Intramuscular Phenylephrine HCL for Prevention of Spinal Anesthesia Induced Hypotension

Study Overview
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Brief Summary
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Background: Spinal anesthesia (SA) is preferred over general anesthesia in Cesarean section (CS) due to its better safety profile but SA induced hypotension remains a big challenge for the clinical Anesthetist. Different methods including 15° left lateral table tilt, leftward uterine manual displacement, fluid pre-and co-loading have been used but drop in Systolic Blood Pressure (SBP) jeopardizing maternal and fetal well-being still occurs. Timely administered Phenylephrine HCL, an α-1 adrenergic agonist, is a recommended remedy. Subjects and methods: Sixty parturients of American Society of Anaesthesiologists (ASA) physical status 1 and 2, scheduled for elective CS under SA were enrolled in this prospective double-blinded study and randomly divided into two equal groups, P4 and P8. They received intramuscular (IM) Phenylephrine HCL 04 mg and 08 mg respectively before SA. Spinal block up to T6 was achieved with 12.5 mg 0.5% Bupivacaine HCl heavy. The incidence and intensity of hypotension, rescue doses of Phenylephrine HCL and any adverse event, were recorded. Data collected was analyzed using Epi lnfo ™ version 7.2.

Detailed Description
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Introduction: World Health Organization (WHO) defines maternal death as a death while pregnant or within 42 days of the end of gestation, from any cause related to or aggravated by the pregnancy or its management (excluding accidental or incidental causes). In 2017 global Maternal Mortality Ratio (MMR) reported by United Nations (UN) is 211 deaths per 100,000 live births. MMR in Pakistan, with inter-provincial variability, is 186 deaths per 100,000 live births according to the latest Pakistan Maternal Mortality Survey (PMMS) report published in August, 2020 by United Nations Population Fund (UNFPA), a subsidiary organ of United Nations General Assembly. CS requires general anesthesia, SA or epidural anesthesia; however, SA is preferred. SA is believed to be safe, though severe complications like profound hypotension compounded by aorto-caval compression might happen . World Health Organization (WHO) defines ideal CS rate below 10 to 15 %. According to 1990-91 and 2017-18 Pakistan Demographic and Health Survey data, rate of C-section has been raised from 3.2 % to 19.6 - 22.3 % . Higher rate of anesthesia and surgery in a developing country like Pakistan has a direct bearing on MMR, patient's morbidity, cost of medical services and siphoning scarce resources. The first case of cardiac arrest occurring after SA was reported in 1940 and since then, the ability of SA to cause cardio-pulmonary arrest was considered. Hypotension and bradycardia are the most common side effects of SA. SA induced hypotension, which is a substantial clinical challenge, is caused by pharmacological sympathectomy. The incidence is reported around 80 %. Hypotension occurs despite fluid preload, left lateral uterine displacement and left lateral table tilt. Duration and severity of hypotension is responsible for maternal ill effects like nausea/vomiting initially and later culminating to dyspnoea, apnea and circulatory arrest if poorly managed. Additionally there will be poor apgar score or even fetal demise depending upon the severity. Energetic use of strong vasopressors has been recommended. Phenylephrine HCL is considered to be the vasopressor of choice in parturients due to its propensity to cause less fetal acidosis. Phenylephrine HCL being an α-1adrenergic agonist counters the decrease in Systemic Vascular Resistance (SVR) induced by SA and can be administered by subcutaneous, intravenous and IM routes. Its onset and duration of action are 1-3 minutes and 5- 20 minutes respectively, when given intravenously (IV); and 10-20 minutes and an hour respectively when given IM. Clinically, 50-100 microgram boluses of Phenylephrine HCL is used intravenously to address hypotension. The investigators, in the current study exploited its lesser reported IM route. Rationale: IM Phenylephrine HCL shortly before administering SA can prove a better option to prevent hypotension even for longer duration due to its slower absorption and can provide longer hemodynamic stability, lesser drop in fetal pH and apgar score. Objectives: The primary objective of the study was to determine appropriate dose of IM Phenylephrine HCL in preventing hypotension due to SA administered for CS in ASA 1 and 2 parturients. Secondary objectives were to determine the need for total rescue doses of Phenylephrine HCL, measure drop in SBP in the two trial groups; and observe any side effects associated with IM injection of Phenylephrine HCL.

Official Title
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Comparison of Two Different Doses of Intramuscular Phenylephrine HCL for Prevention of Spinal Anesthesia Induced Hypotension During Cesarean Section: A Prospective Randomized Double-blinded Parallel Study

Conditions
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Hypotension, Anesthesia

Intervention / Treatment
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* Drug: Phenylephrine Hydrochloride 4 mg
* Drug: Phenylephrine Hydrochloride 8 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All pregnant ladies of American Society of Anesthesiologists (ASA) physical status 1 or 2 with Singleton Pregnancy, Full term pregnancy, and Admitted for elective CS Exclusion Criteria: All those participants having; Blood pressure ≥140/90 mm of Hg, ASA 3 or above status, Contraindication to spinal anesthesia Fetal anomalies/ Abnormal placentae Refusal to consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study design was prospective double-blinded randomized parallel with allocation ratio of 1:1.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Phenylephrine 4mg<br>Inj Phenylephrine HCL 04 mg as Group P4. | Drug: Phenylephrine Hydrochloride 4 mg<br>* Intramuscular Phenylephrine HCL 04 mg were administered as prophylactic stat dose in Vastus lateralis muscle of thigh 05 minutes before giving spinal anesthesia.<br>* Other names: Injection Synephrine (Atco Laboratories Ltd. Pakistan;|
| Active Comparator: Phenylephrine 8mg<br>Inj Phenylephrine HCL 08 mg as Group P8. | Drug: Phenylephrine Hydrochloride 8 mg<br>* Intramuscular Phenylephrine HCL 08 mg were administered as prophylactic stat dose in Vastus lateralis muscle of thigh 05 minutes before giving spinal anesthesia.<br>* Other names: Injection Synephrine (Atco Laboratories Ltd. Pakistan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of hypotension in both groups | The primary outcome is to find incidence of hypotension in each group P4 and P8 i.e. number of participants who develop hypotension in the relevant group multiplied by 100. Incidence= number of participants who develop hypotension/ total participants in the group *100. Hypotension is defined as a decrease of more than 20 % from baseline systolic blood pressure measured through non-invasive method. | One and half hour post spinal anesthesia | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To find the rescue dose/ doses of intravenous Phenylephrine HCL. | To find the rescue dose/ doses of intravenous Phenylephrine in the two groups P4 and P8. | One and half hour post spinal anesthesia | 
| Onset of hypotension | Determine the onset of hypotension in the two groups P4 and P8 (keeping starting time 0 minute at the administration of intrathecal hyperbaric Bupivacaine). | Half hour/ 30 minutes post spinal anesthesia | 
| Adverse events associated with any groups | Record any adverse event associated with any groups e.g. bradycardia, hypotension, Nausea, Vomiting, Hypertension, Cardiac arrest. | One and half hour post spinal anesthesia | 
| Neonatal APGAR Score | Neonatal APGAR (Appearance, Pulse, Grimace response, Activity, and Respiration)Score from 0 - 10 will be measured at 01 and 05 minutes for each neonate delivered. The higher score is considered good i.e. 10 while lower score is considered bad/ worse e.g. 0 -3. The Apgar score measures five things to check a baby's health. Each is scored on a scale of 0 to 2, with 2 being the best score: Appearance (skin color) Pulse (heart rate) Grimace response (reflexes) Activity (muscle tone) Respiration (breathing rate and effort) | 5 minutes post delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cesarean section.