CCI Institute for Excellence: Precision in Practice: Unraveling the Complexities of Oxytocin Administration in Cesarean Sections
Problem Statement
Oxytocin dosing during cesarean section recently came up as a topic of discussion in the anesthesiology department in Tillamook, Oregon. Subsequently, in January 2024, the author performed an informal review of the practice of oxytocin administration during and after cesarean with 15 anesthesiology providers. The general providers reported injecting 20 to 50 units of oxytocin into one liter of Lactated Ringer’s or Normal Saline or using a premade 30-unit oxytocin/500 ml Normal Saline bag. After delivery of the neonate, they let the infusion drip without a pump intraoperatively. This infusion was continued in the postoperative period for variable amounts of time. The estimated rates and quantity of oxytocin varied significantly across providers. The providers did not explicitly differentiate between types of cesareans (non-laboring or “elective” vs. intrapartum cesareans) in their regimen. This heterogeneity in the practice of oxytocin administration is consistent with what has been historically observed in the literature (1). Many providers I engaged with reflected that their practice needed to be more informed and evidence-based and that it was simply a continuation of a system learned in their training. I realized that practitioners might benefit from a review of current literature, expert opinions and guidance on this topic.
What is oxytocin?
Produced in and released from the hypothalamus and posterior pituitary gland, respectively, oxytocin is a peptide hormone that has receptors throughout the body. It has numerous central and peripheral effects. In the peripartum period, oxytocin is appreciated for its ability to cause uterine muscular contraction. Oxytocin is considered a first-line uterotonic agent and is used clinically to augment labor. It is also nationally endorsed as a first-line prophylaxis in the prevention of postpartum hemorrhage (PPH) by the American College of Obstetricians and Gynecologists (2) and internationally by the World Health Organization (3). Oxytocin effectively reduces the risk of PPH and has fewer side effects than other therapeutic agents (3). Oxytocin has a plasma half-life of one to six minutes, with rapid renal and hepatic clearance and enzymatic cleavage. It is usually administered via intravenous infusions for the prevention of PPH, and a steady state is achieved in approximately 40 minutes. The uterine response to intravenous administration of oxytocin occurs within seconds and subsides within one hour (4).
What are the clinically significant side effects?
Intraoperative oxytocin administration can contribute to nausea and vomiting. Oxytocin has antidiuretic effects and may also cause water retention and hyponatremia with prolonged infusions and higher doses. This is thought to be secondary to the similarity in the amino acid structure of vasopressin. Oxytocin is also known to have cardiovascular and hemodynamic effects. Invasive monitoring of the physiological response to a 10-unit bolus of oxytocin revealed a reduction in arterial pressure and systemic vascular resistance as well as increased heart rate, stroke volume and pulmonary artery pressure in health parturients (9). In a clinical trial, bolus administration of 10 units of oxytocin caused hypotension, tachycardia, ST depression and ST changes, with concomitant symptoms of flushing, chest pain and dyspnea in parturients under spinal anesthesia as well as healthy control volunteers (4). Because of cases of maternal cardiac and circulatory arrest following oxytocin administration, some countries recommend limiting boluses to five units or fewer of oxytocin (6). Supratherapeutic dosing and inappropriate administration of oxytocin are also associated with uterine muscle hypertonicity and rupture.
What is the appropriate dosing and administration of oxytocin during a cesarean for the prevention of PPH?
For non-laboring patients undergoing cesarean, dosing requirements to increase uterine tone are significantly lower than that often administered by anesthesiology providers. Doses between 0.35 and 3 units of an intravenous bolus and infusions of 0.29 units/min (15 units/hour) have been demonstrated to have adequate uterine tone response and similar blood loss compared to higher dosing regimens (6).
For patients undergoing intrapartum cesarean, there is an exponential increase in oxytocin dosing requirements to increase uterine tone (up to nine times the dose) (6). This difference has been attributed to ongoing oxytocin exposure for labor augmentation and maternal desensitization. The dose and duration of exposure determine the degree of oxytocin desensitization. Patients undergoing an intrapartum cesarean are much more likely to experience PPH despite higher oxytocin dosing, and high-dose oxytocin regimens are associated with an increased risk of PPH (6). This highlights the importance of utilizing second-line agents early in hemorrhage prevention for intrapartum cesareans and high-risk patients (6). Of note, the second-line agents have different mechanisms and cell signaling pathways and do not appear to have the desensitization seen with oxytocin (6).
Recommendations
In response to the substantial variability in the administration of uterotonic agents for cesarean sections, the lack of specific guidance on their usage and the significant consequences of appropriate administration, the International Consensus Statement on the Use of Uterotonic Agents During Cesarean Section was published in the journal Anesthesiology in 2019 (1). These guidelines aim to address all aspects of medication administration and differentiate between the management of patients undergoing elective and intrapartum cesareans. Guidance on second-line medication administration is also included. They are summarized in the table below.
