y, Narchi P, Messiah A. Hypotension during neuraxial blocks. Anesthesiology 2000; 91:521–29. 59. Reynolds LP, Borowicz PP, Caton JS, et al. Uteroplacental vascular development and placental function: an update. Int J Dev Biol 2010; 54:355. 60. Ramesar SV, Mackraj I, Gathiram P, Moodley J. Sildenafil citrate improves fetal outcomes in pregnant, L-NAME treated, Sprague-Dawley rats. Eur J Obstet Gynecol Reprod Biol 2010; 149:22. 61. Mets B. Should norepinephrine, rather than phenylephrine, be considered the primary vasopressor in anesthetic practice?. Anesthesia & Analgesia. 2016; 122(5):1707-14. 62. Kinsella M, Dob D, Holdcroft A. Regional anaesthesia. InCrises in Childbirth-Why Mothers Survive 2018 Apr 19 (pp. 67-86). CRC Press. 63. Dusitkasem S, Herndon BH, Somjit M, Stahl DL, Bitticker E, Coffman JC. Comparison of Phenylephrine and Ephedrine in Treatment of Spinal-Induced Hypotension in High-Risk Pregnancies: A Narrative Review. Frontiers in Medicine. 2017; 4:2. 64. Goetz AE, Heckel K. Perioperative fluid and volume management: goal-directed therapy necessary. Anesthesist 2007; 56:745-6. 65. Demling RH. Shock and fluids. In Shoemaker WC. Critical Care: 4 th edition, California, Fullerton, 1986; 301-11. 66. Mercier FJ, Bonnet MP, De la Dorie A, Moufouki M, Banu F, Hanaf A, Edouard D, Roger-Christoph S. Spinal anaesthesia for caesarean section: fluid loading, vasopressor and hypotension. Ann Fr Anesth Reanim 2007; 26:688-93. 67. Campagna JA, Cartner C. Clinical relevance of Bezold Jarisch reflex. Anesthesiology 2003; 98 (5): 1250- 60. 68. Hossain N, Tayab S, Mamood T. Spinal anaesthesia for caesarean section. J Surg Pak 2002; 7: 19-21. 69. Shimokaze T, Akaba K, Saito E. Oscillometric and intra-arterial blood pressure in preterm and term infants: extent of discrepancy and factors associated with inaccuracy. Am J Perinatol 2015; 32:277. 70. Mojica JL, Meléndez HJ, Bautista LE. The Timing of Intravenous Crystalloid Administration and Incidence of Cardiovascular Side Effects during Spinal Anesthesia: The Results from a Randomized Controlled Trial. Anesth Analg 2002; 94:432-7. 71. Vercauteren MP, Coppejans HC, Hoffmann VH, Mertens E. Prevention of hypotension by a single 5-mg dose of ephedrine during spinal anesthesia in prehydrated caesarean delivery patients. Anesth Analg 2000; 90:324-7. 72. Gajraj NM. Comparison of an Ephedrine Infusion with Crystalloid Administration for Prevention of Hypotension During Spinal Anesthesia. Anesth Analg 1993; 76:1023-6. 73. Bhovi MRA. Comparitive Study of Ephedrine Infusion with the Preload of Crystalloids for Prevention of Hypotension During Spinal Anaesthesia for Elective Caesarean Section, Indian Journal of Applied Research 2014; 4(2): 2249-555X. 74. Thiangtham K, Asampinwat T. Intravenous ephedrine infusion for prophylaxis of hypotension during spinal anesthesia for cesarean section. Songkla Med J 2009; 27(4):291-300. 75. Iclal OK, Kenan K, Sinan G, Ali C, Zeki K, et al. The Effects of Intravenous Ephedrine during Spinal Anesthesia for Cesarean Delivery: A Randomized Controlled Trial J Korean Med Sci 2009; 24: 883-8. 76. Minj SD, Beck R, Kumar A, Tiwari P, Chandan RK and Sen S. The incidence and management of hypotension in the pregnant parturients undergoing caesarean section following spinal anaesthesia with 0.5% bupivacaine. International Journal of Reproduction, Contraception, Obstetrics and Gynecology 2018; 7(3):1205-1211.

المـلـخـص الـعـربــي ان منع حدوث هبوط فى ضغط الدم اثناء التخدير النصفى للولادة القيصرية يودى الى نتائج افضل من معالاجته، فى هذه الدراسة تم مقارنة كفاءة اعطاء المحاليل الوريدية او اعطاء عقار الافدرين عن طريق الحقن الوريدى المستمر فى منع حدوث هبوط فى ضغط الدم. خمسون مريضة تم تقسيمهم عشواءيا الى مجموعتين,25مريضة فى كل مجموعة. المجموعة الاولى تم اعطاءها 15مل/كجم محلول لاكتات الرينجرقبل اعطاء التخدير النصفى . والمجموعة الثانية تم اعطاءها عقار الافدرين عن طريق الحقن الوريدى (5 مجم فى اول دقيقة بعد اعطاء التخدير النصفى و5 مجم فى ثانى دقيقة وواحد مجم فى كل دقيقة بعد ذلك لمدة 15 دقيقة) فى حالة حدوث هبوط فى ضغط الدم السيستولى بنسبة اكثر من 20% من الضغط السيستولى قبل اعطاء التخدير النصفى يتم اعطاء جرعة 5مجم اضافية من الافدرين. وجدنا ان نسبة حدوث هبوط فى ضغط الدم كانت اقل فى المجموعة الثانية بنسبة(24%) مقارنة بالمجموعة الاولى بنسبة (48%) . لم يكن هناك فرق ملحوظ فى سرعة ضربات القلب بين المجموعتين. نسبة حدوث الغثيان و الترجيع كانت اكثر فى المجموعة الاولى بنسبة (20%) بالمقارنة بالمجموعة الثانية بنسبة (12%). استنتجت الدراسة ان اعطاء عقار الافدرين عن طريق الحقن الوريدى المستمر بعد اعطاء التخدير النصفى اكثر كفاءة فى منع حدوث هبوط فى ضغط الدم من اعطاء المحاليل الوريدية للحوامل اللاتى يخغون للولادة القيصرية تحت تاثير التخدير النصفى وذلك بدون حدوث زيادة ملحوظة فى سرعة ضربات القلب.

دراسة مقارنة بين محاليل وريده مقابل الإيفيدرين بالتسريب للوقاية من انخفاض ضغط الدم بسبب التخدير النصفي للولادات القيصرية رسالة توطئة للحصول علي درجة الماجستير في التخدير مقدمة من الطبيبة/ أمنية سامي محمد الكردي بكالوريوس الطب والجراحة تحت إشراف أ.د/ سامية عبد المحسن عبد اللطيف أستاذ التخدير والعناية المركزة كلية الطب - جامعة عين شمس د/ امل حامد عبد الحميد ربيع مدرس التخدير والعناية المركزة كلية الطب - جامعة عين شمس د/ احمد عبد الدايم عبد الحق مدرس التخدير والعناية المركزة كلية الطب - جامعة عين شمس كلية الطب - جامعة عين شمس 2019

Introduction

Aim of the Work

Review of Literature

Patients and Methods

Results

Discussion

Summary Conclusion

References Comparative Study between Volume Preload versus Ephedrine Infusion for Prevention of Hypotension Due to Spinal Anesthesia for Caesarean Section Thesis Submitted for Partial Fulfillment of Master Degree in Anaesthesia By Omnia Samy Mohamed Elkordy M.B.B.Ch., Under Supervi Professor of Anaesthesia and Intensive Care Faculty of Medicine – Ain Shams UniversitySpinal anaesthesia produces few adverse effects caesarean section (C-section), is a form of childbirth in which a surgical incision is made through a mother's abdomen (laparotomy) and uterus (hysterotomy) to deliver one or more babies. It is usually performed when a vaginal delivery would lead to medical complications. The anesthetic plan for cesarean delivery should take into account the well-being of two patients: the mother and the fetus. Regional anesthesia is the most common method of anesthesia for delivery because it allows the mother to be awake and immediately interact with her baby. It is also safer for the mother than general anesthesia.(1) Spinal anesthesia is often used for genital, urinary tract, or lower body procedures. A successful regional anaesthesia effectively suppresses many of the pain mediated stress responses to surgery such as rise in blood pressure, heart rate and increase in plasma concentrations of catecholamines, cortisol and glucose. Spinal block is also associated with lesser amount of surgical on the respiratory system as long as unduly high blocks are avoided.(3) As control of the airway is not compromised, there is a reduced risk of airway obstruction or Dr./ Amal Hamed Abdel Hamid Rabie Lecturer of Anaesthesia and Intensive Care Faculty of Medicine – Ain Shams University Dr./ Ahmed Abdel Dayem Abdel Haak Lecturer of Anaesthesia and Intensive Care Faculty of Medicine – Ain Shams University Faculty of Medicine Ain Shams University 2019

بسم الله الرحمن الرحيم وَقُلِ اعْمَلُواْ فَسَيَرَى اللّهُ عَمَلَكُمْ وَرَسُولُهُ وَالْمُؤْمِنُونَ

صدق الله العظيم [سورة: التوبة - الآية: 105]

Acknowledgments First and foremost, I feel always indebted to Allah the Most Beneficent and Merciful. I wish to express my deepest thanks, gratitude and appreciation to Prof./ Samia Abdel Mohsen Abdel Latif, Professor of Anaesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, for her meticulous supervision, kind guidance, valuable instructions and generous help. Special thanks are due to Dr./ Amal Hamed Abdel Hamid Rabie, Lecturer of Anaesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, for her sincere efforts, fruitful encouragement. I am deeply thankful to Dr./ Ahmed Abdel Dayem Abdel Haak, Lecturer of Anaesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, for his great help, outstanding support, active participation and guidance. I would like to express my hearty thanks to all my family for their support till this work was completed. Omnia Samy Elkordy

