A ) SUMMARY OF RESEARCH PROPOSAL:-  

1. Name – Dr. Nimisha Bansal  

•  Designation: 1st Year PGT (2023-2026)  

•  Place of posting: Department of Anaesthesiology  

•  Place of research work: ESI-PGIMSR, ESIC Medical college and Hospital, Joka, Kolkata  

•  Broad and specific area: Clinical  

2.  Name of proposed supervisor with designation & institution: Dr. Anil  

Kumar Thakur, Professor and HOD, Department of Anaesthesiology, ESI-  

PGIMSR, ESIC Medical college and Hospital  

3.  Proposed title:  TO EVALUATE THE ROLE OF PROPHYLACTIC  

INTRAVENOUS ONDANSETRON IN PREVENTING HYPOTENSION IN PATIENTS UNDERGOING LOWER LIMB SURGERY UNDER SPINAL ANAESTHESIA, A RANDOMISED CONTROLLED STUDY.  

4.  Objective of proposed research: This study is aimed to compare intravenous ondansetron with placebo in reducing the incidence of spinal  induced hypotension in a patient undergoing lower limb surgery.  

  5.Background of present study:  

Spinal Anaesthesia was introduced by German surgeon Karl August Bier in 1898[1].The recommended anaesthetic technique for various surgical procedures, including caesarean section, orthopaedic surgery, and lower abdominal general surgery, is spinal anaesthesia, also known as a subarachnoid block. However, hypotension caused by spinal anaesthesia is a common problem that plagues doctors and patients, occurring in approximately 80% of cases . A reduction in blood pressure can cause a series of intraoperative adverse effects, such as dizziness, nausea and vomiting, regurgitation, and aspiration [2] .Therefore, it is important to investigate methods to reduce the incidence of hypotension following spinal anaesthesia that are economical, safe, and effective.The mechanism of hypotension following spinal anaesthesia involves the reduction in vascular resistance caused by the sympathetic blockade which in turn causes vasodilation and finally leads to drop in arterial pressure[3,4].  

Parasympathetic overactivity, activation of Bezold– Jarisch reflex, and increased baroreceptor activity also lead to hypotension and bradycardia.

Peripheral serotonin receptors, 5-Hydroxytryptamine3 (5HT3), are required for the activation of the Bezold–Jarisch reflex [5]. Thus, numerous clinical trials have been performed to demonstrate the preventive effect of ondansetron on hypotension following spinal anaesthesia.  

6.Methodology:   

120 patients of either sex, aged between 50-80 years of age, with a physical status of I–II (classified according to the American Society of  

Anaesthesiologists), who are posted for elective lower limb orthopaedic surgery under spinal anaesthesia will be randomly allocated into 2 groups. One group will receive 4mg ondansetron intravenously 5 minutes before induction of spinal anaesthesia, and another group will receive same volume of 0.9%normal saline. 0.5% hyperbaric bupivacaine ( dose calculated according to the height) will be injected intrathecally .Mean arterial pressure, Systolic blood pressure, diastolic blood pressure will be recorded at 3minute intervals for first 30 minutes.  

 7.Expected outcome: Based on previous clinical studies, prophylactic use of ondansetron before spinal anaesthesia will decrease the incidence of hypotension, and requirement of vasopressors.  

(B ) OUTLINE OF PROPOSED RESEARCH TOPIC:  

1.    TITLE:  

 TO EVALUATE THE ROLE OF PROPHYLACTIC INTRAVENOUS  ONDANSETRON IN PREVENTING HYPOTENSION IN PATIENTS  

UNDERGOING LOWER LIMB SURGERY UNDER SPINAL  

ANAESTHESIA, A RANDOMISED CONTROLLED STUDY  

 2. AIM AND OBJECTIVES:  

Aim:  

       To evaluate the role of prophylactic intravenous ondansetron in preventing hypotension in patients undergoing lower limb surgery under spinal anaesthesia.   

