Intravenous Ondansetron to Attenuate the Hypotensive, Bradycardic Response to Spinal Anesthesia in Healthy Parturients

Pregnancy Clinical Trial

Official title:

IRB-HSR# 14583: Intravenous Ondansetron to Attenuate the Hypotensive, Bradycardic Response to Spinal Anesthesia in Healthy Parturients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01414777
• Other study ID #: 14583
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: November 2009
• Est. completion date: June 2011

Study information

• Verified date: March 2022
• Source: University of Virginia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators hypothesize that given prophylactically, intravenous ondansetron will attenuate the drop in blood pressure and heart rate frequently seen after spinal anesthesia.

Eighty-six American Society of Anesthesiologists (ASA) physical status I or II in preoperative patient assessment, parturients age of 18 to 45 years scheduled to undergo elective caesarean section will be enrolled.

Patients will be randomized to 2 groups: the ondansetron group, receiving 8 mg intravenous ondansetron diluted in 10 mL of saline; or the placebo group, who were administered 10 mL of saline given 5 minutes prior to performing the spinal anesthetic. Investigational Pharmacy will randomize and dispense study drug.

Baseline measurements of vital signs will be taken. Otherwise standard management will then be used:

• Patients must be NPO for 8 hours

• Pulse oximetry, EKG monitoring, noninvasive blood pressure at a minimum of every 3 minutes, more frequently if decided by the provider.

• Standard lumbar puncture in a sitting position the L3-L4 or L4-L5

• Whitacre pencil-point, 25 gauge

• Injectate: 2 mL of 0.75% hyperbaric bupivacaine, 100 mcg preservative free morphine, 20 mcg fentanyl

• Immediately after completing the subarachnoid injection, patients will be laid supine with left lateral uterine displacement

The sensory level of anesthesia will be assessed in the standard fashion every five minutes using ice. The motor component will tested using the Bromage scale for spinal anesthesia (0, no paralysis; 1, inability to lift the thigh [only knee/feet]; 2, inability to flex the knee [only feet]; 3, inability to move any joint in the legs).

Description:

Over the last 30 years, regional anesthesia has emerged as the method of choice for elective caesarean section because it avoids risks involved in managing the airway of the parturient and has the added significant benefit of mother being awake for the birth of her child. Indeed, this changing practice patterns is thought to have lead to a significant drop in anesthesia related maternal morbidity and mortality.

At the same time, regional anesthesia is associated with both minor and significant risk.

Most common among these effects is hypotension and bradycardia, occurring in 33% and 13% of cases, respectively. In the pregnant patient, supine positioning required for surgery is associated hypotension due to aortocaval compression by the gravid uterus in 8% of patients, even without spinal anesthesia. During caesarean section, the combination of these factors can lead to hypotension include decreased placental blood flow, impaired fetal oxygenation and fetal acidosis. Maternal symptoms of low blood pressures include nausea, vomiting, dizziness, and decreased consciousness. This situation has lead to dozens of publications seeking to prevent or minimize the hypotensive response.

Hypotension after a spinal is initially due to a blockade of sympathetic fibers leading to a drop in systemic vascular resistance. Spinal-induced bradycardia is multifactorial but is in part due to the Bezold-Jarisch Reflex (BJR). This reflex is mediated by serotonin receptors within the wall of the ventricle in response to systemic hypotension. These receptors, the 5HT3 subtype, cause an increase efferent vagal signaling when bound by serotonin released during hypovolemic states, clinically leading to bradycardia and further hypotension.

Ondansetron, a widely used anti-emetic and serotonin antagonist, has been safely used to blunt the BJR, resulting in less bradycardia and hypotension first in animals and later in humans undergoing spinal anesthesia. ,

Use During Pregnancy:

The FDA labels ondansetron as a class B. Studies in pregnant rats and rabbits at doses up to 70 times higher than clinically used doses revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, few prospective studies in pregnant women. Nevertheless, the drug is widely used has a long safety history for use in pregnancy and during anesthesia for caesarean section.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: June 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Elective Caesarean section

• Consent to be in the study

• Age 18-45

• ASA 1 or 2

Exclusion Criteria:

• Patient refusal

• Patients with known allergy to ondansetron will be excluded

• Contraindications to spinal anesthetic

• Known Coagulopathy (acquired e.g. anticoagulation or existing such as liver disease; using patient history, physical examination to determine bleeding risks, a platelet count under 100 or a PT INR over 1.4)

