Oxytocin: A guide for Anaesthetists 157Oxytocin: A guide for AnaesthetistsDR CELINE ANDREA BABER MBCHB, FANZCA, PGDIPCUResearch Fellow, King Edward Memorial Hospital for Women, Perth, Western AustraliaPO Box 2043, Subiaco, WA 6904, Australiaceline.baber@yahoo.comDr Baber is a part-time consultant at King Edward Memorial Hospital for Women <strong>and</strong> part-time at Sir CharlesGairdner Hospital. Her interests include teaching <strong>and</strong> cardiac echocardiography for anaesthesia.INTRODUCTIONIn the United Kingdom CMACE (Centre for Maternal <strong>and</strong> Child Enquiries, previously CEMACH) report for the triennium2006–2008, released in May <strong>2011</strong>, haemorrhage accounted for nine direct maternal deaths – making it the sixthleading cause of direct deaths in the UK. 1 In Australia, there were four deaths (out of 95 direct deaths) attributableto genital tract haemorrhage, in the 2003-2005 triennium. This was the fourth-ranked cause of direct deaths inmothers. 2 The synthetic uterotonic agent, Syntocinon, is widely used to prevent <strong>and</strong> treat uterine atony <strong>and</strong> postpartumhaemorrhage in labouring women, <strong>and</strong> at elective <strong>and</strong> non-elective caesarean delivery. Women deliveringby caesarean are at an increased risk of obstetric haemorrhage, most commonly due to uterine atony. 3Syntocinon has remained a topical uterotonic drug since its routine use started in the 1980s, <strong>and</strong> in particular,after a maternal death reported in the 1997 – 1999 CEMACH report. 4 This report identified a rapid 10 IU bolus ofSyntocinon in a hypovolaemic patient as a factor contributing to the subsequent death of the woman. The optimaldose at that time was previously unclear but recent data suggests that initial doses less than 5 IU are adequate,for both elective <strong>and</strong> non-elective caesarean deliveries.This report reviews the history <strong>and</strong> background of oxytocin <strong>and</strong> its synthetic form Syntocinon <strong>and</strong> discussesthe appropriate use of Syntocinon in the theatre environment.HISTORYSir Henry Dale, a physiologist <strong>and</strong> zoologist, lays claim to discovering the posterior pituitary extract, oxytocin, <strong>and</strong>describing its uterine contractile effects on the uterus in 1909. Interestingly, his work on the effects of histaminealso led to studies on anaphylaxis <strong>and</strong> shock. By 1911, this pituitary extract was being used to induce <strong>and</strong> augmentlabour. In 1953, Vincent du Vigneaud wrote a letter to the editor of The Journal of American Chemical Society titled“The Synthesis of an Octapeptideamide with the Hormonal Activity of Oxytocin”. This letter described the methodof synthesis of a highly purified preparation of oxytocin <strong>and</strong> identified its polypeptide structure. This new syntheticproduct had been successfully tested on isolated rats’ uteruses <strong>and</strong> du Vigneaud claimed it was “fully effective instimulating labour in the human”. 5 This finding led to du Vigneaud being awarded the Nobel Prize in Chemistryin 1955. 6The haemodynamic effects of oxytocin were studied in the 1970s, but in women undergoing termination ofpregnancy in the first trimester. In 1980, the Food <strong>and</strong> Drug Administration (FDA) of the USA approved the use ofSyntocinon in pregnancy <strong>and</strong> a paper in 1998 supported its routine use in the management of the third stage labour 7Shortly after this paper, reports <strong>and</strong> studies showing adverse cardiovascular effects, such as hypotension <strong>and</strong> ECGchanges, started to appear.Oxytocin, the natural hormone, has been implicated in much complex social behaviour, such as parental care,bonding <strong>and</strong> sexual arousal. The prairie vole is a socially monogamous rodent found in the USA <strong>and</strong> heavily studiedbecause of its high oxytocin receptor density. These animals, along with humans, have been found to have thehighest density of oxytocin receptors, <strong>and</strong> thus have been implicated in the monogamous behavior of both species.Oxytocin is also known as the “cuddle hormone”. 