     Objectives:  

A. PRIMARY:. To compare the incidence of hypotension (fall in  

MAP>20% from baseline) in both the study groups.  B. SECONDARY:  

•       To assess the effect of ondansetron on heart rate after spinal anaesthesia.  

•       To assess any complications arising during the course of the study.  

   3.RESEARCH HYPOTHESIS:  

      Prophylactic administration of intravenous ondansetron to individuals undergoing lower limb surgery under spinal anaesthesia does not prevent the incidence of hypotension. 

4.BACKGROUND OF RESEARCH:  

      a)Rationale of study:  

Spinal Anaesthesia is most frequently performed in elderly patients in spite of their higher risk of hypotension and its consequences. The rate of hypotension in the elderly population is estimated to be over 70%. On the other hand, methods that are routinely used for prevention of hypotensive episodes like volume preloading or ephedrine administration may be risky for the elderly because they may experience hypervolemia or myocardial ischemia. Ondansetron is highly selective serotonergic antagonist . It has been shown that ondansetron could suppress serotonin induced vasodilation by reducing the Bezold-Jarisch reflex[6]. Exploring its use could offer a potentially effective approach to prevent spinal-induced hypotension. Ondansetron is generally well-tolerated and widely used for managing nausea and vomiting in various clinical settings. Assessing its safety and efficacy for preventing hypotension during spinal anaesthesia is therefore warranted. If ondansetron proves effective in preventing hypotension, it could lead to reduced healthcare costs associated with managing hypotensive episodes, such as the need for vasopressor medications or additional monitoring. Ondansetron therapy to minimise spinal-induced hypotension could improve the overall quality of care and patient satisfaction, leading to better perioperative outcomes and shorter hospital stays.  

b)  Introduction:   

Spinal anaesthesia is a simple, reliable, and most common anaesthetic technique practiced worldwide[7,8]. Lower limb surgeries performed under spinal anaesthesia are commonly associated with hypotension, posing significant challenges in perioperative management. Hypotension during surgery not only compromises tissue perfusion but also increases the risk of adverse outcomes such as myocardial ischemia and stroke, particularly in patients with pre-existing cardiovascular comorbidities. Various pharmacological interventions have been explored to mitigate the occurrence of hypotension in this setting. Among these interventions, prophylactic intravenous ondansetron, a 5-HT3 receptor antagonist primarily used for preventing postoperative nausea and vomiting (PONV), has shown promise in maintaining hemodynamic stability during surgery.

Ondansetron’s mechanism of action includes modulation of vagal tone and inhibition of sympathetic activity, which may contribute to its potential role in preventing spinal anaesthesia-induced hypotension.  

c)   Review of literature:  

1.    Yuan Zhang et al (2024) did a prospective RCT Intravenous ondansetron for the prevention of supine hypotensive syndrome during spinal anaesthesia for cesarean section where 80 women undergoing elective cesarean delivery were randomly assigned to two groups. The inclusion criteria were as follows: singleton, American Society of

Anaesthesiologists (ASA) physical status I–II, gestational age >37 weeks, height ranged from 153 to 175 cm, and weight ranged between 55 and 90 kg. The exclusion criteria included pregnancy-related hypertensive disease, cerebrovascular disease, and any spinal anaesthesia contraindications. The ondansetron group received 0.075 mg/kg of ondansetron intravenously 5 min before the induction of spinal anaesthesia; the control group was given the same volume of saline solution. The blood pressure and heart rate were measured. Umbilical artery pH was analysed, and the incidence of nausea and vomiting and vasoconstrictor drug usage were noted. They found that ondansetron can effectively prevent supine hypotensive syndrome, reduce the incidence of nausea, vomiting, and vasoconstrictor drug use, and improve neonatal umbilical arterial pH during spinal anaesthesia for cesarean section.  

