Abstract. Med. J. Cairo Univ., Vol. 84, No. 1, March: 77-83,

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1 Med. J. Cairo Univ., Vol. 84, No. 1, March: 77-83, Effects on the Maternal Nausea and Vomiting after Giving Prohylactic Ehedrine Versus Phenylehrine for Prevention of Hyotension in Severe Pre-Eclamtic Parturients Uundergoing Cesarean Section Under Sinal Anesthesia MOHAMED YEHYA MOHAMED, M.Sc.; JEHAN H. IBRAHIM, M.D. and TAMER F. SAFAN, M.D. The Deartment of Anesthesiology, Faculty of Medicine, Cairo University Abstract Objective: Is to comare the incidence of of nausea and vomiting after giving henylehrine and ehedrine for the revention of sinal anesthesia induced hyotension in severe reeclamtic atients undergoing cesarean delivery. Methods: 60 severely re-eclamtic atients randomly allocated into 2 equal grous (30 atients each) using comuter generated numbers and concealed using sequentially numbered, sealed oaque enveloe technique. (ehedrine): Patients received bolus of 10 milligram of ehedrine i.v immediately after the subarachnoid block. Grou P (henylehrine): Patients received bolus of 100 microgram of henylehrine i.v immediately after the subarachnoid block. Nausea and vomiting were observed, recorded reoerative, intraoerative and ostoerative. They were treated by atroine if occurred intraoerative or ondansetron if occurred ostoerative. Results: Intraoeratively, in ehedrine grou, four atients suffered from nausea and one atient suffered from vomiting and they were treated by 0.5mg atroine. While in henylehrine grou, no atients suffered from nausea or vomiting. Conclusion: Ehedrine administration is associated with higher incidence of nausea and vomiting in the mother. Key Words: Nausea Vomiting Preeclamsia Sinal anesthesia Hyotension Phenylehrine Ehedrine. Introduction PRE-ECLAMPSIA is a regnancy secific disorder characterized by hyertension and roteinuria. It constitutes major cause of morbidity and mortality in develoing countries, and it is 5-10% of Corresondence to: Dr. Mohamed Yehya Mohamed, The Deartment of Anesthesiology, Faculty of Medicine, Cairo University all regnancies. The clinical manifestations of reeclamsia reflect widesread endothelial dysfunction, with vasoconstriction and end organ ischemia [1]. There are increased sensitivity of the vasculature to ressor agents, activation of the coagulation cascade, micro thrombi, intravascular fluid loss, vasosasm, hemoconcentration, and ischemic changes in the lacenta, kidney, liver and brain [2]. Pre-eclamsia is classified as either mild or severe. Pre-eclamsia is severe when the systolic arterial ressure is 160mmHg or more, and/or the diastolic arterial ressure is 1 1 0mmHg or higher [3]. Eidural anesthesia has been acceted as the referred anesthetic technique for C.S in severe re-eclamtic atients among both the anesthiologists and the obstetricians. However a number of studies have demonstrated that sinal and combined sinal-eidural can be safely administered without increasing the risk to the mother or the fetus in severe re-eclamsia [4]. Hyotension during sinal block for C.S is secondary to the symathetic blockade and it can be harmful to both the fetus and mother. Among the deleterious effects, one can mention maternal symtoms of reduced cardiac outut such as nausea, vomiting, and altered level of consciousness [5]. Ehedrine is a non-catecholamine symathomimetic agent that stimulates alha and beta adrenergic recetors directly and indirectly, roducing its effects by releasing nor einehrine from nerve endings in the autonomous nervous system [6]. The 77