List of Contents Title Page No. List of Tables 5 List of Figures 6 Introduction - 1 - Aim of the Work 11 Review of Literature 12 Patients and Methods 34 Results 47 Discussion 55 Summary 61 Conclusion 63 References 64 Arabic Summary

List of Tables Table No. Title Page No. Table (1): Demographic Data of patients included in the study 47 Table (2): Systolic BP 48 Table (3): Heart Rate trends. 50 Table (4): Incidence of Complications: 52 Table (5): Number of ephedrine boluses required to correct hypotension: 53 Table (6): Oxygen saturation: 54

List of Figures Fig. No. Title Page No. Figure (1): Chemical formula of bupivacaine 25 Figure (2): Pharmacological structure of ephedrine. 29 Figure (3): Systolic Blood pressure trends. 49 Figure (4): Heart rate trends. 51 Figure (5): Incidence of complications. 52 Figure (6): Number of ephedrine boluses required to correct hypotension. 53

List of Abbreviations Abb. Full term ABP Arterial blood pressure ACC Aortocaval compression ACTH Adreno cortico tropic hormone AP Arterial pressure ASA American society of anesthesiologists BMI Body mass index BP Blood pressure CO Cardiac output COPD Chronic obstructive pulmonary disease C-section Ceasarean section CSF Cerebrospinal fluid EBP Epidural blood patch ECG Electrocardigraphy FRC Functional residual capacity GA General anesthesia GFR Glomerular filtration rate HR Heart rate IM Intra-muscular INR International normalized ratio IV Intra-venous IVC Inferior venacava L.As Local anesthetics MAP Mean arterial blood pressure NIBP Non-invasive arterial blood pressure PDPH Post dural puncture headache PT Prothrombin time PTT Partial thromboplastin time RR Respiratory rate SPO2 Peripheral oxygen saturation SVR Systemic vascular resistance TNS Transient neurological symptoms

INTRODUCTION A caesarean section (C-section), is a form of childbirth in which a surgical incision is made through a mother's abdomen (laparotomy) and uterus (hysterotomy) to deliver one or more babies. It is usually performed when a vaginal delivery would lead to medical complications. The anesthetic plan for cesarean delivery should take into account the well-being of two patients: the mother and the fetus. Regional anesthesia is the most common method of anesthesia for delivery because it allows the mother to be awake and immediately interact with her baby. It is also safer for the mother than general anesthesia.(1) Spinal anesthesia is often used for genital, urinary tract, or lower body procedures. A successful regional anaesthesia effectively suppresses many of the pain mediated stress responses to surgery such as rise in blood pressure, heart rate and increase in plasma concentrations of catecholamines, cortisol and glucose. Spinal block is also associated with lesser amount of surgical haemorrhage. (2) Spinal anaesthesia produces few adverse effects on the respiratory system as long as unduly high blocks are avoided.(3) As control of the airway is not compromised, there is a reduced risk of airway obstruction or the aspiration of gastric contents. post-operative deep vein thrombosis and pulmonary emboli are less common following spinal anesthesia.(4) Hypotension is the most common complication of spinal anaesthesia for cesarean section. It can cause significant morbidity and mortality. It could be associated with severe nausea and vomiting and serious risk to the mother (unconsciousness and pulmonary aspiration) and baby (hypoxia, acidosis, and neurological injuries). (5) Hypotension is due to sympathetic nervous system blockade which result to decreased systemic vascular resistance and peripheral pooling of blood with decreases cardiac output. Aortocaval compression (ACC) can result in haemodynamic disturbances and uteroplacental hypoperfusion in parturients. The incidence of hypotension and high spinal anaesthesia is higher in cesarean sections (6). Various attempts have been made to reduce the incidence and severity of hypotension including expansion of intravascular volume with up to 2liters of fluids. The use of lateral uterine displacement is a routine procedure to prevent hypotension. intravenous fluid preload has been shown to reduce the risk of hypotension but doesn't eliminate it and many patients still need vasopressor treatment to correct hypotension. parenteral ephedrine may be an effective alternative. (7) Ephedrine is a non-catecholamine sympathomimetic agent that stimulates alpha and beta adrenergic receptors directly and predominantly indirectly, producing its effects by releasing norepinephrine from nerve endings in the autonomous nervous system. Traditionally it is the vasopressor of choice in spinal anesthesia despite the lack of confirmation of its superiority over other vasopressors.(8)

AIM OF THE WORK T he aim of this study is to evaluate the efficacy of intravenous ephedrine versus preload crystalloid administration in reducing the incidence of hypotension during spinal anaesthesia.

Spinal anaesthesia produces few adverse effects caesarean section (C-section), is a form of childbirth in which a surgical incision is made through a mother's abdomen (laparotomy) and uterus (hysterotomy) to deliver one or more babies. It is usually performed when a vaginal delivery would lead to medical complications. The anesthetic plan for cesarean delivery should take into account the well-being of two patients: the mother athe fetus. Regional anesthesia is the most common method of anesthesia for delivery because it allows the mother to be awake and immediately interact with her baby. It is also safer for the mother than general anesthesia.(1) Spinal anesthesia is often used for genital, urinary tract, or lower body procedures. A successful regional anaesthesia effectively suppresses many of the pain mediated stress responses to surgery such as rise in blood pressure, heart rate and increase in plasma concentrations of catecholamines, cortisol and glucose. Spinal block is also associated with lesser amount of surgical on the respiratory system as long as unduly high blocks are avoided.(3) As control of the airway is not compromised, there is a reduced risk of airway obstruction or

REVIEW OF LITERATURE Physiological changes during pregnancy: P regnancy and delivery are associated with vast physiological changes. Those related to pulmonary and cardiovascular systems are of fundamental importance to anaesthesiologist. Respiratory system: To accommodate the increased O2 demand and requirement for carbon dioxide elimination, pregnancy is associated with an increase in the respiratory minute volume and work of breathing. The most impressive change in maternal lung dynamics is a decrease in functional residual capacity (FRC), which at term may have changed by as much as 20% of pr e pregnancy values. Minute ventilation increases by 45% primarily as a result of an increase in the tidal volume because the respiratory rate is essentially unchanged. There is a liability to rapid development of hypoxia as result of decreased FRC and increased oxygen consumption. (9) Capillary engorgement of mucosa and oedema of the orophyranx, larynx, and trachea may result in a difficult intubation. (9)

Cardiovascular system: Cardiac output increases from the fifth week of pregnancy and reaches its maximum levels (approximately 40% of non pregnant values) at 32 weeks. It is due to an increase in the heart rate and the more important factor is the stroke volume. Changes in heart rate are difficult to quantify but it is thought that approximately 20% increase in heart rate present by fourth week of pregnancy. Tachyarrhythmias are more common especially later in pregnancy as a result of both hormonal and autonomic factors. (10) Aortocaval compression by the gravid uterus (supine hypotension syndrome): It occurs in 10-20 % of pregnant females, after 28 weeks of pregnancy. (11) Hematologic system: Maternal blood volume begins to increase early in pregnancy as a result of changes in osmoregulation and the renin- angiotension system causing sodium retention and increasing the total body water by 8.5 litters (L). By term, blood volume increases up to 45% whereas red cell volume increase by only 30%, this differential increase leads to physiological anemia of pregnancy. A state of hypercoaguability exists in pregnancy with an increased level of most coagulation factors mainly fibrinogen and factor VII. (12)

Gastrointestinal system: Although progesterone relaxes smooth muscles, it impairs esophageal and intestinal motility during pregnancy. It has recently been suggested that gastric emptying is not always delayed in pregnant woman, however risk of aspiration remains when caesarean section is done under general anaesthesia. (13) Central nervous system: From early pregnancy, when neuroaxial anaesthesia is administered women require less local anaesthetic than non pregnant women to reach a given dermatomal sensory level because the epidural veins become congested secondary to increase in intra abdominal pressure and epidural space becomes narrower. (14) Renal system: It undergoes many changes in pregnancy, mainly because of the effect of progesterone and the mechanical effects of compression of the gravid uterus. Urea, creatinine and uric acid clearance all increase. Renal plasma flow and glomerular filtration rate (GFR) both also increase rapidly. Glycosuria is common finding in pregnancy. (15)

Physiological changes in anatomy of epidural and subarchnoid spaces in pregnancy: The epidural space in pregnant women might be reduced due to engorgement of veins in the extra-dural space, compression of the subarachnoid space, and reduction in the volume of cerebrospinal fluid. Engorgement of veins in the extra-dural space and increased pressure are secondary to the increased intra-abdominal pressure, which causes compression of the inferior vena cava and consequent reduction in the volume of cerebrospinal fluid. Thus, it is more difficult to predict the extension of the blockade when using the same dose of local anaesthetics in obese and non-obese pregnants. (16) Besides, it is known that the need of local anesthetic in spinal anaesthesia is lower in pregnants especially obese. Mechanisms suggested for this include pregnancy-specific hormonal changes, which affect the action of neurotransmitters in the spinal column, increased permeability of neural membranes. Also, exaggerated lumber lordosis may increase cephaled spread of L.As. (17) Physiological changes during subarachnoid analgesia In pregnancy there are haemodynamic changes in the form of: (18) • Cardiac output rises by 30-40% gradually till the time of delivery. • Blood volume increases by 15-45%, with relative anaemia • Blood pressure slightly decreases as pregnancy progresses. These are accompanied with changes in peripheral blood distribution; the uterus enlarges in size with growth of foetus and placenta. At full term the uterus contains about one-sixth of the mother`s blood volume. The result of such an increase of peripheral blood volume with a concomitant decrease in central blood volume may worsen hypotension during spinal analgesia. (18) Even with the same level of spinal analgesia, hypotension is greater in pregnant than non pregnant women. Moreover, the gravid uterus affects the circulation by its weight compressing the inferior vena cava and partially obstructing the aorta. (19)This will diminish the venous return to the heart, also the arterial blood supply to the pelvic organ and lower extremities are decreased, but the clinical manifestations of compression vary individually according to the degree of the obstruction as well as the degree of compensation. Decreased venous return due to mild to moderate inferior vena cava obstruction can be compensated by an increase in heart rate. (18) Only when such compensatory mechanism is attenuated, cardiac output decreases dramatically and supine hypotension occurs, 10% of women show severe hypotension in supine position in late pregnancy. Pulmonary ventilation mechanisms are little changed even at full term. The elevation of diaphragm during the last trimester tends to decrease the vital capacity but is compensated by widening of the subcostal angle. (18) Effect of spinal anaesthesia on the foetus Spinal anaesthesia has no direct effect on the foetus, but indirectly it impairs maternal circulation to the placenta to an extent causing reduction of oxygen supply across the placenta. But this impairment to the placental circulation does not reach a point that foetal oxygenation is handicapped.(20)

