Atropine to Prevent Nausea and Vomiting After Spinal Anesthesia for Caesarean Section

Intrathecal Atropine to Prevent Nausea and Vomiting After Spinal Anesthesia With Morphine for Elective Caesarean Section: a Randomized Controlled Trial

The aim of this study is to assess the efficacy of atropine in preventing nausea and vomiting after spinal anesthesia with local anesthetic and morphine for elective Caesarean section.

Patients enrolling in the study will be assigned to one of three groups. One will receive a small dose of intrathecal atropine; another will receive small-dose intravenous atropine; the third group will receive placebo.

Study Overview

• Status: Completed
• Conditions: Cesarean Section; Postoperative Nausea and Vomiting; Anesthesia,Spinal
• Intervention / Treatment: Drug: Bupivacaine; Drug: Morphine; Drug: Isotonic saline solution; Drug: Atropine

Detailed Description

Intrathecal (IT) morphine grants effective, durable and safe analgesia after Caesarean section. The most common adverse effects after IT morphine are widespread pruritus and postoperative nausea and vomiting (PONV).

Postoperative nausea and vomiting is multifactorial in origin; in addition to general and pre-existing risk factors, such as elevated gonadotropin and progesterone serum levels, parturients undergoing Caesarean section are exposed to drug-induced, hemodynamic and surgical (manipulation of the uterus) stimuli.

Anticholinergic agents, and particularly scopolamine, have long been known to decrease opioid-related nausea and vomiting, although their narrow therapeutic range and inconvenient route of administration (typically transdermal) has limited their application. Anticholinergic agents are thought to act via inhibition of muscarinic receptors in several regions of the medulla oblongata, which are implicated with nausea and vomiting generation; in addition to the chemoceptor trigger zone, these receptors are particularly concentrated in, but not limited to the nucleus tractus solitarius. Cholinergic receptors have been typically associated with motion sickness, but cholinergic agonists such as neostigmine have been shown to increase the incidence of PONV, especially when injected intrathecally.

Anticholinergic agents with muscarinic selectivity may be effective in preventing and treating PONV. Intravenous (IV) administration of scopolamine or atropine, but not glycopyrrolate, reduces the incidence of PONV. Intuitively, as glycopyrrolate does not cross the blood-brain barrier, most postoperative anti-emetic effects of anticholinergic drugs should be mediated by central receptors.

Few studies have specifically evaluated the antiemetic effect of IV atropine after balanced general or opioid-based regional anesthesia, with conflicting results. Atropine may represent a valid alternative to scopolamine and its adverse effects; however, its apparent duration of action is "brief" (minutes to 1 hour) when administered IV.

After we became aware of several observations by Ramaioli and De Amici on the efficacy of small-dose intrathecal (IT) atropine for the treatment of PONV after IT morphine administration, we set out to investigate the use of this agent for prophylaxis of PONV in a high-risk population, such as patients receiving IT morphine for postoperative analgesia after elective Caesarean section.

• Study Type: Interventional
• Enrollment (Actual): 216
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • ME
    • Messina, ME, Italy, 98122
      • University of Messina
  • PR
    • Parma, PR, Italy, 43126
      • University and Hospital of Parma (Azienda Ospedaliero-Universitaria di Parma)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients scheduled for elective Cesarean section at up to 42 weeks and 2 days
• Patients in ASA Physical Status Class I or II
• Informed written consent to participation
• No known gestosis

Exclusion Criteria:

