ONDANSETRON AND EFFECTIVE DOSE IN 50% OF SUBJECTS OF PROPHYLACTIC NOREPINEPHRINE INFUSIONS FOR PREVENTING SPINAL ANESTHESIA-INDUCED HYPOTENSION DURING CESAREAN DELIVERY

A PROSPECTIVE, RANDOMIZED, DOUBLE-BLINDED STUDY OF THE EFFECT OF A STANDARD DOSE OF INTRAVENOUS ONDANSETRON ON THE EFFECTIVE DOSE IN 50% OF SUBJECTS OF PROPHYLACTIC NOREPINEPHRINE INFUSIONS FOR PREVENTING SPINAL ANESTHESIA-INDUCED HYPOTENSION DURING CESAREAN DELIVERY

Spinal anesthesia is the preferred technique for elective cesarean section as per ASA guidelines. Hypotension is the main complication of this technique and is secondary to both sympatholysis and its associated decrease in systemic vascular resistance and to the Bezold-Jarisch reflex, which causes hypotension and bradycardia in response to noxious stimuli detected in the cardiac ventricles. In pregnant patients, spinal anesthesia induced hypotension is worsened by compression of the aorta and inferior vena cava by the gravid uterus. In this setting, hypotension could lead to uteroplacental hypoperfusion and fetal distress.

In its 2020 guidelines for enhanced recovery after cesarean section, SOAP states that preventing spinal-induced hypotension is an important strategy to enhance maternal and neonatal outcomes in cesarean delivery

Recent studies showed that 5-hydroxytryptamine-3 receptor antagonists, mostly used as nausea and vomiting prophylaxis agents, also contributed to inhibit the Bezold-Jarisch reflex and its associated hemodynamic consequences. Ondansetron is the most studied molecule in this field.

Many recent studies and meta-analyses show renewed interest in the use of norepinephrine as a first line agent for preventing and treating spinal anesthesia-induced hypotension in obstetric anesthesia practice instead of phenylephrine. Norepinephrine has the advantage of a better cardiac output and cardiac frequency as compared to phenylephrine without any fetal side effect. The combination of ondansetron and phenylephrine for the prevention of spinal anesthesia-induced hypotension has been studied, but not the combination of ondansetron and norepinephrine.

The main objective of this study is to evaluate the sparing effect of a standard dose of ondansetron on norepinephrine consumption during elective cesarean section under spinal anesthesia by determining the effective dose in 50% of subjects (ED50) of a prophylactic norepinephrine infusion after receiving a single dose of 4 mg of ondansetron or a saline control.

Vital signs are measured in the preparation area before entrance in the operation theater. The following measures are taken in the supine position every three minutes for three measures: blood pressure and cardiac frequency. The mean blood pressure and cardiac frequency become the reference measure for each patient.

Upon entrance in the operation theater, anesthesia care is given in a standardized manner:

• Supine positioning of the parturient on the operating table
• Standard monitoring of vitals signs every minute for the time of the study, including systolic, diastolic an mean blood pressures, cardiac frequency and SpO2
• 18G intravenous catheter insertion on the forearm
• Randomization of the patient in one of the two groups followed by blind administration of ondansetron or saline
• 5 minute wait period before sitting the patient for spinal anesthesia
• Standardized spinal anesthesia: Whitacre 25G spinal needle, L4-L5 intervertebral space, hyperbaric bupivacaine 12mg + fentanyl 10 mcg + morphine 100 mcg
• Upon injection of the spinal medication: 1000 ml Ringer lactate coloading and start of the iv norepinephrine infusion upon study protocol.
• Evaluation of the sensitive block level at 5 and 10 minutes, a level of T6 is needed to start surgery
• Nausea and vomiting prophylaxis in both groups with metoclopramide 10 mg and dexamethasone 4 mg if no contraindication. Nausea and vomiting per cesarean section will be treated with dimenhydrinate 25 mg
• Bradycardia (HR below 60) will be treated with atropine 0,4 mg
• Multimodal post-operative analgesia with intra rectal acetaminophen 1000 mg and indomethacin 100 mg

Norepinephrine infusion protocol:

• The rate of the infusion pump is blindly set in mcg/kg/min by one of the investigators before the entrance of the patient and the anesthesia team in the operating room. The setting is hidden from the main physician at all times and the perfusion is started when the spinal medication is injected.
• For the first patient of each group (saline and ondansetron) the norepinephrine infusion is started at 0,05 mcg/kg/min until the end of the study
• Hypotension (as defined as a value inferior or equal to 80% of the systolic blood pressure reference value) is treated by the anesthesiologist with a 4 mcg bolus of norepinephrine from a prepared syringe of norepinephrine 4 mcg/ml
• Hypertension (as defined as a value superior or equal to 120% of the systolic blood pressure reference value) is treated by stopping the norephineprine infusion and restarting it when the value is inferior to 120% of the reference value.
• For the following patients, the norepinephrine infusion rate will be adjusted by up and down allocation following the results of the previous patient: if no hypotension occurred (no bolus needed): the infusion rate is decreased by 0,005 mcg/kg/min (for example from 0,05 mcg/kg/min to 0,045 mcg/kg/min) / if at least one hypotension occurred (at least one bolus needed): the infusion rate is increased by 0,005 mcg/kg/min (for example from 0,05 mcg/kg/min to 0,055 mcg/kg/min)

The study is stopped at the fetal delivery.

Inclusion Criteria:

• parturients with a singleton pregnancy at term (37 week's gestation and more)
• elective cesarean delivery under spinal anesthesia
• American Society of Anesthesiologists physical status < III

Exclusion Criteria:

• patient refusal
• allergy or hypersensitivity to Norepinephrine or Ondansetron
• Use of monoamine oxidase inhibitors, triptyline or imipramine antidepressants
• Long QT syndrome or another cause of prolonged QT
• significant preexisting maternal disease (cardiovascular or cerebrovascular disease or coagulopathy, diabetes mellitus)
• pre-existing or pregnancy-induced hypertension
• pathological pregnancy (ruptured membranes, pre-eclampsia, placenta praevia, gestational diabetes)
• body mass index < 18 or > 40
• height < 150 or > 180
• fetal abnormalities
• contraindication to spinal anesthesia