Minimal Effective Weight-based Dosing of Ondansetron to Reduce Hypotension in Cesarean Section Under Spinal Anesthesia

A Randomized Controlled Superiority Trial

Maliwan Oofuvong; Thitikan Kunapaisal; Orarat Karnjanawanichkul; Nussara Dilokrattanaphijit; Jaranya Leeratiwong

Disclosures

BMC Anesthesiol. 2018;18(105) 

In This Article

Methods

This was a prospective triple-blinded parallel randomized controlled superiority trial. The study was approved by the Institutional Ethics Committee of The Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand on March 3, 2016 (EC 58382081), Clinicaltrials.in.th number TCTR 20160323001 on March 22, 2016.

Participants

A written informed consent was obtained from all participants. The eligible participants were singleton pregnant women at a gestational age of 37–42 weeks who underwent elective cesarean section under spinal anesthesia and had no abnormal signs on electrocardiography. The study was carried out between May 2016 and February 2017 at Songklanagarind Hospital which is an 853–bed tertiary care hospital in southern Thailand. The exclusion criteria included the inability to communicate, history of hypertension, history of being allergic to ondansetron, congenital abnormality or acquired heart disease, coagulopathy, morbid obesity (body mass index > 35 kg/m2), abnormal pregnancy with intrauterine growth retardation, congenital anomalies, poly- or oligo-hydramnios, and placenta previa. These criteria were meant to exclude patients who had a high risk of hemodynamic instability.

Standard Operating Procedures

After obtaining written informed consent from the participants by TK, baseline electrocardiography was performed and the women were randomized with a 1:1:1 allocation ratio to receive intravenously either normal saline (group NS) or ondansetron 0.05 mg/kg (group O1) or ondansetron 0.1 mg/kg (group O2) (maximal dose of 8 mg). Block randomization was performed in blocks of three by computer generated tables by a hospital research assistant who was not involved in the trial. A 4 mL clear solution was prepared for all study participants in sequential numbers by a nurse anesthetist in the recovery room who was not involved in the operation. The vial containing the solution was put into a concealed envelope for the nurse anesthetist who was in charge in the operating room. The syringes had no identifying markers indicating group allocation. The patient, anesthesiologist in charge, and the investigators were blinded to the group allocation. The intention-to-treat protocol was applied in this study. Premedication by ranitidine or metoclopramide or both could be given according to the decision of the anesthesiologist in charge.

In the operating room, 1000 mL of isotonic crystalloid was given to every patient. Philips IntelliVue MX700 was used to monitor non-invasive blood pressure, pulse oximetry, and electrocardiography during the period of anesthesia. Before spinal anesthesia was performed, the 4 mL clear solution containing the allocated treatment was administered intravenously five min before spinal anesthesia. Spinal anesthesia was performed at level L2–L3 or L3–L4 in the vertebral space with 2.0 mL of 0.5% hyperbaric bupivacaine and 0.2 mg of intrathecal morphine at a rate of 0.2 mL/sec by an experienced resident anesthetist. After spinal anesthesia was performed, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP) were recorded every one min for 15 min and then every five minutes, while the heart rates were recorded every five minutes until the end of the operation by a nurse anesthetist who was masked to the group allocation. Left uterine displacement of 15 to 20 degrees was performed after spinal anesthesia by placing a wedge under the right hip until the baby was delivered. After the baby was delivered, oxytocin (20 units per 1000 mL of isotonic crystalloid) was routinely given while methylergometrine would be given only upon request of the gynecologist surgeon. The doses of oxytocin and methylergometrine were measured.

Outcomes of the Study

The primary outcomes of the study were the incidence of hypotension and the change in MAP. Hypotension was defined as a decrease in MAP > 30% from baseline. If hypotension occurred, 6 mg of ephedrine or 5 mcg of norepinephrine was administered intravenously according to the discretion of the anesthesiologist in charge.

The secondary outcomes were maternal complications during the intraoperative period and in the post-anesthetic care unit and neonatal complications 24 h postoperatively. If itching occurred, 10 mg of chlorpheniramine was given intravenously. Metoclopramide (10 mg) was given intravenously for treatment of nausea and vomiting during the intraoperative period. Any side effects from ondansetron such as burning and QT prolongation were evaluated. The QT prolongation was determined by a QT interval more than half of the preceding RR interval in 3-lead electrocardiogram monitoring intraoperatively and at post-anesthetic care unit. The well-being of the newborn baby was evaluated as well as any adverse events 24 h postoperatively.

Sample Size Determination

The sample size calculation was based on a difference in the incidence of hypotension between the control group (0.85) and the ondansetron group (8 mg) from a previous study which reported the incidence as 0.6.[7] For a power of 90% to detect this difference and a type I error rate of 0.05, 73 patients per group were required under the assumption that 10% of the study participants would withdraw from the study.

Statistical Analysis

Continuous variables are presented as median and interquartile range for non-normally distributed data or mean and standard deviation for normally distributed data. Categorical variables are presented as frequency and percentage. Continuous variables were compared using two-way analysis of variance and the Kruskal–Wallis test for normally and non-normally distributed data, respectively. Categorical variables were compared using Pearson's Chi-square test or Fisher's exact test for normally and non-normally distributed data, respectively. Post-hoc analysis was performed for multiple comparisons between groups when the overall differences were significant. Changes in SBP, DBP, MAP, and heart rate were compared using the generalized estimating equations method. A P value < 0.05 was considered statistically significant. Group allocation was also blinded to the statistician who analyzed the data.

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