Complications of spinal analgesia in obstetric: 1. Hypotension Hypotension represents incidence of about 55–100%, so it is the most frequent complication. Moreover, hypotension is hazardous for the mother and the baby as it can cause loss of consciousness, aspiration. (21) Hypotension after spinal anaesthesia occurs mainly due to sympathetic block which depend on the height of block. (22) This sympathectomy causes venous and arterial vasodilation, but because of the large amount of blood in the venous system (approximately 75% of the total volume of blood), the venodilation effect predominates as a result of the limited amount of smooth muscle in venules; in contrast, the vascular smooth muscle on the arterial side of the circulation retains a considerable degree of autonomous tone. After neuraxial block–induced sympathectomy, if normal cardiac output is maintained, total peripheral resistance should decrease only 15% to 18% in normovolamic healthy patients. (23) Pregnant women have an elevated resting sympathetic tone and thus increased effects of sympathetic blockade. This also leads to decreased sensitivity to vasopressors, secondary to downregulation of adrenergic receptors and increased synthesis of endothelium-derived vasodilators during pregnancy. Spinal anaesthesia abolishes labor pain, which can decrease maternal blood pressure. (24) Pregnant women have increased sensitivity (i.e. increased peak block height and block duration) to spinal anaesthesia, due to a combination of reduced volume of spinal cerebrospinal fluid (CSF) and enhanced neural susceptibility to local anaesthetics. Aortocaval compression by he gravid uterus,if present, further contributes to hypotension.(24) Aortocaval compression (ACC) occurs when the gravid uterus compresses the maternal abdominal aorta and inferior vena cava (IVC). Compression of the IVC impedes venous return which decreases cardiac output (CO), and compression of the aorta may reduce utero-placental perfusion which may result in fetal acidosis . (25)It is recommended that the ACC be avoided by applying lateral uterine displacement. This can be achieved by tilting the operating table, although the effectiveness of this manoeuvre is unclear and the optimal degree of tilt is unknown. (26) The majority of patients who have ACC are clinically asymptomatic and supine hypotension develops only if ACC is severe, in nearly 8% of the patients. (27) Patients who are asymptomatic with ‘concealed’ ACC are able to maintain their arterial pressure (AP), despite a reduction in CO by compensatory mechanisms such as an increased systemic vascular resistance (SVR). However, these patients may develop severe hypotension as a result of sympathetic blockade during spinal anaesthesia. (28) Treatment of supine hypotension syndrome after 28th week of pregnancy by: 1. Lateral uterine displacement (usually to the left side, >15 degree) by;  Rotating the delivery table to the left.  Placing a pillow or wedge under the right side of the back and buttock. 2. I.v. fluids. 3. I.v. ephedrine (if hypotension occurs). (29) 2. Postdural Puncture Headache (PDPH) PDPH is a common complication of spinal analgesia. Parturient constitutes the highest risk category, the reported incidence in these patients varying between 0 and 30%.The risk of PDPH is less with epidural anaesthesia, but it occurs in up to 50% of young patients following accidental meningeal puncture with large-diameter needles. The headache is characteristically mild or absent when the patient is supine, but head elevation rapidly leads to a severe fronto-occipital headache, which again improves on returning to the supine position. Occasionally, cranial nerve symptoms (e.g., diplopia, tinnitus) and nausea and vomiting are also present. The headache is believed to result from the loss of CSF through the meningeal needle hole, resulting in decreased beyond the support for the brain. In the upright position the brain sags in the cranial vault, putting traction on pain-sensitive structures. Traction on cranial nerves is believed to cause the cranial nerve palsies that are seen occasionally. (30) The incidence of PDPH decreases with increasing age and with the use of small-diameter spinal needles with non cutting tips to less than 3%.(31) Inserting cutting needles with the bevel aligned parallel to the long axis of the meninges has also been shown to decrease the incidence of PDPH. (32) PDPH is usually self-limiting and spontaneous resolution may occur in few days. Therefore, many authors recommend approximately 24 h of conservative therapy. Various pharmacological (e.g. Methylxanthines, ACTH, Caffeine) and interventional measures (e.g., epidural saline/dextran) are available to treat PDPH; epidural blood patch (EBP) has a 96–98% success rate and has been recognized as the definitive treatment for PDPH. (33) 3. Backache Back pain in women during pregnancy is up to 76%. Also, has been cited in one study as the most common reason for patients to refuse future spinal block. (34) The etiology of backache is not clear, although needle trauma, local anaesthetic irritation, and ligamentous strain secondary to muscle relaxation have been offered as explanations. (35)

4. Needle breakage, infection, haematoma and oedema. Infections such as epidural abscess or meningitis are extremely rare. Infection may be exogenous in origin and be caused by the contamination of equipment or pharmacologic agents or by colonization of the catheter. Endogenous spread may occur from a site of infection elsewhere in the body. (36) The incidence of neurologic injury resulting from haematoma associated with neuraxial anaesthesia is very low, with estimates of 1 in 150,000 and 1 in 220,000 for epidural and spinal anaesthesia, respectively. A review of 61 cases of spinal haematoma associated with spinal or epidural anaesthesia reported evidence of haemostatic abnormality in 68% of patients and difficult or bloody placement of needles and catheters in 25% of cases. In 15 of the reported cases the patients received spinal anaesthesia, with the remaining 46 receiving epidural anaesthesia. (37) 5. Systemic Toxicity Toxicity occurs due to overdosage or intravascular injection of the local anaesthetic. The signs are excitement, disorientation, twitches, convulsions and perhaps apnea with severe cardiac depression. (38)

6. Total Spinal Anaesthesia Total spinal anaesthesia occurs when local anaesthetic spreads high enough to block the entire spinal cord and occasionally the brainstem during either spinal or epidural analgesia. Profound hypotension and bradycardia are common secondary to complete sympathetic blockade. Respiratory arrest may occur as a result of respiratory muscle paralysis or dysfunction of brainstem respiratory control centers. Management includes vasopressors, atropine, and fluids as necessary to support the cardiovascular system, plus oxygen and controlled ventilation. If the cardiovascular and respiratory consequences are managed appropriately, total spinal block will resolve without sequelae. (39,40) 7. Neurologic Injury Persistent parasthesias and limited motor weakness are the most common injuries, although paraplegia and diffuse injury to cauda equina roots (cauda equina syndrome) do occur rarely. Injury may result from direct needle trauma to the spinal cord or spinal nerves, from spinal cord ischemia, from accidental injection of neurotoxic drugs or chemicals, from introduction of bacteria into the subarachnoid or epidural space, or very rarely from epidural haematoma. (41)

9. Nausea and vomiting Nausea and vomiting are common side effects in parturients undergoing caesarean delivery performed under spinal anaesthesia can be very unpleasant to the patients. The reported incidence of nausea and vomiting during caesarean performed under regional anaesthesia varies from 50% to 80% when no prophylactic antiemetic is given. (42) Nausea and vomiting are commonly associated with hypotension, bradycardia and high sensory block (T5 and above). It is usually corrected as the blood pressure is restored to normal. Persistent nausea and vomiting are treated by antiemetics. (43) 10. Urine retention Not more common after spinal than after general anaesthesia and usually yields to neostigmine 0.5 mg. IM. (44) 11. Shivering Shivering-like tremor in patients given neuraxial anaesthesia is always preceded by core hypothermia and vasoconstriction (above the level of the block). The local anaesthetic blocks the inhibitory pathways in the brain and thus produce excitatory signs such as shivering, It is uncomfortable for the patients and may interfere with monitoring of electrocardiogram, blood pressure (BP) and oxygen saturation.(45) Pharmacological considerations A. Pharmacology of Bupivacaine Bupivacaine hydrochloride is a local anesthetic that is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. It contains an amide linkage between the aromatic nucleus and the piperidine group. (46)