8PHYSIOLOGYOxytocin is a nonapeptide that differs from the hormone vasopressin by two amino acids. It is produced predominantlyin the magnocellular neurons of the paraventricular nuclei <strong>and</strong> to a lesser extent in the supraoptic nucleus. It issynthesized <strong>and</strong> transported in neurosecretory granules by nerve tracts to the neurohypophysis, where it is storedbefore it is released. 9Oxytocin-containing axons extend to the dorsal vagal complex <strong>and</strong> the intermediolateral column in the thoracolumbarportion of the spinal cord, <strong>and</strong> converge on the stellate ganglion. This suggests that they may be involvedin modulation of cardiac responses or cardiac sympathetic activity. 9Secretion of oxytocins is stimulated by pain or suckling of the nipple but predominantly by manipulation ordistension of the female genital tract. 9 In pregnancy, the uterus becomes markedly sensitive to the effects of oxytocinas gestation progresses, with the myometrial receptor population increasing in density to a peak at term (secondaryto the effects of oestrogen), along with an increase in messenger RNA within the receptor. In active labour, oncethe cervix is dilated more than 7cm, the receptor numbers start to decrease 8,10, <strong>and</strong> after partuition, they declinerapidly. 8
158 <strong>Australasian</strong> <strong>Anaesthesia</strong> <strong>2011</strong>was reported to be 0.35IU. These women had no other risk factors for uterine atony. 20 low solute fluids. 12,13Oxytocin: A guide for Anaesthetists 159The effects of oxytocin on uterine tone are likely to be due to the density of receptors in the uterus, rather thanthe plasma concentration. 11 Oxytocin also acts on receptors on the mammary ducts to facilitate milk letdown. 9Oxytocin receptors are also found outside of the uterus, in particular in the heart (atrial <strong>and</strong> ventricular tissue) <strong>and</strong>the vascular endothelium, <strong>and</strong> have also been identified in the thymus, adipose tissue <strong>and</strong> pancreas. 8 Oxytocinmeans “quick birth” in Greek, presumably due to its effects on uterine tone.Oxytocin receptors are G-protein coupled receptors found on the myometrial <strong>and</strong> myoepithelial cells. Stimulationcauses an increase in the force of contraction. Oxytocin has unknown effects in males but it is stored in similarlevels to women. It has a small antidiuretic effect, but only 1/200 th that of vasopressin. 9Oxytocin has an elimination half-life in plasma of 3-5 minutes <strong>and</strong> is removed from the plasma via hydrolysis inthe kidneys <strong>and</strong> the liver (by the action of oxytocinase). 9,123. Butwick AJ, et al. Minimum effective bolus dose of oxytocin during elective caesarean delivery. The study aimwas to quantify the lowest effective bolus dose of oxytocin to produce adequate uterine tone during electivecaesarean delivery. Seventy-five patients were recruited <strong>and</strong> r<strong>and</strong>omized to placebo, 0.5, 1, 3 or 5 IU ofSyntocinon. All patients received a spinal anaesthetic with intrathecal morphine. If uterine tone was deemed“adequate” by the obstetrician 2 minutes after administration, an oxytocin infusion was started. Seventythreepercent of patients in the placebo group had adequate uterine tone at 2 minutes (these patients alsoreceived uterine massage at delivery), although nearly 50% required rescue dose of oxytocin during the studyperiod. The ED 50 <strong>and</strong> ED 90 of sytocinon were unable to be calculated due to this high rate of adequate uterinetone after placebo <strong>and</strong> low dose boluses. There were no significant differences in the prevalence of adequateuterine tone among the study groups, although there was a higher rate of hypotension in the 5 IU group (vs.the placebo). 21SYNTOCINONSyntocinon, the synthetic form of oxytocin, is a nonapeptide identical in structure to oxytocin. It is wholly synthetic<strong>and</strong> has minimal vasopressor activity. One mg of Syntocinon is equivalent to 450 IU of hormone. 9The effect of Syntocinon infused at a low dose is a rhythmic uterine contraction, which is indistinguishable fromlabour. Higher doses cause a sustained tetanic uterine contraction. 