2.    Sumedha Vashishth et al (2022) did a prospective RCT where 240 parturients aged 19 -35 years belonging to American Society of  Anesthesiologists (ASA) physical status I and II, having singleton pregnancy undergoing caesarean section with Pfannenstiel incision under spinal anaesthesia were included in the study. Patients having a history of allergy to ondansetron or local anaesthetic, pregnancy-induced hypertension (PIH) or preeclampsia, any contraindication for spinal anaesthesia, or other co-morbid conditions were excluded from the study and were randomly allocated into four groups (n=60) Group O4, Group O6, Group O8 and Group S to receive either intravenous ondansetron 4 mg, 6 mg, 8 mg or 0.9% normal saline respectively. Haemodynamic variables (systolic blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure [MAP], heart rate [HR]) were recorded at 2minute intervals for the first 20 minutes and at 5-minute intervals for further 30 minutes.They concluded that all three groups of ondansetron showed a decrease in the incidence of hypotension and use of vasopressor but Group O6 and O8 were more effective in attenuating spinal-induced hypotension in parturients undergoing caesarean section.   

3.    Jose Ramon Ortiz-Gómez et al (2017) conducted a double-blind, randomized, placebo controlled trial in which he included 265 healthy pregnant women scheduled for elective cesarean delivery under SA. Women were randomly allocated into four groups to receive either placebo (control), ondansetron (O) 8 mg intravenously before induction of SA, phenylephrine infusion (50 mcg/min) (P) or ondansetron plus phenylephrine (OP). Demographic, obstetric, intraoperative timing, and anesthetic variables were assessed at 16 time points. Anesthetic variables assessed included blood pressure, heart rate, oxygen saturation, nausea, vomiting, electrocardiographic changes, skin flushing, discomfort or pruritus, and vasopressor requirements. They concluded a 50 μg/min phenylephrine infusion reduces by 50%, the incidence of maternal hypotension compared with placebo and Prophylactic ondansetron 8 mg might be considered in this situation, because it does not reduce the incidence of maternal hypotension but diminishes its severity, reducing the number of hypotensive events per patient by 50%.   

4.    Walid Trabelsi et al (2015) did a A Prospective, Randomized, Controlled, Double-Blind Study in which he included 80 ASA physical status class I primipare parturients undergoing elective caesarean section at term. Patients were randomized (during preanesthetic consultation) to one of 2 groups using a random sequence (https://www.random.org/): group O received intravenously 4 mg ondansetron in 10 mL saline, 5 minutes before spinal puncture, and the control group received 10 mL of saline in the same way and same timing.   

5.    R. Owczuk et al (2015) conducted a study evaluate the efficacy of Ondansetron in attenuating the decrease in blood pressure due to spinal anesthesia in Fifty-three elderly patients older than 70 years , 26 in the ondansetron group (received 8 mg intravenous ondansetron) and 27 in the placebo group (received 0.9% NaCl solution). The heart rate and arterial blood pressure were measured every 5 minutes after spinal anaesthesia, which was performed with 2.5 to 3 mL of 0.5% hyperbaric bupivacaine solution. Decreases in both the heart rate and mean systolic, as well as diastolic, arterial pressure compared to the baseline values were noted in both groups. The minimum diastolic and mean blood pressure values obtained over a 20-minute observation period were significantly higher in the ondansetron group. There were no significant differences in the systolic blood pressure and heart rate values between the groups. So they concluded that administration of intravenous ondansetron prior to spinal anaesthesia in geriatric patients attenuates the drop in the diastolic and mean arterial pressure without substantially affecting the systolic blood pressure.  