2 78 Effects on the Maternal Nausea & Vomiting after Giving Prohylactic Ehedrine Versus Phenylehrine intercurrences of ehedrine include maternal suraventricular tachycardia, tachyhylaxis, and fetal acidosis [7]. Phenylehrine is considered a ure alha-1 adrenergic agonist. It romotes dose-deendent vasoconstriction, which is more ronounced in the venous than arterial bed, imroving venous return after the symathetic blockade during sinal block [8,9]. Patients and Methods The study was done in the Obstetrics and Gynecology Deartment of Cairo University Hositals from Feb May 2015 on 60 severely reeclamtic atients after aroval of the ethic and scientific committee and written informed consent obtained from each atient and oerated uon by the same surgeon. Severe re-eclamsia was defined as a systolic blood ressure of 160mmHg or more and/or diastolic blood ressure exceeds 1 1 0mmHg obtained at least at 3 searate occasions, and roteinuria on urine disticks 3+ or more. Inclusion criteria were diagnosis of severe reeclamsia, ASA hysical status II, age ^! 18 years, gestations ^34 weeks. Exclusion criteria were nausea or vomiting occurring reoerative, history of hyeremesis gravidarum, atient refusal, urgent or emergency cesarean delivery, atients in labor, contraindications to sinal anesthesia and Imminent eclamsia (severe headache, visual disturbance, eigastric ain, hyerreflexia, dizziness and fainting). Each atient received 2 hours rior to surgery i.v magnesium sulfate (MgSo4) 4 grams initially followed by 1 gram/hour for 24 hours for seizure rohylaxis while checking serum magnesium level every six hours and i.v hydralazine 5mg at 20 minutes intervals to decrease the diastolic blood ressure to aroximately 90mmHg. Before giving the sinal anaesthetic, a 18 gauge i.v. cannula was inserted and re-oerative rehydration was started by infusion of 250mL of Hartmann's solution (lactated Ringer's solution) over minutes followed by lactated Ringer's solution 100mL/h. Intra-oerative blood loss was relaced with Hartmann's solution or blood (if Hct >28). Postoeratively, fluids were restricted to 80mL/h lus losses. Patients were randomly allocated into 2 equal grous (30 atients each) using comuter generated numbers and concealed using sequentially numbered, sealed oaque enveloe technique. (ehedrine) where atients received bolus of 10 milligram of ehedrine i.v immediately after the subarachnoid block. Grou P (henylehrine) where atients received bolus of 100 microgram of henylehrine i.v immediately after the subarachnoid block. Systolic Blood Pressure (SAP), Diastolic Blood Pressure (DAP) and Mean Blood Pressure (MAP) were measured and recorded every minute for the first 20min, then every 2min for the next 10min, then every 5min thereafter until the end of the surgery then every hour for the first 24 hours ostoerative. Severity and duration of hyotension were observed and recorded. Maternal hyotension was defined as blood ressure equal or lower than 20% of baseline values and was treated with 50% of the initial dose of vasoressor. Nausea and vomiting were observed and recorded for 30min before sinal anesthesia, and during oeration and the first 24 hours ostoerative. They are treated by atroine if occurred intraoerative or ondansetron if occurred ostoerative. 100% Oxygen was given at 5L/min via face mask. Surgery was allowed after 10 minutes of giving sinal anesthesia. Oxytocin 5 I.U was given over 5 minutes immediately after delivery of the baby then IU was given by slow IV infusion. The incidence of nausea and vomiting, maternal hyotension, reactive hyertension, bradycardia, number of vasoressor doses, number of atroine doses were observed and recorded. Data was resented as median and range, mean ± SD or ercentage as aroriate. Continuous data was comared by one-way ANOVA and reeated measures with two-way ANOVA as osthoc rocedure for comarison against baseline values to further investigate any statistically significant findings. Indices were analyzed using Chi-square test or Ficher's exact where aroriate. Values less than 0.05 was considered significant.

