Oxytocin in cesarean sections: what is the best way to use it?

Abstracts

JUSTIFICATIVA E OBJETIVOS: A ocitocina é uterotônico utilizado em anestesia obstétrica, cuja administração, tanto profilática quanto terapêutica, justifica-se por reduzir a incidência de hemorragia após o parto. No entanto, ainda não está estabelecido o regime ideal de infusão em cesarianas eletivas. Este estudo tem o intuito de revisar as principais características fisiológicas e farmacológicas da ocitocina e discutir o seu uso racional pelos anestesiologistas, tendo em vista os seus efeitos colaterais. CONTEÚDO: A ocitocina é produzida pelo hipotálamo e armazenada pela hipófise posterior. No útero ela determina contração da musculatura lisa que é bastante importante para o controle de hemorragia após a dequitação. Ela atua, também, em outros sistemas, sendo relevante a diminuição da resistência vascular periférica com conseqüente hipotensão arterial. As ações extra-uterinas passam a ser importantes quando a ocitocina é feita em altas doses ou em bolus, especialmente em gestantes sob anestesia (seja bloqueio espinal ou anestesia geral) apresentando hipovolemia, ou com alteração prévia no sistema cardiovascular. Diversos regimes de infusão têm sido estudados, variando-se a dose e/ou velocidade de infusão na tentativa de se estabelecer qual a maneira mais adequada de sua utilização. CONCLUSÕES: A ocitocina permanece como fármaco de primeira escolha para a prevenção e tratamento da atonia uterina após cesariana, especialmente por seu amplo espectro terapêutico. Apesar de estar disponível para a prática clínica há quase 50 anos, ainda não está estabelecido qual o regime adequado de sua infusão em cesarianas. A tendência atual é a utilização em infusão contínua de doses reduzidas, devendo ser evitada a administração em bolus.

ANESTESIA, Regional; CIRURGIA, Obstétrica; DROGAS

REVIEW ARTICLE

Oxytocin in cesarean sections. What is the best way to use it?^*

Ocitocina en cesáreas. ¿Cuál es la mejor manera de utilizarla?

Eduardo Tsuyoshi Yamaguchi, TSA^I; Mônica Maria Siaulys Capel Cardoso, TSA^II; Marcelo Luis Abramides Torres, TSA^III

^IAnestesiologista do HU-FMUSP

^IIDoutora em Anestesiologia pela FMUSP; Supervisora da Anestesia Obstétrica do Hospital das Clínicas da FMUSP

^IIIProfessor Doutor da Disciplina de Anestesiologia da FMUSP

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: Oxytocin is the uterotonic used in obstetric anesthesia, and its prophylactic and therapeutic administration is justified because it reduces the incidence of post-partum hemorrhage. However, the ideal infusion regimen in elective cesarean sections has not been determined yet. The objective of this study was to review the main physiological and pharmacological characteristics of oxytocin and to discuss its rational use by anesthesiologists in view of its side effects.

CONTENTS: Oxytocin is produced by the hypothalamus and stored in the posterior lobe of the pituitary gland. In the uterus, is causes contraction of the smooth muscle, which is very important to control hemorrhage after uterine emptying. It also affects other systems, and the reduction in peripheral vascular resistance with consequent hypotension is very important. The extra-uterine actions of oxytocin are important when administered in high doses or in bolus, especially in parturients under anesthesia (spinal block or general anesthesia) with hypovolemia or preexistent alterations in the cardiovascular system. Several infusion regimens have been studied, varying the dose and/or the speed of administration, in an attempt to establish the most adequate.

CONCLUSIONS: Due to its wide therapeutic spectrum, oxytocin remains the drug of choice to prevent uterine atony after cesarean sections. Although it has been used for almost 50 years, the adequate infusion regimen in cesarean sections has not been determined yet. The current tendency is to use continual infusion of low doses, and bolus administration should be avoided.

Keywords: ANESTHESIA, Regional: spinal block, epidural; DRUGS: oxytocin; SURGERY, Obstetric: cesarean section.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La ocitocina es un uterotónico utilizado en anestesia obstétrica, cuya administración, tanto profiláctica, como terapéutica, se justifica por reducir la incidencia de hemorragia después del alumbramiento. Sin embargo, todavía no se estableció el régimen ideal de infusión en cesáreas electivas. Este estudio tiene la intención de revisar las principales características fisiológicas y farmacológicas de la ocitocina y discutir su uso racional por parte de los anestesiólogos, teniendo en cuenta sus efectos colaterales.