Figure (1): Chemical formula of bupivacaine.(46) Bupivacaine is present in a hyperbaric or plain form. The hyperbaric one is prepared by the addition of glucose and is suitable for spinal anesthesia. Its specific gravity is between 1.030 and 1.035. (47) Levobupivacaine hydrochloride is the S (-) - stereoisomer of bupivacaine that is less cardiotoxic than the later on a per milligram basis. Also, levobupivacaine provides sensory block that is more intense than that of bupivacaine although motor block is greater for the later. This could be explained by the ability of levobupivacaine to widen the sensory-motor dissociation. (48) Pharmacokinetics: 1- Absorption: The rate of systemic absorption of bupivacaine, as other local anesthetics, is dependent upon: (49) • The total dose and concentration of bupivacaine administered. • Route of administration. • Vascularity of the administration site. • The presence or absence of epinephrine in the anesthetic solution. 2- Distribution: Bupivacaine has a high binding capacity to non-albumin proteins (95%). It crosses the placenta by passive diffusion. After injection for caudal, epidural or peripheral nerve blocks, peak levels in blood are reached in 30 to 45 minutes, followed by decline to insignificant levels during the next three to six hours. The half life in adults is approximately 2.7 hours.(50) 3- Metabolism: Bupivacaine is metabolized in the liver via conjugation with glucuronic acid. Pipecoloxylidine is its major metabolite.(50) 4- Excretion: Bupivacaine is excreted through the kidney. Only 6 to 7% are excreted unchanged in the urine.(50) 5- Duration of action: The duration following spinal administration is about 90 to 120 minutes. The duration of two segments regression following epidural administration is approximately 2.5 hours.(50) Mechanism of action: Bupivacaine acts by binding to sodium channels in the inactivated state, preventing subsequent channel activation and the large transient sodium influx associated with membrane depolarization. (51) Contraindication: The drug is contraindicated in case of known hypersensitivity to any local anesthetic of the amide type. Also, it is not used for obstetrical paracervical block anesthesia as it may cause fetal bradycardia and death (52) Special conditions: Geriatric patients: elderly patients may require lower doses of bupivacaine hydrochloride. They also may be at increased risk for developing hypotension particularly those with hypertension. (53) Patients with severe hepatic disease: may be more susceptible to the potential toxicity. Adverse reactions: These reactions are related to excessive plasma levels due to overdosage (maximum safe dose is 3 mg/kg)(54), unintentional intravascular injection or slow metabolic degradation. One of the specific features of bupivacaine is that its toxic effects on the cardiovascular system appear earlier than on the central nervous system. This is due to the fact that bupivacaine is highly protein bound, the free concentration of the drug in plasma remains low until all the protein binding sites are fully occupied, after which, it increases rapidly and toxicity occurs without patients exhibiting signs of central nervous system toxicity. (55) This cardiotoxic effect is much less with levobupivacaine.(56) CNS reactions:  Excitation and/or depression.  Restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors and finally convulsions.  Drowsiness merging into unconsciousness and respiratory arrest. (57) CVS reactions: Decreased cardiac output, heart block, hypotension and bradycardia. Ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation and cardiac arrest. (57) B. Pharmacology of ephedrine: Description: • Ephedrine is a sympathomimetic drug. • Chemically designated α-[1-(methylamino) ethyl] benzenemethanol sulfate (2:1) (salt). It has the following structural formula. Figure 3 (58)

Figure (2): Pharmacological structure of ephedrine.

Mechanism of Action: Two mechanisms of action direct and indirect: • Indirect sympathomimetic effect: ephedrine releases endogenous norepinephrine from its storage sites. Norepinephrine, in turn, stimulates various alpha and beta-receptors. • Direct effect: by stimulate beta-receptors directly, particularly in bronchiolar smooth muscle. Beta-adrenergic effects result from the production of cyclic-AMP by activation of the enzyme adenylate cyclase .(59) • Up to 40% of a single dose of ephedrine is excreted unchanged in the urine. Some ephedrine is deanimated by MAO in the liver, and conjugation also occurs.(60) Pharmacokinetic data • Metabolism: minimal liver • Onset of action: IV (seconds), IM (10 min to 20 min) • Elimination half-life: 3 h to 6 h • Duration of action: IV/IM (60 min) • Excretion: 22% to 99% (urine) • Dose: Initial dose: 5-10 mg IV bolus (must dilute) Administer additional boluses as needed, not to exceed a total cumulative dosage of 50 mg.(61) Cardiovascular effects of ephedrine: The cardiovascular effects of ephedrine resemble epinephrine, but its blood pressure-elevating response is less intense and lasts approximately 10 times longer. It requires approximately 250 times more ephedrine than epinephrine to produce equivalent blood pressure responses. Intravenous administration of ephedrine results in increases in systolic and diastolic blood pressure, heart rate, and cardiac output. Renal and splanchnic blood flows are decreased, whereas coronary and skeletal muscle blood flows are increased.(62) Systemic vascular resistance may be altered minimally because vasoconstriction in some vascular beds is offset by vasodilation (beta-2 stimulation) in other areas. These cardiovascular effects are due, in part, to alpha receptor-mediated peripheral arterial and venous constriction.(63) The principal mechanism, however, for cardiovascular effects produced by ephedrine is increased myocardial contractility owing to activation of beta-1 receptors. In the presence of preexisting beta blockade, the cardiovascular effects of ephedrine may resemble responses more typical of alpha-receptor stimulation.(63) A second dose of ephedrine produces a less intense blood pressure response than the first dose. This phenomenon, known as tachyphylaxis, occurs with many sympathomimetics and is related to the duration of action of these drugs. Tachyphylaxis probably represents a persistent blockade of adrenergic receptors. For example, ephedrine-induced activation of adrenergic receptors persists even after blood pressure has returned to near predrug levels by virtue of compensatory cardiovascular changes. When ephedrine is administered at this time, the receptors still occupied by ephedrine limit available sites and the blood pressure response is less. Alternatively, tachyphylaxis may be due to depletion of norepinephrine stores.(64) Pharmacology of Ringer's solution Ringer's solution may be considered as normal saline solution. Modified by the substitution of potassium and calcium for some of the sodium, in concentrations approximately those of plasma.(65)

Composition Sodium chloride 0.86gm/100ml Potassium chloride 0.030gm/100ml Calcium chloride 0.033gm/100ml Indications  Dehydration following reduced water intake or increased water loss (vomiting, diarrhea, fistulous drainage),  Ringer's solution can be used to treat mild alkalosis and hypochloremia.(66) Contraindications Addison's disease. Dosage and administration The usual dose for adults is 1-2 litres per day, may be given as rapidly as 30 ml per kg per body weight per hour unless there are cardiac or other contraindications to rapid infusion.(66)

PATIENTS AND METHODS T his study was conducted in the obstetric department of Al Matarya Teaching Hospital on fifty parturient undergoing elective caesarean section after the approval of the ethical medical committee. A written consent was taken from all patients who were either class I or II according to the classification of the American society of Anesthesiologists ASA I, II. This study was a prospective double blind randomized controlled study where the patients were allocated into two equal groups twenty five patients each: Group F & Group E (by closed envelope method):  Group F: those who received crystalloid preloading.  Group E: those who received prophylactic ephedrine intravenously after spinal anesthesia. Inclusion criteria:  The patient selected according to ASA status (ASA I, II).  prime gravida  Normal coagulation profile.  Age range between 20 till 45 years old.  BMI not more than 35  Height 160 to 170 cm. Exclusion criteria:  Patient refusal.  Hypertensive and Diabetic patients.  Pre-eclampsia and eclampsia.  Patients having any coagulopathy disorder or receiving any anticoagulant drugs.  Patients with signs suggesting cardiac or respiratory system failure.  Infection at site of the injection.  Patients with known history of allergy to local anaesthetics’ drugs.  Any pre-existing neurological or psychological disease. Anesthetic management: I. Preoperative management: 1- Preoperative assessment: a) History for: • Cardiac problems, hypertension, ischemic heart disease. • Diabetes mellitus or any endocrinal disorders. • Bronchial asthma, COPD (chronic obstructive pulmonary disease) and smoking. • Bleeding tendency, antiplatelet drugs or anticoagulants. • Hepatic or renal impairments. • Convulsions or any neurological disease. • History of drug intake, history of allergy and sensitivity to any drug and previous anesthetic experiences. b) Examination: • Clinical examination of the chest and heart. • Vital data (HR, RR, ABP, Body Temperature). • Examination of spines. • Examination for jaundice, anemia, cyanosis, clubbing and edema. • Airway examination. c) Investigations: • Complete blood count. • Coagulation profile (PT, PTT, INR, bleeding time) • Liver and kidney function tests. • Random blood sugar. • ECG. 2- Preoperative preparation: a) Preparation of the patient: • Patient consent was taken for spinal anesthesia. • Zantac ampoule the last evening and the morning of operation 75mg and sodium citrate 30ml/ oral. • No premedication was taken before the procedure. b) Preparation of equipments and drugs: I. Equipment: • Spinal needle (pencan, 25 gauge with introducer). • Intravenous cannulas 18 gauge its trade name is (venocath). • Ringer solution, its trade name (Ringer). • Sterilized gown, towels and gauze. • Povidine iodine 10% for sterilization. • Syringes (5cc, 3cc, insulin) and adhesive tape. • Intravenous line. • Disposable face mask. • GA equipment (tubes size 6.5 / 7, laryngoscope) must be available; if needed. II. Drugs: • Lidocaine available as vial containing 20 ml of xylocaine 2%; each 1 ml contains 20mg. • Hyperbaric bupivacaine available as an ampoule containing 4ml. • Fentanyl citrate available as an ampoule containing 100mcg/2ml. • GA drugs (propofol, succinylcholine, atracurium) must be available, if needed. III. Emergency drugs: • Atropine sulphate available as an ampoule 1 mg/ml, diluted with normal saline to a concentrateion of 0.1 mg/ml in a 10 ml syringe, Atropine was only used if needed for bradycardia. • Ephedrine hydrochloride available as an ampoule 30mg/ml, diluted with normal saline to a consaneatetion of 3mg/ml in a 10 ml syringe, Ephedrine was only used if needed for hypotension.