3 Mohamed Y. Mohamed, et al. 79 All statistical data analysis was erformed using SPSS version 11.5 (SPSS, Chicago, IL). Results Sixty severely reeclamtic female atients (ASA II) undergoing elective cesarean section under sinal anesthesia comleted the study. Patients characteristics and baseline haemodynamic arameters are resented. The two grous were comarable in age, weight, height, BMI, gestational age and baseline haemodynamic data. Haemodynamic changes were comared between the two grous after induction of sinal anaesthesia u to 24 hours ostoerative. This difference over time in heart rate between ehedrine and henylehrine grous was statistically significantly between 12 to 18 minutes after sinal anesthesia (<0.05). Patients in the henylehrine grou were more likely than the Ehedrine grou to develo bradycardia. Bradycardia (heart rate below 60 beats/min) occurred in one atient in ehedrine grou, and eight atients in henylehrine grou and those atients were treated by 0.5mg atroine. Overall, the systolic, diastolic, and mean arterial blood ressure readings from sinal anesthesia until 24 hours ostoerative were were similar for both grous. The blood ressure readings over time were comarable for both grous. The incidence of hyotension (systolic arterial ressure <20% of baseline) was similar for both grous, where one atient in each grou had a decrease in her systolic arterial ressure <20% of baseline. Minimum systolic ressure was 105 ±5.4mmHg in ehedrine grou and 108 ±6.2mmHg in henylehrine grou. Maximum systolic ressure was 150 ±8.9mmHg in ehedrine grou and 159±5.2mmHg in henylehrine grou. Reactive hyertension did not occur in either grou. Both Bradycardia (Heart rate <60 beats/min) and hyotension (blood ressure lower than 20% of baseline values) occurred together in one atient in ehedrine grou and one atient in henylehrine grou. Where in the ehedrine grou, that atient was given 10 milligrams ehedrine immediately after sinal anesthesia and the second dose of ehedrine was given at 10 minutes when hyotension occurred [blood ressue was 105/80 (88)] and heart rate was 58 beats/min. The second dose of ehedrine was 5 milligrams (50% of the initial dose of vasoressor). While the other atient in the henylehrine grou, she was given henylehrine immediately after sinal anesthesia and the second dose was given at 12 minutes when hyotension occurred [blood ressue was 108/83 (9 1)] and heart rate was 53 beats/min. The second dose of henylehrine was 50 micrograms (50% of the initial dose of vasoressor). Before sinal anesthesia, atients did not suffer from nausea and vomiting in both grous. Intraoeratively, in ehedrine grou, four atients suffered from nausea and one atient suffered from vomiting and they were treated by 0.5mg atroine. While in henylehrine grou, no atients suffered from nausea or vomiting. Nausea and vomiting were lower in the henylehrine grou than in the ehedrine grou which is statistically significant (<0.0001). In the ehedrine grou, that one eisode of vomiting occurred 10 minutes after sinal anesthesia and was associated with decreased systolic arterial ressure, decreased heart rate, increased ehedrine dose, and the block height was T4. Postoeratively, no eisodes of nausea and vomiting occurred in either grou. Number of atroine doses given in ehedrine grou was six doses. One of them was due to bradycardia, four of them were due to nausea, and the last one was due to vomiting. While in henylehrine grou, number of atroine doses given was eight doses and they were given due to bradycardia. Table (1): Patient characteristics and baseline hemodynamic data (Values are resented as Mean ± SD). Grou P Age (years) 27.2± ± Weight (kg) 79.1 ± ± Height (cm) 160.2± ± BMI (kg/m 2) 31.1 ± ± Gestational age (weeks) 35.9± ± Birth weight (kg) 2.54± ± Baseline systolic ressure (mmhg) 140± ± Baseline diastolic ressure (mmhg) 92± ± Baseline mean arterial ressure 115± ± (mmhg) Baseline heart rate (beats/min) 98±4 97± : Ehedrine grou. Grou P: Phenylehrine grou.