6.    Meng Wang et al (2014) did double-blinded and randomized study to compare the efficacy of different doses of ondansetron preloading combined with rapid crystalloid coloading on reducing maternal hypotension during cesarean delivery. In this study 150 parturient women scheduled for elective cesarean section were randomly assigned to five groups (n=30). Five minutes prior to spinal anesthesia, women were injected with 5 ml of physiological saline (S), 2 mg (O2), 4 mg (O4), 6 mg (O6), or 8 mg (O8) of ondansetron in saline, respectively. Maternal blood pressure and heart rate were measured at 2-min intervals for 30 min. The serum parameters in umbilical cord blood were analyzed after delivery. They found that as compared with group S, the incidence of maternal hypotension was significantly lower in groups O4 and O6 (Moreover, minimal changes of systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were observed in group O4 (P

< 0.05). So they concluded that the optimal dose of ondansetron preloading was 4 mg during cesarean delivery.  

d)  Gap in existing research:  

There are various case reports [9-11] which showed that prophylactic use of ondansetron had a significant effect on prevention of hypotension following spinal anaesthesia. They usually depict that it can be given safely in patients undergoing cesarean section, young heathy patients undergoing infraumbilical surgeries. However, despite some evidence suggesting the beneficial effects of ondansetron in reducing the incidence of hypotension during spinal anaesthesia, the available literature remains inconclusive[12]. Many studies have reported conflicting results, highlighting the need for further investigation through well-designed randomized controlled trials (RCTs).Limited study has been found and there is still lack of concrete data available on Google scholar, PubMed Central, Medscape on usage of ondansetron and the minimum dose needed to prevent hypotension in elderly population with age more than 50 years in whom there is a decrease in vagal modulation with advancing age. Hence, in my study I have included patients with aged between 50-80 years undergoing lower limb surgery under spinal anaesthesia.  

e)   Expected outcome:  

    Prophylactic use of ondansetron before spinal anaesthesia will decrease the incidence of hypotension, and requirement of vasopressors.  

5.       METHODOLOGY  

a)   STUDY SETTING: Study will be done in operation theatre of ESI-

PGIMSR, ESIC MEDICAL COLLEGE & HOSPITAL, JOKA, KOLKATA   

b)   STUDY TIMELINE: The study will be done over a span of approximately

12 months after getting permission from the Institute’s Ethics Committee and approval of The West Bengal University of Health Sciences.  

c)   STUDY DESIGN: Interventional , prospective randomised controlled, single blinded study

d)   STUDY POPULATION: The study will be carried out in the patients of ASA grade 1&2 of either sex, aged 50-80 years posted for elective lower limb surgery under spinal anaesthesia.  

e)   SAMPLE SIZE CALCULATION : The sample size is calculated in accordance with the study done by Yuan Zhang who performed a prospective randomised controlled trial at department of Anesthesiology, Jiaxing Women and Children’s Hospital, China. The minimal mean arterial pressure was higher in ondanserton group 71.4 as compared to control group 68.8 with standard deviation of 4.9 with an alpha error of 0.05 and a power of 0.8.  

n= (2.58+1.36)2 * (4.9)2  / (2.6)2

  n= 56  

Total number of participants in each group = 56  

To account for dropout the sample size is increased to 60 in each group. n = sample size for group #1 and group #2. α = probability of type I error (usually 0.05)  β = probability of type II error (usually 0.2)  z = critical Z value for a given α or β   

f)    METHOD OF RESEARCH PARTICIPANT RECRUITMENT:  

   Inclusion criteria  

Patients   

•      of ASA physical status I – II  

•      between 50-80 years of age  

•      of either sex  

•      scheduled for elective lower limb surgery will be included in the study   

  Exclusion criteria  

Patients  

•      Refusal  

•      in whom spinal Anaesthesia is contraindicated.   

•      having known allergy to ondansetron  

•      receiving Ondansetron 8 hours prior to surgery.