II. Intraoperative management: a) Anesthetic technique: 1. On the day of surgery, the patient was admitted to the operating room earlier than the expected time of surgery by about 10 min. 2. On arrival to the operation room, two 18 gauge intervenous cannula were inserted. Group F (fluid group) will receive crystalloid preloading 15ml/kg (Ringer solution) over 20 minutes before spinal anesthesia and group E (ephedrine group) will receive 8 ml/kg of Ringer solution as preload (500-1000ml). 3. Anti-aspiration measures as Ranitidine (Zantac) were given IV slowly on the previous infusion evening and morning and sodium citrate. 4. Standard monitoring was applied; electrocardiography (ECG), non-invasive arterial blood pressure (NIBP) and peripheral oxygen saturation (SPO2) was monitored via datex Ohmeda monitor. 5. After fluid preload, all patients received spinal anesthesia by spinal needle. 6. Patients were placed in sitting position. 7. Sterilization of the back was done with povidone iodine solution in a circular manner with covering the back by sterilized towels just exposing the spinal segments to be injected. 8. Identification of the level using intercrestal line (Tuffier`s line) which passes through L4-L5 intervertebral space. 9. The skin and subcutaneous tissue were infiltrated with 3ml of xylocaine 2%. 10. A 25G spinal needle pencil point was placed through distal port facing laterally at L4-L5 inter-space. After penetration of ligamentum flavum, dura and arachnoid matter, correct needle placement was identified by free flow of cerebrospinal fluid. 11. A local anesthetic solution {2ml of 0.5% heavy Bupivacaine + fentanyl (25 µg)} was injected over 10-15 seconds. 12. The patients were placed supine immediately after injection with elevation of the head by a pillow and left uterine tilt. 13. Oxygen was supplied to the patient 4L/min via disposable face mask. 14. Group E: will receive prophylactic ephedrine intravenously (30 mg in 60ml saline) by infusion pump, 5mg (10ml) over 2 minute provided 1mg/2ml and 1mg at every minute thereafter for 15 minutes after spinal anesthesia.

b) Patient assessment: I. Intraoperative assessment: 1. Spinal anesthesia parameters: a) Sensory block assessment:  Onset of sensory block: The onset is the time between injection of intrathecal local anesthetic till the absence of pain at specified dermatome. Sensory block was tested in a caudal to cephald caudal direction with a pin prick test using the needle of 3ml syringe. The upper spread of sensory block was determined bilaterally using pin prick test to identify affected dermatomes.  Duration of sensory block: Duration oh the block is the time between intrathecal injection of local anesthetic till analgesics are required or till normal sensation is regained. b) Motor block assessment:  Density of motor block: The degree of motor block was assessed at the same time points as sensory block using a modified Bromage scale. Modified Bromage Scale: 0= full leg movement 1= inability to rise extended leg, can flex knee 2= inability to flex the knee, can flex ankle. 3= no movement  Duration of motor block: Duration of motor block is the time between intrathecal injections of local anesthesia till normal function is regained. 2. Hemodynamic and respiratory parameters:  Non invasive mean arterial blood pressure (MAP): Mean arterial blood pressure (MAP) was measured with an autonomic cycling device. It was recorded preoperatively (before the subarachnoid injection), after induction of spinal anesthesia, during surgery at 3 min intervals until the end of the procedure and postoperatively every 15 min for 24 hour. If MAP decreased more than 30% below the preanesthetic value or to less than 90 mmHg it was considered to be significant hypotension and ephedrine 5 mg increments were given intravenously together with additional 500 ml ringer solution.  Heart rate (HR): Heart rate (HR) was continuously monitored from the electrocardiogram and recorded before the subarachnoid injection, after induction of spinal anesthesia, during surgery at 5 min intervals till the end of procedure and postoperative for 2 hours. Significant bradycardia affecting hemodynamic (HR<50 beats/min) was treated with atropine sulphate 0.5 mg intravenously.  Respiratory rate (RR): Continuously monitored and recorded before subarachnoid injection, after induction of spinal anesthesia, during surgery at 5 minutes interval until the end of procedures and postoperative every 2 hours for 24 hours.  Peripheral oxygen saturation(SPO2): Using pulse oximeter, SPO2 was continuously monitored and recorded before the subarachnoid injection, after induction of spinal anesthesia, every 5 min till the end of the procedure. II. Post-operative assessment: Postoperative assessment was done every 1 hour and continued till spinal effect till off and includes: 1. Hemodynamic and respiratory parameters:  MAP  HR  RR  SPO2 2. Incidence of complications: The incidence of intraoperative complications as (vomiting, hypotension, pruritus, bradycardia, total spinal) as well as postoperative complications as (respiratory depression, backache, post dural puncture headache (PDPH), and transient neurological symptoms (TNS). Patients were notified to contact the emergency room team if any remote complication appears for days postoperative as PDPH or TNS in the form of pain or dysesthesias on back, buttocks or legs irradiating to lower extrimities or any other complication. Evaluation criteria: 1. Hemodynamic parameters:  MAP  HR  RR  SPO2  Need for extra fluid or extra ephedrine 2. Incidence of complication:  Hypotension  Bradycardia  Vomiting  Respiratory depression  PDPH  TNS  Hypoxia  Backache  Pruritus Statistical Analysis A prospective power study showed that a sample size of 25 per study group will have 80% power at the 5%signficance level to detect a difference of 50%in the incidence of hypotension in the E group compared with F group assuming a baseline incidence of 80% as reported by a published study of a similar patient group. Statistical analysis will be done with mixed ANOVA design to compare inter-groupal& intra-groupal results. Obtained data will be presented as mean ± standard deviation or median, interquartile range (IQR) or count &percentage as appropriate. Comparisons will be performed using student t-test, Chi square test, or analysis of variance according to type of variance data. Data will be analyzed using computer package SPSS (version 20, 2012) and Microsoft Excel 2013. P value ≤ 0.05 will be considered statistically significant.

Data collection form Patient Name: Date: / /2018 MR/Unit: / Age: ASA: □ I □II □III □IV CS: □Elective Anesthetist Experience: □RY1 □RY2 □RY3 □Others Bundle therapy Check list: Position: □ Sitting □ Lateral preload 15 ml/kg □ Yes □NO Approach: □Midline □Para median ephedrine IV □ Yes □NO Interspace: □ L2-3 □L3-4 □L4-5 □Others Supine wedged position □ Yes □NO Needle: G Type: CSF: □ Clear □ Blood stained CSF Flow: □ Acceptable □ Fair □ Poor. Barbotage during technique: □ Yes □NO. Local anesthetic solution: □ Hyperbaric Bupivacaine 0.5% □Others Please state: Dose: mg Adjuvant: □ Fentanyl Dose µg □ others Type: Dose T0 (Base) T1 T2 T3 T4 (End) Bromage Scale: □0 □1 □2 □3 MAP mmHg Sensory:□>T4 □ T4-6 □T7-9 □ Failed HR (Beat/min) Nausea: □YES □NO SPO2 (%) Vomiting: □YES □NO Hypotensive episode: □ Yes □ NO Number of episodes: Additional ephedrine total dose: mg Bradycardia: □ Yes □ NO Number of episodes: Total atropine dose: mg Intraoperative anesthetic events and Medications (sedatives, oxytocic, antiemetics, antacid) List Event/Medication Remarks (management, dose, etc) 1 2 3 4 5 Total volume (including 15 ml/kg bundle therapy): ml Urine output: ml Surgeon: □ Resident □ AL/specialist □ Lecturer/consultant Duration of surgery: (min) □ Successful spinal anesthesia □ Inadequate spinal anesthesia (requires heavy sedation/analgesia) □ Failed (GA) Ry:-residency-years

RESULTS Fifty patients were recruited for this study and randomly allocated into 2 groups, F group (fluid) and E group(ephedrine). 1) Demographic Data: They showed no significant differences as regard age, BMI, height and parity (table 1). Table (1): Demographic Data of patients included in the study P value E Group F Group 0.21 27 (20-40) 27 (20-39) Age 0.40 35.3±1.7 35.2±1.7 BMI 0.24 163.3±3.7 162.7±2.9 Height 0.44 1(0-5) 2 (0-4) Parity Data represented as Mean ± SD or Median (Range) 2) Blood Pressure: SBP was generally higher in E group when compared to F group, however the results were statistically unsignificant except at 4 and 22 min. post spinal. (table 2)(figure 4). Incidence of hypotension was significantly lower in E group 6/25 (24%) when compared to F group12/25 (38%), P value(0.03).

Table (2): Systolic BP P value E Group F Group 0.09 119 ±9.9 122.6±7.8 Baseline 0.48 116.4±12.3 116.3±12.3 1 min 0.04* 110.2±15.5 103.9±8.8 4 min 0.4 111.7±13.7 110.6±12.8 7 min 0.4 112.4±13.2 111.7±10.1 10 min 0.3 110.4±12.0 108.7±6.6 13min 0.08 115.6±10.9 111.4±10.2 16 min 0.3 113.7±13.5 111.9±10.9 19 min 0.04* 117.8±10.8 112.1±11.8 22 min 0.1 116.4±9.7 113.3±8.6 25 min 0.08 117.5±11.9 113.3±12.5 28 min 0.0 118.1±9.7 114.3±8.3 31 min 0.0 116±9 112.4±9.7 36 min 0.3 116.2±6.0 115.1±6.1 41 min 0.1 116.4±9.8 113.4±6.8 46 min 0.3 118±6.7 117.0±5.4 51 min 0.4 119.7±6.2 119.1±9 56 min 0.4 122.9±5.2 122.5±6.2 61 min 0.3 121.4±7.59 120.5±6.5 90 min Data represented as Mean ± SD *= P value ≤ 0.05

Figure (3): Systolic Blood pressure trends. 3) Heart rate: The heart rate was generally higher in E group when compared to F group, In (F Group) mean pulse rate changed from baseline of 90.1 ± 8.5 to a maximum of 92.6 ± 11.7 at 28 minute. In (E Group) mean pulse rate increased from baseline of 92.5 ± 5 to maximum of 95.6 ± 8 at 7 minute after spinal block, however it was not statistically significant (table 3) (figure 5).