• Any known fetal pathology
• Indication to general anesthesia
• Known allergy to any of the study drugs
• Baseline bradycardia or any cardiovascular disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Patients in this group will receive both an intrathecal and intravenous injection of saline solution, as a placebo comparator.	Drug: Bupivacaine; 12.5 mg of a 5 mg/ml hyperbaric solution, intrathecally; Other Names: Local Anesthetic; Hyperbaric Bupivacaine; Marcain Heavy Injection; Drug: Morphine; 200 µg of a 200 µg/ml solution, intrathecally; Drug: Isotonic saline solution; 0.9% NaCl solution 0.1 ml, intrathecally in group Control and IV Atropine 0.1 ml, intravenously in group Control and Intrathecal Atropine; Other Names: Sodium chloride
Experimental: Intrathecal Atropine; Patients in this group will receive intrathecal atropine as a prophylactic antiemetic agent. They will also receive intravenous saline solution to maintain blinding.	Drug: Bupivacaine; 12.5 mg of a 5 mg/ml hyperbaric solution, intrathecally; Other Names: Local Anesthetic; Hyperbaric Bupivacaine; Marcain Heavy Injection; Drug: Morphine; 200 µg of a 200 µg/ml solution, intrathecally; Drug: Isotonic saline solution; 0.9% NaCl solution 0.1 ml, intrathecally in group Control and IV Atropine 0.1 ml, intravenously in group Control and Intrathecal Atropine; Other Names: Sodium chloride; Drug: Atropine; 100 µg of a 1 mg/ml preservative-free solution; intrathecally in group Intrathecal Atropine; intravenously in group IV Atropine
Active Comparator: IV Atropine; Patients in this group will receive a small dose of atropine via the intravenous route to examine its possible antiemetic activity. They will also receive intravenous saline solution to maintain blinding.	Drug: Bupivacaine; 12.5 mg of a 5 mg/ml hyperbaric solution, intrathecally; Other Names: Local Anesthetic; Hyperbaric Bupivacaine; Marcain Heavy Injection; Drug: Morphine; 200 µg of a 200 µg/ml solution, intrathecally; Drug: Isotonic saline solution; 0.9% NaCl solution 0.1 ml, intrathecally in group Control and IV Atropine 0.1 ml, intravenously in group Control and Intrathecal Atropine; Other Names: Sodium chloride; Drug: Atropine; 100 µg of a 1 mg/ml preservative-free solution; intrathecally in group Intrathecal Atropine; intravenously in group IV Atropine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of postoperative nausea and vomiting (PONV) as expressed by at least one rating > 3 on a numerical rating scale (0-10).	12 hours post-operatively

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence and prevalence of PONV up to 24 h postoperatively, expressed as both ratings on a numerical rating scale and as the area under the curve of these ratings over time.	Up to 24 h postoperatively
Incidence of atropine-related side effects such as xerostomia, anxiety, tachycardia.	Up to 24 h postoperatively
Postoperative pain expressed as time to first request for supplemental analgesia and as rating on a numerical rating scale.	Up to 24 h postoperatively

Collaborators and Investigators

• Sponsor: University of Parma
• Investigators: Study Chair: Guido Fanelli, MD, University of Parma; Principal Investigator: Andrea Cornini, MD, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

Publications and helpful links

General Publications

• Griffiths JD, Gyte GM, Popham PA, Williams K, Paranjothy S, Broughton HK, Brown HC, Thomas J. Interventions for preventing nausea and vomiting in women undergoing regional anaesthesia for caesarean section. Cochrane Database Syst Rev. 2021 May 18;5(5):CD007579. doi: 10.1002/14651858.CD007579.pub3.
• Ramaioli F, De Amici D. Central antiemetic effect of atropine: our personal experience. Can J Anaesth. 1996 Oct;43(10):1079. doi: 10.1007/BF03011915. No abstract available.
• Salmenpera M, Kuoppamaki R, Salmenpera A. Do anticholinergic agents affect the occurrence of postanaesthetic nausea? Acta Anaesthesiol Scand. 1992 Jul;36(5):445-8. doi: 10.1111/j.1399-6576.1992.tb03494.x.
• Moscovici R, Prego G, Schwartz M, Steinfeld O. Epidural scopolamine administration in preventing nausea after epidural morphine. J Clin Anesth. 1995 Sep;7(6):474-6. doi: 10.1016/0952-8180(95)00056-n.
• Kotelko DM, Rottman RL, Wright WC, Stone JJ, Yamashiro AY, Rosenblatt RM. Transdermal scopolamine decreases nausea and vomiting following cesarean section in patients receiving epidural morphine. Anesthesiology. 1989 Nov;71(5):675-8. doi: 10.1097/00000542-198911000-00009.

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): May 1, 2008

Study Registration Dates

• First Submitted: June 15, 2009
• First Submitted That Met QC Criteria: June 15, 2009
• First Posted (Estimate): June 16, 2009

Study Record Updates

• Last Update Posted (Estimate): June 16, 2009
• Last Update Submitted That Met QC Criteria: June 15, 2009
• Last Verified: June 1, 2009

More Information

Terms related to this study

• Keywords: Morphine; Atropine; Analgesics, Opioid; Antiemetics
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Signs and Symptoms, Digestive; Nausea; Vomiting; Postoperative Nausea and Vomiting; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Mydriatics; Anesthetics; Anesthetics, Local; Bupivacaine; Morphine; Atropine
• Other Study ID Numbers: ANEST-OST-01