4 80 Effects on the Maternal Nausea & Vomiting after Giving Prohylactic Ehedrine Versus Phenylehrine Table (2): Heart rate (Values are resented as Mean ± SD or median (range), >0.05 is considered significant). Heart rate (n=-30) Grou P Table (3): Systolic blood ressure (Values are resented as Mean ± SD). Systolic blood ressure Grou P Baseline (reinduction) 98±4.2 97± Baseline (reinduction) 140± ± Intraoerative until delivery: Intraoerative until delivery: At 2 minutes 99±4.4 94± At 2 minutes 135± ± At 4 minutes 95±7.1 87± At 4 minutes 132± ± At 6 minutes 90±3.5 82± At 6 minutes 127± ± At 8 minutes 79±4.3 75± At 8 minutes 110± ± At 10 minutes 63±5.8 68± At 10 minutes 105± ± At 12 minutes 70± ±2.4* At 12 minutes 115± ± At 14 minutes 80±4.8 59±2.2* At 14 minutes 129± ± At 16 minutes 88±5.9 57±4.1* At 16 minutes 150± ± At 18 minutes 94± ±3.6* At 18 minutes 149± ± At 20 minutes 92±3.5 67± At 20 minutes 148± ± At 22 minutes 94±4.1 69± At 22 minutes 146± ± At 24 minutes 95± ± At 24 minutes 145± ± At 26 minutes 96±5.2 75± At 26 minutes 145± ± At 28 minutes 97±5.4 80± At 28 minutes 144± ± At 30 minutes 99±5.2 76± At 30 minutes 146± ± At 32 minutes 98±4.7 82± At 32 minutes 145± ± At 34 minutes 96±3.9 78± At 34 minutes 141± ± At 36 minutes 97±2.9 75± At 36 minutes 144± ± Postoerative 95±4.8 97± Postoerative 142± ± : Ehedrine grou. : Ehedrine grou. Grou P: Phenylehrine grou. Grou P: Phenylehrine grou. Table (4): Diastolic blood ressure (Values are resented as Mean ± SD). Table (5): Mean blood ressure (Values are resented as Mean ± SD). Diastolic blood ressure (n=-30) Grou P Mean blood ressure Grou P Baseline (reinduction) 92± ± Baseline (reinduction) 105± ± Intraoerative until delivery: Intraoerative until delivery: At 2 minutes 89±8.5 92± At 2 minutes 104± ± At 4 minutes 88±7.2 90± At 4 minutes 102± ± At 6 minutes 85±5.9 89± At 6 minutes 99± ± At 8 minutes 83±6.3 85± At 8 minutes 92±4.8 99± At 10 minutes 80±4.9 84± At 10 minutes 88±5.2 97± At 12 minutes 82± ± At 12 minutes 93 ± ± At 14 minutes 86±3.9 88± At 14 minutes 100± ± At 16 minutes 92±2.8 95± At 16 minutes 111 ± ± At 18 minutes 90±3.5 94± At 18 minutes 109± ± At 20 minutes 89±3.9 95± At 20 minutes 108± ± At 22 minutes 90± ± At 22 minutes 108± ± At 24 minutes 88±6.3 92± At 24 minutes 107± ± At 26 minutes 86±5.1 90± At 26 minutes 105± ± At 28 minutes 88± ± At 28 minutes 107± ± At 30 minutes 85±3.5 92± At 30 minutes 105± ± At 32 minutes 87±4.1 90± At 32 minutes 108± ± At 34 minutes 86±2.8 89± At 34 minutes 106± ± At 36 minutes 87± ± At 36 minutes 105± ± Postoerative 90±5.4 92± Postoerative 105± ± : Ehedrine grou. : Ehedrine grou. Grou P: Phenylehrine grou. Grou P: Phenylehrine grou.