Table (3): Heart Rate trends. P value E Group F Group 0.1 92.5 ±5 90.1±8.5 Baseline 0.35 93.9±7.4 92.7±13.4 1 min 0.32 92.2±9.1 90.5±16.5 4 min 0.11 95.6±8 91.9±13 7 min 0.17 94.7±9.5 92±10.6 10 min 0.15 94.7±10.6 91.5±11.3 13min 0.11 95±10.4 91.6±8.8 16 min 0.11 93.2±8.4 90±10.5 19 min 0.11 91.6±7.5 87.9±13.6 22 min 0.27 92.6±9.2 90.6±14.2 25 min 0.3 94.2±9.6 92.6±11.7 28 min 0.10 94.5±8.9 91.2±9.4 31 min 0.2 93.4±8.4 91±10.9 36 min 0.42 91.2±6.5 90.7±12 41 min 0.10 91.4±7.2 88.7±10.9 46 min 0.10 91.4±7.2 88.4±9.4 51 min 0.10 90.5±5.6 87.9±8.7 56 min 0.10 91±5.9 88.3±9 61 min 0.17 87.7±6.3 85.6±9.5 90 min Data represented as Mean ± SD

Figure (4): Heart rate trends. 4) Incidence of complications: Regarding incidence of complications; incidence of hypotension was significantly higher in F group when compared to E group, incidence of nausea and vomiting was higher in F group when compared to E group but it was not statistically significant, and there was no chest symptoms in both groups (table 4)(figure 6).

Table (4): Incidence of Complications: P value E Group F Group 0.03 * 6/25(24%) 12/25(48%) Hypotension 0.23 3/25(12%) 5/25(20%) Nausea& Vomiting 0 0/25(0%) 0/25(0%) Chest symptoms Data represented as Number of positive cases /total number of patients (%) *= P value ≤ 0.05

Figure (5): Incidence of complications.

5) Number of ephedrine boluses: Number of boluses of ephedrine required to correct hypotension were significantly lower in ephedrine group when compared to fluid group (f group) 0.6±0.8 and (E group) 0.3±0.54 with a p value 0.046 (table 5)(figure 7). Table (5): Number of ephedrine boluses required to correct hypotension: P value E Group F Group 0.046* 0.3±0.54 0.6±0.8 Number of boluses Data represented as Mean ± SD *= P value ≤ 0.05

Figure (6): Number of ephedrine boluses required to correct hypotension. 6) Oxygen saturation: Regarding oxygen saturation there was no significant differences between the 2 groups (table 6). Table (6): Oxygen saturation: P value E Group F Group 0.23 98.3±0.7 98.5±0.8 Baseline 0.26 99.8±0.4 99.7±0.5 30 min 0.5 99.8±0.4 99.8±0.4 60 min 0.11 98.7±0.6 98.9±0.5 90 min (Post) Data represented as Mean ± SD

DISCUSSION S pinal anaesthesia is considered to be safe as compared to general anaesthesia for caesarean section.General anesthesia is associated with higher mortality rate in comparison to regional anesthesia. However spinal anesthesia is not without risk, Hypotension during caesarean section under spinal anaesthesia is very frequent and if not prevented, it can induce complication for the mother and/ or the fetus(67). Untreated, severe hypotension can pose serious risks to both mother (unconsciousness, pulmonary aspiration, apnoea or even cardiac arrest) and baby (impaired placental perfusion leading to hypoxia, fetal acidosis and neurological injury) .Even mild hypotension can reduce the uteroplacental blood flow and can contribute to fetal acidosis(68). Intravenous preloading is the most popular non-pharmacological method. Early studies had impressive results and it became established as an accepted standard of care. However, more recent controlled studies have questioned the efficacy of preloading. Some had shown that it reduced the severity of hypotension, and some showed that preloading have minimal effect on the incidence of hypotension (69). Vercauteren et al. (2000) stated that ephedrine is the vasopressor of choice for hypotension associated with spinal anesthesia in the parturient because of its ability to maintain uteroplacental blood flow since Ephedrine’s action is considered to be mainly indirect, via stimulating release of norepinephrine from sympathetic nerve terminals; and the uteroplacental circulation is largely devoid of direct sympathetic innervation, so it is relatively resistant to the vasoconstrictive effects of ephedrine .The appropriate route and dose of ephedrine that should be used to prevent hypotension after spinal anaesthesia during caesarean section still remains controversial.(70) In this study we compared the efficacy of fluid preloading with 15ml/Kg ringer (F group) versus prophylactic IV ephedrine infusion without fluid preload(E group) for prevention of hypotension after spinal anesthesia for cesarean section. The changes in blood pressure are related to the level of block, and the risk of hypotension increase with height of block due to higher level of sympathetic block. (71) In this study, there was no significant difference in the distributions by dermatome levels for patients of both groups ranged between T4 – T5 upper sensory level block, so patients treated was having similar degrees of sympathetic block. Therefore, the differences in the incidence of hypotension observed between the two groups to were due to presence or absence of preventive measures only. Our findings showed that SBP was generally higher in ephedrine group when compared to fluid group and it was high statistically significant difference found between two groups from 4min till 28min post spinal, statistically significant difference found between two groups from 33min till 38min post spinal. The heart rate was generally higher in E group when compared to F group, In (F Group) mean pulse rate changed from baseline 89.68 ± 0.48to a maximum of 92.64 ± 1.21at 16 minute. In (E Group) mean pulse rate increased from baseline of 92.40 ± 0.71to maximum of 95.12 ± 1.33at 7 minute after spinal block. Number of boluses of ephedrine required to correct hypotension were significantly lower in ephedrine group (E group) 1.60±0.71 when compared to fluid group (f group) 2.20±0.96 and with a p value 0.015. Also the incidence of nausea and vomiting was lower in the E group when compared with F group. Gajraj et al. (1993)(72) compared the efficacy of an ephedrine infusion with crystalloid administration for reducing the incidence of hypotension during spinal anesthesia for patients scheduled for postpartum tubal ligations under spinal anesthesia, the patients were randomly allocated to receive either 15 mL/kg of crystalloid (crystalloid group) or ephedrine infusion (infusion group). Spinal anesthesia was performed using 70-90 mg of hyperbaric 5% lidocaine. Patients in the infusion group immediately thereafter received an ephedrine infusion at the same rate as in our study. He found that the incidence of hypotension was significantly higher in the crystalloid group compared to the infusion group (P < 0.05). There was no significant difference between the groups in relation to the level of anesthesia or maximal heart rate, and hypertension did not occur in either group which is similar to our results but there was no difference in the incidence of nausea and vomiting in contrast with our study, which may be due different type of patient (pregnant versus non pregnant) and different type of surgical procedure(cesarean section versus postpartum tubal ligation). Bhovi et al. (2014)(73), studied the efficacy of ephedrine for preventing hypotension in patients undergoing caesarean section under spinal anesthesia. The patients were randomly allocated to receive either ephedrine infusion 50mg in 500ml of Ringer’s Lactate immediately after administration of spinal anesthesia at rate of 50ml/min for first 2 minutes, and 10ml/min for next 18 min. or 20ml/kg of Ringer’s Lactate solution as preloading solution prior to subarachnoid block. The study revealed that the incidence of hypotension was significantly higher in the patient group who received fluid preload (60%) compared with (12%) in the patients group who received ephedrine infusion. The incidence of hypotension in the ephedrine group in this study was(12%)in comparison with our study the incidence of hypotension in the ephedrine group was (24%), this difference may be due to different doses of ephedrine used and different volume of infusion. In contrast to this study; Thiangtham et al. (2009)(74) performed a concealed randomized study, 96 parturients were divided into two groups, the study group received ephedrine 18 mg (3 ml) added to 100 ml normal saline, while the control group received 3 ml of normal saline instead of ephedrine given by intravenous continuous infusion over 10 minutes. All patients had preloading fluid with lactated Ringer's solution 20 ml/kg 10 minutes before spinal block was done with 0.5% hyperbaric bupivacaine mixed with preservative free morphine. He found that there was no statistically significant difference in the incidence of hypotension between the two groups, the incidence of hypotension was 93.8% in the control group and 85.4% in the study group, this may be due to the small dose of ephedrine used and different infusion rate. In contrast to this study; Iclal et al. (2009)(75) designed a randomized, double-blinded study to determine the efficacy and safety of 0.5 mg/kg intravenous ephedrine for the prevention of hypotension during spinal anesthesia for cesarean delivery, and its effect on neonatal outcome and umblical artery PH. Patients were randomly allocated into two groups: ephedrine group and control group. All patients received preloading with 15ml/kg lactated ringer before spinal block, patients of the ephedrine group were injected with 0.5mg/kg ephedrine intravenously over 60 seconds while patients of control group were injected with saline. He found that there were significant lower incidences of hypotension and nausea and vomiting in the ephedrine group compared with the control group. In consistence with our results, Minj et al. (2018) (76) comparing the incidence of hypotension and the need for vasopressors in patients submitted to caesarean section under spinal anaesthesia following preload crystalloid with vasopressors conclude that the combined use of volume preloading to compensate for vasodilatation and vasopressor to counteract arterial dilatation is a very effective method in reducing the incidence, severity and duration of spiral hypotension. The combination group with decreased volume of preload and reduced dose of vasoconstrictor provides better haemodynamic stability when compared to preloading of vasoconstrictors alone. It differ from our study by different method (combined preload and vasopressor group and preloading of vasoconstrictors alone group) Limitations in our study; the umbilical artery PH and neonatal APGAR score were not measured to demonstrate the effect of ephedrine on acid base status of the fetus and whether it is clinically significant or not. Recommendations for further studies; to compare neonatal APGAR score and fetal acid base status in both groups ephedrine and phenylephrine.