13The effect of Syntocinon lasts 30 to 60 minutes after intramuscular injection, <strong>and</strong> is likely shorter after intravenousinjection. Its half-life is approximately 30-60 minutes after intramuscular injection <strong>and</strong> 4–10 minutes after intravenousinjection. Syntocinon distributes into the extracellular fluid, has low plasma protein binding <strong>and</strong> is eliminated in theliver <strong>and</strong> kidneys. 13Oxytocinase is a glycoprotein aminopeptidase produced during pregnancy, which degrades Syntocinon. Enzymeactivity increases until term, rises steeply at term, <strong>and</strong> then declines post delivery. There is little or no degradationof Syntocinon in men, non-pregnant women or cord blood. 13 The plasma levels of oxytocinase are raised in womenTachyphylaxisThe oxytocin G-protein coupled receptor undergoes desensitization in the face of persistent agonist stimulation.There are numerous potential cellular mechanisms responsible for this. Initially, the receptor <strong>and</strong> the G proteinuncouple. This occurs within a matter of seconds to minutes. Once uncoupled, the receptor undergoes internalizationor sequestration. Once internalized, the receptor can undergo degradation within lysosomes. 8 The oxytocin receptorundergoes rapid internalization in the setting of persistent agonist stimulation, which probably partly explains whywomen having a non-elective caesarean delivery require more Syntocinon than those having an elective caesarean. 9The internalization of oxytocin receptors with agonist exposure has been postulated as a cause for the reducedeffect of Syntocinon after either repeat dosing or among patients who have received a Syntocinon infusion. In astudy of haemodynamic changes among women in the first trimester receiving a 10 IU bolus of oxytocin, lesspronounced changes in haemodynamics occurred after a second dose. 22receiving Syntocinon infusions, during prolonged labour <strong>and</strong> in multiple pregnancies. Plasma oxytocinase is derivedpredominantly from the placenta. 14In Australia <strong>and</strong> <strong>New</strong> Zeal<strong>and</strong>, Syntocinon (Novartis) is supplied in 1 mL ampoules with either 5 IU or 10 IU ofhormone. The formulation also contains sodium acetate, glacial acetic acid, chlorobutanol, ethanol <strong>and</strong> water. Astudy in 1998 investigated the effect of oxytocin <strong>and</strong> its preservative, chlorobutanol, on (non pregnant) human rightatrial tissue samples. Chlorobutanol alone inhibited myocardial contractility, as well as synthetic oxytocin containingchlorobutanol. The magnitude of the negative inotropic effect on the atrial preparations was no different fromchlorobutanol alone versus oxytocin <strong>and</strong> chlorobutanol. Thus, some of the haemodynamic changes witnessed maynot be due solely to Syntocinon, as one of its preservatives may be contributing to the negative haemodynamiceffects. 15CONSIDERATIONS WHEN ADMINISTERING OXYTOCINDoseIn the triennium 1997 – 1999, the British National Formulary recommended a 5 IU dose of Syntocinon, given slowly. 16Despite this, the CEMACH report suggested that a request from the surgical team for a 10 IU bolus was a commonrequest. This was the dose that was administered to a woman that was hypotensive as a result of a high spinalblock <strong>and</strong> a post partum haemorrhage, <strong>and</strong> the injection was followed by cardiovascular collapse <strong>and</strong> death. 4 Thecurrent United Kingdom Royal College of Obstetrics <strong>and</strong> Gynaecology <strong>and</strong> the NICE guidelines are to administera 5 IU intravenous bolus, regardless of the indication for caesarean delivery. 17Interestingly, a survey of Fellows of the Royal <strong>Australian</strong> <strong>and</strong> <strong>New</strong> Zeal<strong>and</strong> College of Obstetricians <strong>and</strong>Gynaecologists resident in Australia <strong>and</strong> <strong>New</strong> Zeal<strong>and</strong> <strong>and</strong> published in 2010, noted that the most common doseof IV oxytocin used at caesarean delivery was 10 IU (67% of respondents). Two of the 700 Fellows who respondedgave or requested a 20 IU IV bolus dose. This survey did not ask anaesthetists what dose was actually administered. 