CONTENIDO: La ocitocina es producida por el hipotálamo y almacenada por la hipófisis posterior. En el útero, hay una contracción de la musculatura lisa que es bastante importante para el control de la hemorragia después de la expulsión de la placenta. Actúa también en otros sistemas, siendo relevante la reducción de la resistencia vascular periférica con la consecuente hipotensión arterial. Las acciones extra-uterinas pasan a ser importantes cuando la ocitocina se crea en altas dosis o en bolus, especialmente en embarazadas bajo anestesia (sea bloqueo espinal o anestesia general) presentando hipovolemia, o con alteración previa en el sistema cardiovascular. Diversos regímenes de infusión han sido estudiados, variando la dosis y/o la velocidad de infusión en la tentativa de establecer cuál es la manera más adecuada para su utilización.

CONCLUSIONES: La ocitocina permanece como fármaco de primera elección para la prevención y el tratamiento de la atonía uterina después de la cesárea, especialmente por su amplio espectro terapéutico. A pesar de estar disponible para la práctica clínica hace casi 50 años, todavía no está establecido cuál es el régimen adecuado de su infusión en cesáreas. La tendencia actual es la utilización en infusión continua de dosis reducidas, debiendo ser evitada la administración en bolus.

INTRODUCTION

The administration of oxytocin, after uterine emptying, is routine in obstetric anesthesia in parturients undergoing cesarean sections. It promotes the contraction of the uterine smooth muscle, reducing blood loss at the place of placental detachment. Therefore, both its prophylactic and therapeutic use are justified to decrease the incidence if postpartum hemorrhage ^1-3. However, since it also has extra-uterine actions, the improper use of exogenous oxytocin can have deleterious consequences for the patient. Thus, the objective of this article was to discuss the rational use of oxytocin by the anesthesiologist, studying its main actions in the body, and the recommendations for its use in clinical practice.

PHYSIOLOGY AND PHARMACOLOGY

Historically, posterior pituitary gland "extract" have been used since 1901 in the presence of postpartum hemorrhage ⁴. In 1928, Kamm et al. separated this "extract" in two fractions: oxytocic and vasopressor ⁵. Although its structure was defined in 1953 ⁶, pure oxytocin was available for clinical use only in 1957.

Oxytocin is a polypeptide synthesized in the paraventricular and supraoptic nucleus of the hypothalamus and stored in the neurohypophysis ⁷. Structurally, its molecule has a ring conformation, which is extremely important to determine its biological effects. Even more important is the similarity of its molecule with the anti-diuretic hormone (ADH), differing only by the substitution of two amino acids, what explains its anti-diuretic and vasoactive properties when administered in high doses; besides, both are degraded by the same aminopeptidases.

Oxytocin is released by the neurohypophysis in intermittent bursts, determined by neurosensory stimuli, such as sucking the nipple, stimulation of the inferior genital tract, and cervical dilation. The increase in plasma osmolality ⁸ also triggers the release of oxytocin and ADH ⁸. On the other hand, ethanol suppresses the release of both oxytocin and ADH, and it is interesting that in the past, ethanol was used to inhibit labor.

Exogenous oxytocin can stimulate the frequency and the strength of uterine smooth muscle contraction at any time. However, in the first two trimesters it only happens with extremely high doses, with sustained reduction in resting membrane potential ⁹. This resistance of the uterine smooth muscle occurs because the effects of oxytocin are highly dependent on the actions of estrogen. Under the influence of estrogen, the density of receptors specific for oxytocin in the myometrium varies in the different stages of labor. As a consequence of this hormonal influence, the capacity of the uterine response increases about eight times between the 20^th and 39^th weeks of gestation. In this phase, although there is great individual variability, labor can be triggered with small amounts of oxytocin, such as 0.5 mU.min^-1. When oxytocin binds to its receptor, it activates phospholipase C and the intracellular release of Ca⁺⁺ via inositol-1,4,5-triphosphate, and also causes direct activation or activation induced by the depolarization of voltage-gated Ca⁺⁺ channels. It was possible to describe those events after cloning the human receptor for oxytocin, although the signaling mechanisms that mediate the effects of oxytocin in the hypothalamus, pituitary gland, and uterus are unknown ¹⁰.