SUMMARY A caesarean section (C-section), is a form of childbirth in which a surgical incision is made through a mother's abdomen (laparotomy) and uterus (hysterotomy) to deliver one or more babies. It is usually performed when a vaginal delivery would lead to medical complications. The anesthetic plan for cesarean delivery should take into account the well-being of two patients: the mother and the fetus. Regional anesthesia is the most common method of anesthesia for delivery because it allows the mother to be awake and immediately interact with her baby. It is also safer for the mother than general anesthesia. Regional anesthesia is used for 95 percent of planned cesarean deliveries in the United States. The aim of this study is to evaluate the efficacy of ephedrine infusion versus preload crystalloid administration in reducing the incidence of hypotension during spinal anaesthesia. This study was conducted in the obstetric department of Al Matarya Teaching Hospital on fifty parturient undergoing elective caesarean section after the approval of the ethical medical committee. A written consent was taken from all patients who were either class II according to the classification of the American society of Anesthesiologists ASA II. This study was a prospective double blind randomized controlled study where the patients were allocated into 2 equal groups 25 patients each. We concluded that prophylactic IV Ephedrine infusion is more effective than fluid preload in prevention of hypotension due to spinal anesthesia for cesarean section without causing significant tachycardia or hypertension.

CONCLUSION W e concluded that prophylactic IV Ephedrine infusion is more effective than fluid preload in prevention of hypotension due to spinal anesthesia for cesarean section without causing significant tachycardia or hypertension.

REFERENCES 1. Bucklin BA, Hawkins JL, Anderson JR, Ullrich FA. Obstetric anesthesia workforce survey: twenty-year update. Anesthesiology 2005; 103:645. 2. Park GE, Hauch MA, Curlin F, Datta S, Bader AM. The effects of varying volumes of crystalloid administration before cesarean delivery on maternal hemodynamics and colloid osmotic pressure. Anesth Analg. 1996; 83:299–303. 3. Hossain N, Tayab S, Mahmood T. Spinal anaesthesia for caesarean section. J Surg Pak 2002; 7: 19-21 4. Ismail S, Huda A. An observational study of anaesthesia and surgical time in elective caesarean section: spinal compared with general anaesthesia. Int J Obstet Anesth. 2009; 18(4):352-5 5. Kuczkopwski KM, Reisner LS, Lin D. Anesthesia for cesarean section. In:Chestnut DH, Polley LS, Tsen LC, Wong CA, editors. Chestnut’s ObstetricAnesthesia: Principles and Practice. 4th ed. Philadelphia: Mosby; 2009. p. 422-5. 6. Cyna AM, Andrew M, Emmett RS, Middleton P, Simmons SW. Techniques for preventing hypotension during spinal anaesthesia for caesarean section. Cochrane Database Syst Rev 2006;18(4) 7. Bhagat H, Malohtra K, Ghildyal SK, Srivastava PC. Evaluation of preloading and vasoconstrictors as a combined prophylaxis for hypotension during subarachnoid anaesthesia. Indian J Anaesth 2004; 48 (4): 299-303 8. Rout CC, Rocke DA. Prophylactic intramuscular ephedrine prior to cesarean section. Anaesthesia and intensive care1992;20:448.52 9. Rout CC, Rocke DA, Levin J et al. — A reevaluation of the role of crystalloid preload in the prevention of hypotension associated with spinal anesthesia for elective cesarean section. Anesthesiology, 1993;79:262-269 10. Tsen LC. What's new and novel in obstetric anaesthesia? contributions from the 2003 scientific literature. Int J Obstet Anaesth 2005; 14(2):126- 46. 11. McKenzie AG. Researches on supine hypotension in pregnancy, Int Congress Series, 2002; 1242: 597-601. 12. Dyer RA, James MF. Maternal hemodynamic monitoring in obstetric anaesthesia. Anesthesiology 2008; 109(5):765- 7. 13. Parker JA, Barroso F, Stanworth SJ, Spiby H, Hopewell S, Doree CJ, et al. Gaps in the evidence for prevention and treatment of maternal anaemia: a review of systematic reviews. BMC Pregnancy Childbirth 2012; 12: 56. 14. Wong CA, Loffredi M, Ganchiff JN, Zhao J, Wang Z, Avram MJ. Gastric emptying of water in term pregnancy. Anesthesiology 2002; 96(6):1395- 400. 15. Karaman S, Akercan F, Akarsu T, Firat V. Comparison of the maternal and neonatal effects of epidural block and of combined spinal-epidural block for cesarean section. Eur J Obstet Gynecol Reprod Biol 2005; 121:18- 23. 16. Saravanakumar K, Rao SG, Cooper GM. Obesity and obstetric anaesthesia. Anaethesia 2006; 61: 36- 48. 17. Andreasen KR, Andersen ML, Schantz AL. Obesity and pregnancy. Acta Obstet Gynecol Scand 2004; 83:1022-9. 18. Karaman S, Akercan F, Akarsu T, Firat V. Comparison of the maternal and neonatal effects of epidural block and of combined spinal-epidural block for cesarean section. Eur J Obstet Gynecol Reprod Biol 2005; 121:18- 23. 19. Dyer RA, James MF. Maternal hemodynamic monitoring in obstetric anaesthesia. Anesthesiology 2008; 109(5):765- 7. 20. Pollard JB. Cardiac arrest during spinal anesthesia:Common mechanisms and strategies for prevention. Anesth Analg 2001; 92:252–6. 21. Edward MG, Maged SM, John ET. Spinal, Eipdural and caudal blocks. 2nd ed. Clinical Anesthesiology 1996; 1: 211-244. 22. Hartmann B, Junger A, Klasen J, Benson M, Jost A, Banzhaf A, et al. The incidence and risk factors for hypotension after spinal anesthesia induction: an analysis with automated data collection. Anesth Analg 2002; 94(6):1521-9. 23. Ellis H, Feldman SJ, Harrop-Griffiths W. Anatomy for anaesthetists. 8thed. Oxford, London: Blackwell Scientific Publication; 2004. 24. Brown DL. Spinal, epidural and caudal anaesthesia. In: Miller ED (ed). Miller’s anesthesia. 7thed. Philadelphia: Churchill Livingstone; 2010. 1611- 39. 25. Clark SL, Cotton DB, Lee W, et al. Central hemodynamic assessment of normal term pregnancy, Am J of Obstet Gynecol, 1989; 161: 1439-42. 26. Bamber JH, Dresner M. Aortocaval compression in pregnancy: the effect of changing the degree and direction of lateral tilt on maternal cardiac output, Anesth Analg , 2003; 97: 256-8. 27. Kinsella SM, Lohmann G. Supine hypotensive syndrome, Obstet Gynecol, 1994; 83: 774-88. 28. McKenzie AG. Researches on supine hypotension in pregnancy, Int Congress Series, 2002; 1242: 597-601. 29. Baysinger CL, Pope JE, Lockhart EM, Mercaldo ND. The management of accidental dural puncture and postdural puncture headache: a North American survey. J Clin Anesth 2011; 23:349. 30. Darvish B, Gupta A, Alahuhta S, Dahl V, Thorsteinsson A, Irestedt L, et al. Management of accidental dural puncture and post-dural puncture headache after labour: a Nordic survey. Acta Anaesthesiol Scand 2011; 55: 46-53. 31. Dahl JB, Jeppesen IS, Jorgensen H. Intraoperative and postoperative analgesic efficacy and adverse effects of intrathecal opioids in patients undergoing cesarean section. Anesthesiology 1999; 91: 1919- 27. 32. Traore M, Diallo A, Coulibaly Y, Guinto C, Timbo S, Thomas J. Cauda equina syndrome and profound hearing loss after spinal anesthesia with isobaric bupivacaine. Anesth Analg 2006; 102:1863- 4. 33. Bromage PR. Neurologic complications of regional anaesthesia for obstetrics. In: Hughes SC, Levinson G, Rosen MA (eds). Shnider and Levinson’s anaesthesia for obstetrics. 4thed. Philadelphia: Lippincott Williams and Wilkins; 2002. 409–16. 34. Kwak KH. Postdural puncture headache. Korean Journal of Anesthesiology. 2017; 70(2):136. 35. Shaikh J, Memon A, Memon M, Khan M. Post dural puncture headache after spinal anaesthesia for caesarean section: a comparison of 25 g Quincke, 27 g Quincke and 27 g Whitacre spinal needles. Ayub Med Coll Abbottabad 2008; 20: 10- 3. 36. Srivastava V, Jindal P, Sharma P. Study of post dural puncture headache with 27G Quincke & Whitacre needles in obstetrics/non obstet. Middle East J 2010; 20: 709- 17. 37. Wong CA, Scavone BM, Dugan S, Smith JC, Prather H, Ganchiff JN, et al. Incidence of postpartum lumbosacral spine and lower extremity nerve injuries. Obstet Gynecol 2003; 101: 279-88. 38. Colc CD, MC Morland GH, Axelson JE. Epidural blockede for cesarean section comparing lidocaine hydrobonated and lidocaine hydrochloride. Anesthesiology 1985; 83: 348- 50. 39. Viitanen H, Porthan L, Viitanen M, Heula AL, Heikkila M. Postpartum neurologic symptoms following single-shot spinal block for labour analgesia. Acta Anaesthesiol Scand 2005; 49: 1015– 22. 40. Bursell B, Ratzan RM, Smally A. Lidocaine toxicity misinterpreted as a stroke. West J Emerg Med 2009; 10: 292- 4. 41. Kitagawa N, Oda M, Totoki T. Possible mechanism of irreversible nerve injury caused by local anesthetics: detergent properties of local anesthetics and membrane disruption. Anesthesiology 2004; 100: 962. 42. Johnson ME, Saenz JA, DaSilva AD. Effect of local anesthetic on neuronal cytoplasmic calcium and plasma membrane lysis (necrosis) in a cell culture model. Anesthesiology 2002; 97: 1466-76. 43. Gozdemir M, Muslu B, Usta B, Sert H, Karatas F, Surgit O. Transient neurological symptoms after spinal anaesthesia with levobupivacaine 5 mg/ml or lidocaine 20 mg/ml. Acta Anaesthesiol Scand 2010; 54: 59- 64. 44. Kovac AL. Prevention and treatment of postoperative nausea and vomiting. Drugs 2000; 59: 213-43. 45. Kamphuis ET, Ionescu TI, Kuipers PW, de Gier J, van Venrooij GE, Boon TA. Recovery of storage and emptying functions of the urinary bladder after spinal anesthesia with lidocaine and with bupivacaine in men. Anesthesiology 1998; 88: 310– 6. 46. Piper SN, Fent MT, Rohm KD. Vrapidil does not prevent postanesthetic shivering: a dose-ranging study. Can J Anaesth 2001; 48: 742-7. 47. Suzuki S, Gerner P, Lirk P. Local anesthetics. InPharmacology and Physiology for Anesthesia 2019 Jan 1 (pp. 390-411). Elsevier. 48. Chen MQ, Chen C, Li L. Effect of Baricity of Bupivacaine on Median Effective Doses for Motor Block. Medical science monitor: international medical journal of experimental and clinical research. 2017; 23:4699. 49. Camorcia M, Capogna G, Berritta C. The relative potencies for motor block after intrathecal ropivacaine, levobupivacaine and bupivacaine. Anesth Analg 2007; 104: 904-7. 50. Muchhal M, Maheshwari RC. Evaluation of Different Local Anesthetic Solutions for Extradural Anaesthesia in Elective Caesarean Section-A Comparative Study. Journal of Advanced Medical and Dental Sciences Research. 2018; 6(2):82-5. 51. Ruiz-Tovar J, Muñoz JL, Gonzalez J, Zubiaga L, García A, Jimenez M, Ferrigni C, Durán M. Postoperative pain after laparoscopic sleeve gastrectomy: comparison of three analgesic schemes (isolated intravenous analgesia, epidural analgesia associated with intravenous analgesia and port-sites infiltration with bupivacaine associated with intravenous analgesia). Surgical endoscopy. 2017; 31(1):231-6. 52. Bay-Nielson L, Klarskov B, Bech K. Levobupivacaine vs bupivacaine as infiltration anaesthesia in inguinal herniorrhaphy. Br J Anaesth 1999; 82: 280-2. 53. Bar-Oz B, Bulkowstein M, Benyamini L. Use of antibiotic and analgesic drugs during lactation. Drug Saf 2003; 26: 925-35. 54. Veering BT, Burm AG, Vletter AA. The effect of age on systemic absorption and systemic disposition of bupivacaine after subarachnoid administration. Anesthesiology 1991; 74: 250-7. 55. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth pain med 2004; 29: 564-75. 56. Desai N, Gardner A, Carvalho B. Labor Epidural Analgesia to Cesarean Section Anesthetic Conversion Failure: A National Survey. Anesthesiology Research and Practice. 2019; 2019. 57. Ohmura S, Kawada M, Ohta T. Systemic toxicity and resuscitation in bupivacaine-, levobupivacaine- or ropivacaine-infused rats. Anesth Analg 2001; 93: 743-8. 58. Autory Y, Narchi P, Messiah A. Hypotension during neuraxial blocks. Anesthesiology 2000; 91:521–29. 59. Reynolds LP, Borowicz PP, Caton JS, et al. Uteroplacental vascular development and placental function: an update. Int J Dev Biol 2010; 54:355. 60. Ramesar SV, Mackraj I, Gathiram P, Moodley J. Sildenafil citrate improves fetal outcomes in pregnant, L-NAME treated, Sprague-Dawley rats. Eur J Obstet Gynecol Reprod Biol 2010; 149:22. 61. Mets B. Should norepinephrine, rather than phenylephrine, be considered the primary vasopressor in anesthetic practice?. Anesthesia & Analgesia. 2016; 122(5):1707-14. 62. Kinsella M, Dob D, Holdcroft A. Regional anaesthesia. InCrises in Childbirth-Why Mothers Survive 2018 Apr 19 (pp. 67-86). CRC Press. 63. Dusitkasem S, Herndon BH, Somjit M, Stahl DL, Bitticker E, Coffman JC. Comparison of Phenylephrine and Ephedrine in Treatment of Spinal-Induced Hypotension in High-Risk Pregnancies: A Narrative Review. Frontiers in Medicine. 2017; 4:2. 64. Goetz AE, Heckel K. Perioperative fluid and volume management: goal-directed therapy necessary. Anesthesist 2007; 56:745-6. 65. Demling RH. Shock and fluids. In Shoemaker WC. Critical Care: 4 th edition, California, Fullerton, 1986; 301-11. 66. Mercier FJ, Bonnet MP, De la Dorie A, Moufouki M, Banu F, Hanaf A, Edouard D, Roger-Christoph S. Spinal anaesthesia for caesarean section: fluid loading, vasopressor and hypotension. Ann Fr Anesth Reanim 2007; 26:688-93. 67. Campagna JA, Cartner C. Clinical relevance of Bezold Jarisch reflex. Anesthesiology 2003; 98 (5): 1250- 60. 68. Hossain N, Tayab S, Mamood T. Spinal anaesthesia for caesarean section. J Surg Pak 2002; 7: 19-21. 69. Shimokaze T, Akaba K, Saito E. Oscillometric and intra-arterial blood pressure in preterm and term infants: extent of discrepancy and factors associated with inaccuracy. Am J Perinatol 2015; 32:277. 70. Mojica JL, Meléndez HJ, Bautista LE. The Timing of Intravenous Crystalloid Administration and Incidence of Cardiovascular Side Effects during Spinal Anesthesia: The Results from a Randomized Controlled Trial. Anesth Analg 2002; 94:432-7. 71. Vercauteren MP, Coppejans HC, Hoffmann VH, Mertens E. Prevention of hypotension by a single 5-mg dose of ephedrine during spinal anesthesia in prehydrated caesarean delivery patients. Anesth Analg 2000; 90:324-7. 72. Gajraj NM. Comparison of an Ephedrine Infusion with Crystalloid Administration for Prevention of Hypotension During Spinal Anesthesia. Anesth Analg 1993; 76:1023-6. 73. Bhovi MRA. Comparitive Study of Ephedrine Infusion with the Preload of Crystalloids for Prevention of Hypotension During Spinal Anaesthesia for Elective Caesarean Section, Indian Journal of Applied Research 2014; 4(2): 2249-555X. 74. Thiangtham K, Asampinwat T. Intravenous ephedrine infusion for prophylaxis of hypotension during spinal anesthesia for cesarean section. Songkla Med J 2009; 27(4):291-300. 75. Iclal OK, Kenan K, Sinan G, Ali C, Zeki K, et al. The Effects of Intravenous Ephedrine during Spinal Anesthesia for Cesarean Delivery: A Randomized Controlled Trial J Korean Med Sci 2009; 24: 883-8. 76. Minj SD, Beck R, Kumar A, Tiwari P, Chandan RK and Sen S. The incidence and management of hypotension in the pregnant parturients undergoing caesarean section following spinal anaesthesia with 0.5% bupivacaine. International Journal of Reproduction, Contraception, Obstetrics and Gynecology 2018; 7(3):1205-1211.