• Severely altered anatomy (e.g. post surgical changes)

• Existing neurological deficits (Women with a history of migraine or tension headache will be allowed to enroll. More severe conditions with daily life limiting symptoms will be excluded. Examples include epilepsy, pseudotumor cerebri, prior stroke with persistent neurologic deficits, or any motor or sensory neuropathy with existing deficits)

• Skin infection overlying site

Related Conditions & MeSH terms

• Hypotension
• Pregnancy

Intervention

Drug:
• ondansetron
Ondansetron 8mg IV or placebo will be administered prior to placement of the spinal anesthetic
• placebo
placebo or ondansetron 8mg IV will be administered prior to placement of the spinal anesthetic

Locations

Country	Name	City	State
United States	University of Virginia Health System	Charlottesville	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
University of Virginia

Country where clinical trial is conducted

United States, 

References & Publications (30)

Abouleish EI, Rashid S, Haque S, Giezentanner A, Joynton P, Chuang AZ. Ondansetron versus placebo for the control of nausea and vomiting during Caesarean section under spinal anaesthesia. Anaesthesia. 1999 May;54(5):479-82. — View Citation

Asker C, Norstedt Wikner B, Källén B. Use of antiemetic drugs during pregnancy in Sweden. Eur J Clin Pharmacol. 2005 Dec;61(12):899-906. Epub 2005 Nov 18. — View Citation

Campagna JA, Carter C. Clinical relevance of the Bezold-Jarisch reflex. Anesthesiology. 2003 May;98(5):1250-60. Review. — View Citation

Dahlgren G, Granath F, Pregner K, Rösblad PG, Wessel H, Irestedt L. Colloid vs. crystalloid preloading to prevent maternal hypotension during spinal anesthesia for elective cesarean section. Acta Anaesthesiol Scand. 2005 Sep;49(8):1200-6. — View Citation

Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G. The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG. 2004 Sep;111(9):940-3. — View Citation

FDA Prescribing Information. Web retrieved 7/8/2009 .http://www.fda.org

George RB, Allen TK, Habib AS. Serotonin receptor antagonists for the prevention and treatment of pruritus, nausea, and vomiting in women undergoing cesarean delivery with intrathecal morphine: a systematic review and meta-analysis. Anesth Analg. 2009 Jul;109(1):174-82. doi: 10.1213/ane.0b013e3181a45a6b. Review. — View Citation

Hawkins JL. Anesthesia-related maternal mortality. Clin Obstet Gynecol. 2003 Sep;46(3):679-87. Review. — View Citation

Jackson R, Reid JA, Thorburn J. Volume preloading is not essential to prevent spinal-induced hypotension at caesarean section. Br J Anaesth. 1995 Sep;75(3):262-5. — View Citation

Kinsella SM, Lohmann G. Supine hypotensive syndrome. Obstet Gynecol. 1994 May;83(5 Pt 1):774-88. Review. — View Citation

Kuscu NK, Koyuncu F. Hyperemesis gravidarum: current concepts and management. Postgrad Med J. 2002 Feb;78(916):76-9. Review. — View Citation

Lee LA, Posner KL, Domino KB, Caplan RA, Cheney FW. Injuries associated with regional anesthesia in the 1980s and 1990s: a closed claims analysis. Anesthesiology. 2004 Jul;101(1):143-52. — View Citation

Liu SS, McDonald SB. Current issues in spinal anesthesia. Anesthesiology. 2001 May;94(5):888-906. Review. — View Citation

Martinek RM. Witnessed asystole during spinal anesthesia treated with atropine and ondansetron: a case report. Can J Anaesth. 2004 Mar;51(3):226-30. — View Citation

Mathru M, Rao TL, Kartha RK, Shanmugham M, Jacobs HK. Intravenous albumin administration for prevention of spinal hypotension during cesarean section. Anesth Analg. 1980 Sep;59(9):655-8. — View Citation

Mhyre JM, Riesner MN, Polley LS, Naughton NN. A series of anesthesia-related maternal deaths in Michigan, 1985-2003. Anesthesiology. 2007 Jun;106(6):1096-104. — View Citation