In the uterus, oxytocin has two functions, regulate the contractile activity of the myometrium and promote the production of prostaglandins by endometrial/decidual cells ¹¹. Prostaglandins also have an important role in the contractile activity of the myometrium. Similar to oxytocin, the sensitivity of the uterus to prostaglandins increases with the progression of the pregnancy. However, when compared with oxytocin, they seem to be more effective in inducing uterine contractions in the first weeks of pregnancy ⁸.

The half-life of oxytocin varies from 5 to 17 minutes ^12,13, and the activated molecule has reduced binding to plasma proteins. It is cleared by the kidneys and liver, and only a small fraction is excreted unchanged in the urine. Although there is evidence that oxytocin crosses the placental barrier in primates, it is unknown the extension of this crossing in the human placenta ¹⁴.

During pregnancy, the plasma concentration of oxyticinase (cystil aminopeptidase) increases approximately ten times ¹⁵. This enzyme is apparently derived from the placenta and is capable of degrading both oxytocin and ADH, and it is responsible for regulating the uterine concentration of oxytocin. It is possible that this aminopeptidase has little action on plasma oxytocin, since the half-life of the hormone is similar in parturients in labor and in men, i.e., apparently its metabolism does not depend on the plasma concentration of aminopeptidase ^12,16,17.

EXTRA-UTERINE ACTIONS

Besides contraction of the uterine smooth muscle and myoepithelium that surrounds the alveolar ramifications in the breast, oxytocin has systemic effects, such as relaxation of the smooth muscle of the vessels, promoting vasodilation; this leads to a reduction in systolic blood pressure and, especially, of the diastolic blood pressure, besides reflex tachycardia. This vasodilation, usually temporary, can be clinically significant when oxytocin is administered in bolus, and may lead to a reduction in coronary perfusion and cardiac collapse; these effects are more prominent in the presence of general anesthesia ⁸. It was demonstrated that the association of the bolus administration of oxytocin with general anesthesia could reduce mean arterial pressure by up to 30% 10 to 40 seconds after the injection, lasting up to 210 seconds ¹⁸.

The cardiovascular effects of oxytocin are known from studies that have been published ^18-21. Although it has a wide therapeutic index, the administration of oxytocin may cause a significant reduction in peripheral vascular resistance and increase in cardiac output. Initially, it was believed that this increase was due to maternal self-transfusion after detachment of the placenta, but it has been shown that the cardiac output also increases when a bolus of oxytocin is administered in the beginning of the pregnancy (in uterine curettage, for example). It was then suggested that pure synthetic oxytocin had a b-stimulating action, increasing chronotropism and inotropism, and promoting peripheral vasodilation. Since this has not been proven yet and the cardiac changes appear from 10 to 20 seconds after vasodilation, it is more probable that this is a reflex phenomenon. More importantly, the cardiovascular effects seem a consequence of the excessive administration of oxytocin and not of its preservative ²².

Thus, it should be clear that parturients that do not have cardiac disorders tolerate the vasodilation, and its cardiovascular consequences, after the administration of bolus or excessive doses of oxytocin. However, this can be fatal in parturients under anesthesia (may it be spinal block or general anesthesia) who present hypovolemia or with preexisting disorders of the cardiovascular system, such as valvulopathy, hypertension, fixed cardiac output, or disease of the myocardium.

The anti-diuretic action is also observed when high doses are administered, and cases of water intoxication with hyponatremia secondary to the retention of free water, resulting in pulmonary edema, seizures, coma, and death ^23-26 have been reported. However, it should be mentioned that when used in physiological doses, in the absence of increased volemia, pure synthetic oxytocin rarely has an anti-diuretic action ^27,28.

USE BY ANESTHESIOLOGISTS IN CESAREAN SECTIONS

The prophylactic use of oxytocin in cesarean sections is justified because it reduces the incidence of uterine atonia, and the consequent postpartum hemorrhage, in up to 40% of the patients when compared to placebo or to the nonprophylactic administration of this drug, and it also reduces the use of other uterotonic agents ^1,2.

The incidence of uterine atonia can be increased in some circumstances as, for example, when there is uterine hyperdistension (multiple pregnancy, polydramnios, fetal macrosomia, and etc.). However, it has been demonstrated that only 74% of the patients who evolved for hysterectomy immediately postpartum had any risk factor for obstetric bleeding. One quarter of these patients did not have any risk factors, indicating the need for prophylactic uterotonics, since uterine atonia is the main cause of postpartum hemorrhage ²⁹.

According to the British National Formulary, oxytocin should be administered slowly at a dose of 5 IU after delivery ³⁰. However, despite its wide use in cesarean sections, there is no consensus regarding the adequate dose and speed of infusion. Its use is empirical, with infusion regimens based on the experience of each institution.