5 Mohamed Y. Mohamed, et al. 81 Table (6): Nausea and vomiting (Values are resented as Mean ± SD). Nausea and vomiting Grou P Baseline (reinduction): Nausea Vomiting Intraoerative until delivery: Nausea 4 0* Vomiting 1 0* Nausea Vomiting Postoerative: Nausea Vomiting : Ehedrine grou. Grou P: Phenylehrine grou. Table (7): Side effects and comlications (Values are resented as number, mean ± SD, or median (range). >0.05 is considered significant). Grou P Heart rate <60 beats/min 1 8* Bradycardia + hyotension Number of atroine doses Heart rate >100 beats/min 13 4* 0.04 Number of vasoressor doses Minimum systolic ressure (mmhg) 105± ± Maximum systolic ressure (mmhg) 150± ± Reactive hyertension Nausea 4 0* <0.03 Vomiting 1 0* <0.02 : Ehedrine grou. Grou P: Phenylehrine grou. *: Denotes significance between comared to Grou P. Discussion In re-eclamsia, vascular endothelial damage occurs, which roduces increased amount of endogenous vasoressors like thromboxane and endothelin that are resonsible in maintaining vessel tone [10]. In ast EA was referred over SAB to be given to re-eclamtics undergoing cesarean section due to the fear of sudden and extensive symathetic block in them after SAB leading to dangerous hyotension comromising mother and fetus. We studied rohylactic minimal doses of vasoressors immediately after sinal anesthesia following rehydration with 250ml Hartmann's solution (lactated Ringer's solution) over minutes in severe reeclamtic atients undergoing elective cesarean section. We gave the atients 100-µg of henylehrine or 10-mg of ehedrine which are considered to be half the doses that should be given in other normal healthy atients undergoing elective cesarean section under sinal anesthesia. These minimal doses were given because Symathetic block following SAB does not alter this vascular resonse, leading to increased sensitivity and exaggerated resonse of those atients to vasoressors drugs [10]. In this study, henylehrine was as effective as ehedrine in maintaining hemodynamic stability in severe reeclamtic atients undergoing cesarean delivery after giving sinal anesthesia. Where the systolic, diastolic, and mean arterial blood ressure readings from sinal anesthesia until 24 hours ostoerative were comarable. The incidence of the decrease in the blood ressure lower than 20% of baseline values was similar for both grous (one atient in each grou). Changes over time in heart rate were significantly different between ehedrine and henylehrine grous between 12 to 18 minutes after sinal anesthesia. Patients in the henylehrine grou were more likely than the Ehedrine grou to develo bradycardia. Bradycardia (heart rate below 60 beats/min) occurred in one atient in ehedrine grou, and eight atients in henylehrine grou, and those atients were treated by 0.5mg atroine. Before sinal anesthesia, atients did not suffer from nausea and vomiting in both grous. Intraoeratively, in ehedrine grou, four atients suffered from nausea and one atient suffered from vomiting and they were treated by 0.5mg atroine. While in henylehrine grou, no atients suffered from nausea or vomiting. Nausea and vomiting were lower in the henylehrine grou than in the ehedrine grou which is statistically significant. In the ehedrine grou, that one eisode of vomiting occurred 10 minutes after sinal anesthesia and was associated with decreased systolic arterial ressure, decreased heart rate, increased ehedrine dose, and the block height was T4. There was no difference in the block height in that atient who vomited, comared with other ehedrine grou atients who did not have nausea or vomiting. Postoeratively, no eisodes of nausea and vomiting occurred in either grou.