Owczuk R, Wenski W, Polak-Krzeminska A, Twardowski P, Arszulowicz 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. Reg Anesth Pain Med. 2008 Jul-Aug;33(4):332-9. doi: 10.1016/j.rapm.2008.01.010. — View Citation

Phillips TW Jr, Broussard DM, Sumrall WD 3rd, Hart SR. Intraoperative oxygen administration does not reduce the incidence or severity of nausea or vomiting associated with neuraxial anesthesia for cesarean delivery. Anesth Analg. 2007 Oct;105(4):1113-7, table of contents. — View Citation

Riley ET, Cohen SE, Rubenstein AJ, Flanagan B. Prevention of hypotension after spinal anesthesia for cesarean section: six percent hetastarch versus lactated Ringer's solution. Anesth Analg. 1995 Oct;81(4):838-42. — View Citation

Rout CC, Rocke DA. Prevention of hypotension following spinal anesthesia for cesarean section. Int Anesthesiol Clin. 1994 Spring;32(2):117-35. Review. — View Citation

Sarvela PJ, Halonen PM, Soikkeli AI, Kainu JP, Korttila KT. Ondansetron and tropisetron do not prevent intraspinal morphine- and fentanyl-induced pruritus in elective cesarean delivery. Acta Anaesthesiol Scand. 2006 Feb;50(2):239-44. — View Citation

Siddik-Sayyid SM, Aouad MT, Taha SK, Azar MS, Hakki MA, Kaddoum RN, Nasr VG, Yazbek VG, Baraka AS. Does ondansetron or granisetron prevent subarachnoid morphine-induced pruritus after cesarean delivery? Anesth Analg. 2007 Feb;104(2):421-4. — View Citation

Sullivan CA, Johnson CA, Roach H, Martin RW, Stewart DK, Morrison JC. A pilot study of intravenous ondansetron for hyperemesis gravidarum. Am J Obstet Gynecol. 1996 May;174(5):1565-8. — View Citation

Tang J, Wang B, White PF, Watcha MF, Qi J, Wender RH. The effect of timing of ondansetron administration on its efficacy, cost-effectiveness, and cost-benefit as a prophylactic antiemetic in the ambulatory setting. Anesth Analg. 1998 Feb;86(2):274-82. — View Citation

Tucker ML, Jackson MR, Scales MD, Spurling NW, Tweats DJ, Capel-Edwards K. Ondansetron: pre-clinical safety evaluation. Eur J Cancer Clin Oncol. 1989;25 Suppl 1:S79-93. — View Citation

Ueyama H, He YL, Tanigami H, Mashimo T, Yoshiya I. Effects of crystalloid and colloid preload on blood volume in the parturient undergoing spinal anesthesia for elective Cesarean section. Anesthesiology. 1999 Dec;91(6):1571-6. — View Citation

Veelken R, Sawin LL, DiBona GF. Epicardial serotonin receptors in circulatory control in conscious Sprague-Dawley rats. Am J Physiol. 1990 Feb;258(2 Pt 2):H466-72. — View Citation

Villalón CM, Centurión D. Cardiovascular responses produced by 5-hydroxytriptamine:a pharmacological update on the receptors/mechanisms involved and therapeutic implications. Naunyn Schmiedebergs Arch Pharmacol. 2007 Oct;376(1-2):45-63. Epub 2007 Aug 17. Review. — View Citation

Yazigi A, Chalhoub V, Madi-Jebara S, Haddad F, Hayek G. Prophylactic ondansetron is effective in the treatment of nausea and vomiting but not on pruritus after cesarean delivery with intrathecal sufentanil-morphine. J Clin Anesth. 2002 May;14(3):183-6. — View Citation

Yeh HM, Chen LK, Lin CJ, Chan WH, Chen YP, Lin CS, Sun WZ, Wang MJ, Tsai SK. Prophylactic intravenous ondansetron reduces the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery. Anesth Analg. 2000 Jul;91(1):172-5. — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants with Adverse Events as a Measure of Safety and Tolerability"	hypotension & bradycardia will be recorded from the placement of the spinal through the end of surgical c-section	day 1
Secondary	dosage of vasopressors administered	vasopressors administered during surgery	day one
Secondary	number of episodes of nausea		24 hours after surgery
Secondary	occurrence & intensity of itching		24 hours after surgery
Secondary	pain scores reported by the patient		24 hours after surgery
Secondary	dosage of anticholinergics administered		24 hours after surgery