There are few works comparing different doses and speed of infusion of oxytocin. Munn et al. demonstrated that the continual infusion (2,667 mU.min^-1) of high doses of oxytocin (80 IU in 500 mL of Ringer's lactate) was superior to low doses (10 IU in 500 mL of Ringer's lactate at 333 mU.min^-1) in the prevention of post-cesarean section hemorrhage, but they did not indicate the differences regarding side effects; besides, the use of higher doses decreased the need of other uterotonic agents ³¹. In elective cesarean sections, there was no advantage in administering a total dose higher than 5 IU when the speed of infusion was fixed (1 IU.min^-1) ³². Higher doses of oxytocin are probably not necessary because the concentration of myometrial receptors reaches its peak at term under the influence of estrogen ³³.

The current tendency is to use smaller doses of oxytocin to promote effective uterine contraction, because smaller doses are necessary to induce and maintain labor. Sarna et al., using a dose of 1 IU.min^-1, described several cases of hypotension after delivery, which required the use of a vasopressor ³². Clinically satisfactory results without significant side effects were obtained infusing a smaller dose, 0.024 IU.min^-1, in parturients undergoing cesarean section with epidural anesthesia ^34,35. Carvalho et al. demonstrated that adequate uterine contraction is achieved with 0.35 IU of oxytocin in women undergoing elective cesarean section under spinal anesthesia; however, the authors stressed the importance of the technique of placental extraction, because in their study there was a considerably long time between the removal of the baby and placental extraction, allowing enough time for this reduced dose of oxytocin to promote satisfactory uterine contraction ³⁶. On the other hand, in parturients undergoing cesarean section for failure in inducing labor, who had already received oxytocin in continual infusion, the minimal dose was nine times greater (rapid infusion of 3 IU), suggesting that there was desensitization of the oxytocin receptor after exogenous administration during labor ³⁷.

The problems secondary to the use of oxytocin occur especially with high doses and, mainly, with bolus administration. A case of death after the bolus administration of 10 units of oxytocin in a hypovolemic parturient has been reported ³⁸. The slow administration of 5 IU of oxytocin is recommended to promote uterine contraction and decrease blood loss ³⁹. The definition of "slow", i.e., the most adequate speed of infusion, has not been determined yet ⁴⁰. Is it simply the case of diluting the drug in the infusing solution and increasing the speed of administration according to the evaluation of the obstetrician? Bolton et al. demonstrated that there was a change in the use of oxytocin in the United Kingdom. In the first phase of the study, they determined that 87% of the anesthesiologists consulted used a bolus dose of 10 IU of oxytocin, both in elective cesarean sections and in postpartum bleeding. After reports of maternal death due to the inadequate use of this drug ³⁸, the authors observed a change in the clinical conduct of these anesthesiologists, because only 23% of them maintained the older conduct ⁴¹.

Regarding the route of administration, although the intramyometrial administration promotes uterine contractility as efficiently as the intravenous route, it causes more hemodynamic changes (hypotension and tachycardia), which can be detrimental in patients with low cardiac reserve or hypovolemic ⁴². Oxytocin is not the only uterotonic available; however, there are restrictions to the other agents due to their side effects. Ergot derivatives can cause hypertension, being contraindicated in hypertensive patients. On the other hand, prostaglandins can cause hypotension, bronchospasm, and gastrointestinal symptoms (nausea, vomiting, diarrhea). There is a report of acute pulmonary edema after the intramyometrial administration of prostaglandin F2a (Carboprost^®) in parturients with uterine atonia non-responsive to oxytocin or ergot derivatives ⁴³.

Therefore, oxytocin remains the first line drug in the prevention of uterine atonia in parturients undergoing cesarean sections, especially due to its high therapeutic index. To reduce the incidence of post-partum hemorrhage, its prophylactic use is justified. Although it has been available for clinical use for almost 50 years, the adequate infusion regimen for cesarean sections has not been established yet. The current tendency is to use the continual infusion of low doses, avoiding the bolus administration.

REFERENCES

Submitted em 12 de julho de 2006

Accepted para publicação em 27 de fevereiro de 2007

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*

Received from Hospital Universitário da Faculdade de Medicina da Universidade de São Paulo (HU-FMUSP)

Publication Dates

• Publication in this collection
  10 May 2007
• Date of issue
  June 2007

History

• Received
  12 July 2006
• Accepted
  27 Feb 2007