•      on selective serotonin reuptake inhibitors   

•      with pregnancy, morbid obesity  

•      having autonomic neuropathy   

•      having QT prolongation on ECG will be excluded from the study   

g)   DATA COLLECTION AND INTERPRETATION:  

Data will be collected and recorded according to the case record form, and will be analysed according to statistical analysis plan.  

h)   LABORATORY INVESTIGATIONS, PARAMETERS AND

PROCEDURE  

•               Complete blood count  

•               Blood sugar fasting and PP  

•               LFT  

•               KFT  

•               Serum Na+ , K+  

•               Serology  

•               Chest X ray P/A view  

•               12 Lead ECG  

i)    STUDY PROCEDURE  

The study will be conducted after approval from the Institutional Ethics Committee and West Bengal University of Health Sciences, patients will be selected considering both inclusion and exclusion criteria. Pre anaesthetic evaluation will be performed in each patient.The protocol will be explained in a detailed manner to all patients in their own understandable language and informed consent will be taken 1 day prior to the surgery.  

 After shifting the patient to operation theatre, standard monitor will be connected to all patients which include, pulse oximeter (SpO2), electrocardiography, and noninvasive arterial blood pressure (NIBP), Temperature probe. After securing i.v. cannula (18 G/20 G) in the upper limb,

i.v. fluids will given at a volume of 5 mL/kg during the study period. Baseline measurements will be taken before ondansetron administration.  Qualified Anaesthesiologist will inject that 2 mL of drug 5 min before performing spinal anaesthesia. Group A patients will receive i.v. ondansetron 4 mg (2 ml). Group B patients received normal saline of 2 ml. All patients will be given spinal anaesthesia in sitting position. 25G Quincke spinal needle will be inserted by midline approach into L3-L4 or L4-L5 interspace. After ensuring the correct position of the needle by checking the free flow of cerebrospinal fluid, we will administer 0.5% hyperbaric bupivacaine according to the following formula : Bupivacaine (mg) = height(cm)*0.06 intrathecally [11]. and the patient will be positioned supine. No surgery-related procedures that include patient positioning, tourniquet placement, and urinary catheterisation will be performed during the study period. At the same time, motor blockade will assessed by Bromage scale. Bromage scale: 0 – no paralysis, 1 – inability to lift the thigh, 2 – inability to flex the knee, 3 – inability to move any joint in leg.   

The hemodynamic parameters such as HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and MAP will be recorded every 3 min for 30 min. Mephentermine  6 mg i.v. will be given in case of hypotension when blood pressure (MAP) decreased by 20% of baseline value. Atropine 0.01mg/kg will be given if HR falls below 45 beats/min. When mephentermine administration will be necessary during the procedure, only values obtained before the medications will be considered. Number of doses of mephentermine needed and timings will be recorded. Patients will be monitored for rare side effects of ondansetron such as prolonged Qtc, headache, and dizziness.  

j)    SAMPLING TECHNIQUE  

The Randomization process of allocating into two groups will be done by purposive sampling method using Computer generated random numbers. Group A patients will receive intravenous 4mg Ondansetron(2ml). Group B patients will receive normal saline of 2ml.  

k)   STUDY TOOLS  

•       25G Quincke Spinal needle  

•       Sterile 18 OR 20 G IV cannula   

•       Pro-forma for informed written consent  

•       Pro forma for data entry  

•       PAC questionnaire  

•       Sterile drape, skin solutions, gauze/sponges.  

•       0.5% Hyperbaric Bupivacaine (Bupicaine- heavy)  

•       Emergency crash trolley  

•       Resuscitation equipment’s  

•       Ondansetron injection 2mg/ml (Tilset)  

6. STATISTICAL ANALYSIS PLAN:  

All data will be analysed by SPSS (Statistical Package for Social Sciences) software version 16. Data will be described by estimating mean, standard deviation, median, proportion etc, and displaying by the help of tables and different chats. Relationship between variables will be established by different statistical tests like student- “t” test, chi- square test, etc. The‘ p’ value of less than 0.05 will be considered as significant, and ‘p’ value of < 0.01 as statistically highly significant.  

7.WORK PLAN  

 ) Preparatory phase – 02 months  

 ) Phase of data collection- 06 months  

 ) Phase of analysis-02 months  

 ) Report writing & submission- 02 months  

8.CONFLICT OF INTEREST   

There is no conflict of interest.  