Oxytocin Dosing Recommendations
by the International Consensus Statement on the Use of Uterotonic Agents During Caesarean Section
Elective Cesarean Section (No Labor) Intrapartum Cesarean Section
Bolus 1 unit oxytocin 3 units oxytocin over ≥ 30 sec
Infusion 2.5–7.5 units/hour (= 0.04–0.125 units/min or 42–125 ml/hr of 30 unit/500 ml NS infusion) 7.5–15 units/hour (= 0.125–0.25 units/min, 125–250 ml/hr of 30 unit/500 ml NS infusion)
Poor Uterine Tone
After Initial Bolus – After 2 min, give an additional bolus of 3 units over ≥ 30 sec – Consider a second-line agent early (after the second bolus)
Second-Line Agents
* Patient medical history and comorbidities should inform the choice of a second-line medication
** Tranexamic acid: Not a uterotonic, but it should be considered early in patients at risk of PPH
Agents Dosing/Route Repeat Dosing
Methylergonovine (Methergine) 200 mcg IM Can repeat in 2 hours
Carboprost (Hemabate)
250 mcg IM or intra-myometrial Can repeat after 15 min if required; max dose 2,000 mcg (8 doses)
Misoprostol 400–600 mcg SL, PR, Vaginal, PO Can repeat after 15 min; max dose 800 mcg
Another practice utilized in many anesthesiology groups is the “Rule of Threes Oxytocin Protocol.” Proposed in 2010 by Tsen et al. (7) before the International Consensus Statement on the Use of Uterotonics, this dosing system is popular because of its simplicity and ease of application. However, a vital critique is the lack of differentiation between elective and intrapartum cesareans. Modifications of the system suggest starting with a bolus of 1–3 units (instead of the standard 3-unit dose), depending on the PPH risk and type of cesarean. This protocol has been demonstrated to reduce the total oxytocin quantity compared to a continuous elective cesarean infusion (8). It calls for a slow administration of three units of oxytocin and a three-minute follow-up on uterine tone performed three times. If the tone is adequate after the third dose of three units, an oxytocin infusion of three units/hour is started. If that is inadequate, a second-line agent is administered. The figure below illustrates the Rule of Threes.
Figure from Balke, M, Tsen, L. Oxytocin Protocols for Cesarean Delivery, International Anesthesiology Clinics, 2014; 52(2): 48–66 (6)
Appropriate Administration Technique
Oxytocin should always be administered through a well-flowing IV. Bolus administration of oxytocin should last between 30 and 60 seconds. As a vasoactive medication, infusions of oxytocin should be controlled via infusion pumps (1). Oxytocin should be administered with caution in patients with pre-existing cardiac disease, and precautions should be taken to correct hypotension with appropriate agents.
Uterine Tone Communication
Preventing hemorrhage through increasing the uterine tone is the ultimate goal in the administration of intra-operative oxytocin for a cesarean. Maternal and surgical factors should inform the determination of appropriate dosing of oxytocin for PPH prevention. It is essential to have clear and timely communication with the surgeon on the uterine tone to help direct prompt and proper administration of oxytocin and other uterotonic agents.
Summary
Significant variability continues to exist in the administration of oxytocin for the prevention of PPH in cesarean section. An informed practice is not only vital to effectively preventing hemorrhage but also to minimizing the risk of toxicity and adverse impacts on the parturient. Anesthesiology practices should consider local education and enhanced awareness among providers regarding oxytocin dosing and its side effects. Furthermore, consideration should be given to adopting a protocolized practice to facilitate safe and reliable care. Because of the vasoactive effects of oxytocin, infusion pumps should be utilized for administration. Intraoperative communication with obstetrical surgeons regarding uterine tone must be encouraged. Second-line uterotonic agents and tranexamic acid should be utilized early in cases of poor uterine tone and elevated risk of hemorrhage.
Author’s Note: A special thanks to Sheena Hembrador, MD, Obstetrical Anesthesiologist at Virginia Mason Medical Center, who was supportive and helpful in the review of this topic.
References
1. Heesen, M, et al. International Consensus Statement on the Use of Uterotonic Agents During Caesarean Section. Anesthesiology, 2019; 74: 1305–1319
2. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin Number 183: Postpartum Hemorrhage. Obstetrics and Gynecology, 2017; 130: 168–186
3. WHO Recommendations: Uterotonics for the Prevention of Postpartum Haemorrhage, 2018 Update. World Health Organization, 2018. https://www.who.int/publications/i/item/9789241550420
4. Svanström, MC, et al. Signs of Myocardial Ischaemia After Injection of Oxytocin: A Randomized Double-Blind Comparison of Oxytocin and Methylergometrine During Caesarean Section. British Journal of Anaesthesia, 2008; 100(5): 683–689
5. FDA. Pitocin. Last accessed 2/27/2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018261s031lbl.pdf
6. Balke, M, Tsen, L. Oxytocin Protocols for Cesarean Delivery. International Anesthesiology Clinics, 2014; 52(2): 48–66
7. Tsen, LC, Balki, M. Oxytocin Protocols During Cesarean Delivery: Time to Acknowledge the Risk/Benefit Ratio? International Journal of Obstetric Anesthesia, 2010; 19: 243–245
8. Kovacheva, V, Soens, M, Tsen, L. A Randomized, Double-Blinded Trial of a “Rule of Threes” Algorithm Versus Continuous Infusion of Oxytocin During Elective Cesarean Delivery. Anesthesiology, 2015; 123: 92–100
9. Secher, N, Arnsbo, P, Wallin, L. Haemodynamic Effects of Oxytocin (Syntocinon) and Methyl Ergometrine (Methergin) on the Systemic and Pulmonary Circulations of Pregnant Anaesthetized Women. Acta Obstetricia et Gynecologica Scandinavica, 1978; 57: 97–103