6 82 Effects on the Maternal Nausea & Vomiting after Giving Prohylactic Ehedrine Versus Phenylehrine Phenylehrine grou still had the lowest incidence of nausea and vomiting but more likely to develo bradycardia than atients who recieved ehedrine. This suggests that the decrease in blood ressure >20% of baseline was not the main reason for the difference in the incidence of nausea and vomiting between the grous. Nausea and vomiting may have been a direct effect of ehedrine, but this is unlikely because ehedrine has been shown to have antiemetic roerties following gynecological surgery. Nausea and vomiting may have been secondary to an absolute, or relative, increase in vagal tone. There is evidence for a vagal mechanism causing nausea during sinal anesthesia [11]. Atroine has been found to be more effective at treating nausea associated with high sinal anesthesia than vasoressors [12]. In this study, in the ehedrine grou, vomiting was associated with a decrease in systolic arterial ressure, but it was also associated with a decrease in heart rate. This rovides evidence of an increase in vagal tone in the ehedrine grou atients who vomited. However, there was no evidence that this was because of more extensive neural blockade. In this study, giving henylehrine may have reduced the risk of a reflex increase in vagal tone by roducing more effective venoconstriction, thereby increasing reload. This may exlain why we found highly significant differences in nausea and vomiting between grous when there was no significant difference in systolic arterial ressure. Ngan Kee et al., however, reorted that the incidence of intraoerative nausea and vomiting is lowest and fetal H highest when blood ressure is maintained at 100% of baseline comared to allowing a 10%-20% decrease in blood ressure [13]. Conclusion: 100gg i.v bolus dose of henylehrine is as effective as 10-mg i.v bolus dose of ehedrine as a rohylactic measure for reventing hyotension after sinal anaesthesia for cesarean section in severe re-eclamtic atients after rehydration with 250ml lactated Ringer's solution. Phenylehrine administration may cause bradycardia in some atients, while ehedrine administration is associated with higher incidence of nausea and vomiting in the mother. Conflict of interest statement: We declare that we have no conflict of interest. Financial suort: We ensure and stated that our study is self-funded by authors. References 1- BONNEY E.A.: Pre-eclamsia: A view through the danger model. J. Rerod. Immunol., 76: 68-74, HAWKINS J.L.: Anesthetic management of the reeclamtic atient. American Society of Anesthesiologists, , TURNER J.A.: Severe re-eclamsia: Anesthetic imlications of the disease and its management. Am. J. of Theraeutics, 16: 284-8, VISAL YAPUTRA S., RODANANT O., SOMBOONVI- BOON W. and TANTIVITAYATAN K.: Sinal versus eidural anesthesia for C.S in severe re-eclamsia. A rosective randomized, multicenter study. Anesth. Analg., 101 (3): 862-8, AYA A.G., VIALLES N. and TANOUBI J.: Sinal anesthesia-induced hyotension: A risk comarison between atients with severe re-eclamsia and healthy women undergoing reterm C.S., Anesth. Analg., 101 (3): , SAHA D., GHOSH S., BHATTACHARYYA S., MALLIK S., PAL R., NIYOGI M. and BANERJEE A.: Comarison of hemodynamic resonse and vasoressor requirement following sinal anesthesia between normotensive and severe re-eclamtic women undergoing C.S.A rosective study, Original Article, 3 (1), 23-6, BURNS S.M., COWAN C.M. and WILKES R.G.: Prevention and management of hyotension during sinal anesthesia for elective C.S: A survey of ractice. Anesthesia., 56: 794-8, JAMES F.M. 3 rd, GREISS F.C. and KEMP R.A.: An evaluation of vasoressor theray for maternal hyotension during sinal anesthesia. Anesthesiology, 7: 76-81, LEE A., NGAN KEE W.D. and GIN T.: A quantitative systematic review of randomized controlled trials of ehedrine versus henylehrine for the management of hyotension during sinal anesthesia for C.S. Anesth. Analg., 94: 920-6, CHAMBERS J.C., FUSI L., MALIK I.S., et al.: Association of maternal endothelial dysfunction with reeclamsia. J.A.M.A., 285: 1607, WATKINS E.J., DRESNER M. and CALOW C.E.: Severe vasovagal attack during regional anaesthesia for caesarean section. Br. J. Anaesth., 84: , URE D., JAMES K.S., MCNEILL M. and BOOTH J.V.: Atroine Reduces Nausea During Sinal Anaesthesia for Caesarean Section Without Affecting Neonatal Outcome. Br. J. Anaesth., 82 (2): 277-9, NGAN KEE W.D., KHAW K. S., TAN P.E., et al.: Placental transfer and fetal metabolic effects of henylehrine and ehedrine during sinal anesthesia for cesarean delivery. Anesthesiology, 111: 506, 2009.

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