9.REFERENCES   

 1. Vashishth S, Lal J, Bangarwa N, Wadhwani J, Smriti M. Efficacy of  Variable Doses of Prophylactic Intravenous Ondansetron in Attenuating Spinal Induced Hypotension in Parturients Undergoing Caesarean Delivery: A Randomised Control Trial. Cureus. 2022 Sep 22;14(9).  

2 . Hou XM, Chen YJ, Lai L, Liu K, Shen QH. Ondansetron reduces the incidence of hypotension after spinal anaesthesia: a systematic review and meta-analysis. Pharmaceuticals. 2022 Dec 19;15(12):1588.  

3 . Kinsella SM, Tuckey JP. Perioperative bradycardia and asystole:  relationship to vasovagal syncope and the Bezold–Jarisch reflex. British Journal of Anaesthesia. 2001 Jun 1;86(6):859-68.  

4 . Trabelsi W, Romdhani C, Elaskri H, Sammoud W, Bensalah M, Labbene I, Ferjani M. Effect of ondansetron on the occurrence of hypotension and on neonatal parameters during spinal anesthesia for elective caesarean section: a prospective, randomized, controlled, double-blind study. Anesthesiology research and practice. 2015 Jan 8;2015.  

5 . Mark AL. The Bezold-Jarisch reflex revisited: clinical implications of inhibitory reflexes originating in the heart. Journal of the American  College of Cardiology. 1983 Jan 1;1(1):90-102  

 6. Warltier DC, Campagna JA, Carter C. Clinical relevance of the Bezold– Jarisch reflex. The Journal of the American Society of Anesthesiologists. 2003 May 1;98(5):1250-60.  

7.    Marashi SM, Soltani-Omid S, Mohammadi SS, Aghajani Y, Movafegh A.

Comparing two different doses of intravenous ondansetron with placebo

on attenuation of spinal-induced hypotension and shivering.

Anesthesiology and pain medicine. 2014 May;4(2).  

8.    Owczuk R, Wenski W, Polak-Krzeminska A, Twardowski P, ArszuÅ‚owicz

R, Dylczyk-Sommer A, Wujtewicz MA, Sawicka W, Morzuch E, Smietanski M, Wujtewicz M. Ondansetron given intravenously attenuates arterial blood pressure drop due to spinal anesthesia: a double-blind, placebo-controlled study. Regional Anesthesia & Pain Medicine. 2008 Jun 1;33(4):332-9  

9.    Zhang Y, Xiao F, Zhang W. Intravenous ondansetron for the prevention of supine hypotensive syndrome during spinal anesthesia for cesarean section: a randomized controlled trial. Frontiers in Pharmacology. 2024 Jan 18;15:1194196  

10.Qian J, Liu L, Zheng X, Xiao F. Does an earlier or late intravenous injection of ondansetron affect the dose of phenylephrine needed to prevent spinal-anesthesia induced hypotension in cesarean sections? Drug

Design, Development and Therapy. 2020 Jul 16:2789-95  

11.Ortiz-Gómez JR, Palacio-Abizanda FJ, Morillas-Ramirez F, Fornet-Ruiz I, Lorenzo-Jiménez A, Bermejo-Albares ML. Reducing by 50% the incidence of maternal hypotension during elective caesarean delivery under spinal anesthesia: Effect of prophylactic ondansetron and/or continuous infusion of phenylephrine-a double-blind, randomized, placebo controlled trial. Saudi journal of anaesthesia. 2017 Oct 1;11(4):408-14.  

12.Samarah WK, Alghanem SM, Bsisu IK, Rahman ZA, Guzu HA, Abufares BN. The effect of ondansetron administration 20 minutes prior to spinal anaesthesia on haemodynamic status in patients undergoing elective caesarean section: A comparison between two different doses. Indian Journal of Anaesthesia. 2020 Nov 1;64(11):954-9.