المـلـخـص الـعـربــي ان منع حدوث هبوط فى ضغط الدم اثناء التخدير النصفى للولادة القيصرية يودى الى نتائج افضل من معالاجته، فى هذه الدراسة تم مقارنة كفاءة اعطاء المحاليل الوريدية او اعطاء عقار الافدرين عن طريق الحقن الوريدى المستمر فى منع حدوث هبوط فى ضغط الدم. خمسون مريضة تم تقسيمهم عشواءيا الى مجموعتين,25مريضة فى كل مجموعة. المجموعة الاولى تم اعطاءها 15مل/كجم محلول لاكتات الرينجرقبل اعطاء التخدير النصفى . والمجموعة الثانية تم اعطاءها عقار الافدرين عن طريق الحقن الوريدى (5 مجم فى اول دقيقة بعد اعطاء التخدير النصفى و5 مجم فى ثانى دقيقة وواحد مجم فى كل دقيقة بعد ذلك لمدة 15 دقيقة) فى حالة حدوث هبوط فى ضغط الدم السيستولى بنسبة اكثر من 20% من الضغط السيستولى قبل اعطاء التخدير النصفى يتم اعطاء جرعة 5مجم اضافية من الافدرين. وجدنا ان نسبة حدوث هبوط فى ضغط الدم كانت اقل فى المجموعة الثانية بنسبة(24%) مقارنة بالمجموعة الاولى بنسبة (48%) . لم يكن هناك فرق ملحوظ فى سرعة ضربات القلب بين المجموعتين. نسبة حدوث الغثيان و الترجيع كانت اكثر فى المجموعة الاولى بنسبة (20%) بالمقارنة بالمجموعة الثانية بنسبة (12%). استنتجت الدراسة ان اعطاء عقار الافدرين عن طريق الحقن الوريدى المستمر بعد اعطاء التخدير النصفى اكثر كفاءة فى منع حدوث هبوط فى ضغط الدم من اعطاء المحاليل الوريدية للحوامل اللاتى يخغون للولادة القيصرية تحت تاثير التخدير النصفى وذلك بدون حدوث زيادة ملحوظة فى سرعة ضربات القلب.

دراسة مقارنة بين محاليل وريده مقابل الإيفيدرين بالتسريب للوقاية من انخفاض ضغط الدم بسبب التخدير النصفي للولادات القيصرية رسالة توطئة للحصول علي درجة الماجستير في التخدير مقدمة من الطبيبة/ أمنية سامي محمد الكردي بكالوريوس الطب والجراحة تحت إشراف أ.د/ سامية عبد المحسن عبد اللطيف أستاذ التخدير والعناية المركزة كلية الطب - جامعة عين شمس د/ امل حامد عبد الحميد ربيع مدرس التخدير والعناية المركزة كلية الطب - جامعة عين شمس د/ احمد عبد الدايم عبد الحق مدرس التخدير والعناية المركزة كلية الطب - جامعة عين شمس كلية الطب - جامعة عين شمس 2019

Introduction

Aim of the Work

Review of Literature

Patients and Methods

Results

Discussion

Summary Conclusion

References

Arabic Summummary