18There is currently no evidence to support better efficacy from a bolus dose of 5 IU compared with smaller doses,<strong>and</strong> side effects are common with a dose of 5 IU. There are studies that evaluated smaller doses in elective <strong>and</strong>non-elective caesarean deliveries. These studies were all performed in patients that received regional anaesthesia,with no studies investigating the dose given during general anaesthesia.InfusionsIt is the author’s experience that it is relatively st<strong>and</strong>ard practice to combine a Syntocinon bolus with a postoperativesytocinon infusion at caesarean delivery. The short half-life of Syntocinon suits the administration of an infusion.A recent study came to the conclusion that a 5 IU bolus prior to an infusion (at 1.3 IU/min for 30 minutes, followedby 0.04 IU/min for 8 hours) did not alter the need for additional uterotonic drugs within the first 24 hours amongwomen with at least one risk factor for uterine atony. 23The recommendation from the CEMACH report for 2003-2005 is that IV oxytocin <strong>and</strong>/or ergometrine are thetreatment of choice for uterine atony <strong>and</strong> should be followed by an oxytocin infusion for 2-4 hours. The infusiondose rate recommended is 40 IU over 4 hours (0.16 IU/min). 24SIDE EFFECTS OF OXYTOCINCardiacMean Arterial Pressure. Intravenous oxytocin injections cause a biphasic change in mean arterial pressure. Initially,there is a rise in the mean arterial pressure that may be associated with a reflex bradycardia <strong>and</strong> subsequentdecrease in cardiac output. This is followed by a prolonged fall in mean arterial pressure <strong>and</strong> increased pulse <strong>and</strong>22, 25cardiac output. These changes are dose dependent.Studies in the 1970s of women in the first trimester having termination of pregnancy demonstrated oxytocininducedhypotension, tachycardia <strong>and</strong> increased cardiac output. 22 More recent studies confirm these changes,which were due to a reduction in systemic vascular resistance among women presenting for caesarean delivery. 26ECG changes. A bolus of 10 IU has been shown to produce ST-T depression in both women undergoing caesare<strong>and</strong>elivery under spinal anaesthesia <strong>and</strong> women who were neither pregnant nor anaesthetised. The ECG changeswere associated with symptoms such as flushing, chest pain <strong>and</strong> shortness of breath. This is now recognised tobe a large dose but it suggests some of the ECG changes are likely related to the oxytocin administration, ratherthan the regional anaesthesia or pregnancy. 27Oxytocin-induced ECG changes are thought to be due to hypotension, tachycardia <strong>and</strong> possibly coronary arteryvasoconstriction. 27,28 The incidence is greater after a 10 IU bolus, but is still possible after a 5 IU dose. 28All dose-response studies concluded that a dose of less than 5 IU of Syntocinon was adequate to maintainuterine tone, but none have been adequately powered to show a difference in clinical outcome (such as blood lossPulmonary Haemodynamicsor incidence of post-partum haemorrhage). A brief summary of three papers follows:The effects of oxytocin on the pulmonary vasculature have not been studied well. In a study of nine women in the1. Sartain JB, et al. Intravenous oxytocin bolus of 2 units is superior to 5 units during elective caesarean section.first trimester who received either a 5 IU or a 10 IU dose of oxytocin, there were significant changes in the pulmonaryEighty patients undergoing elective caesarean delivery were recruited <strong>and</strong> the patients were r<strong>and</strong>omized topressures. The pulmonary artery pressure increased by a maximum of a third, peaking 150 seconds post administration,either 2 or 5 IU of oxytocin followed by an infusion of 10 IU per hour. All the patients had their surgeryat a time when the systolic blood pressure had returned to baseline. The elevation in pulmonary artery pressureperformed under spinal anaesthesia with a phenylephrine infusion. There was no difference between the twopersisted for 10 minutes. The effects were almost as pronounced after 5 IU as after 10 IU. 22groups in blood loss, uterine tone or requests for additional uterotonic drugs. In the 5 IU group, there was agreater increase in heart rate, a larger decrease in mean arterial pressure <strong>and</strong> a higher rate of nausea <strong>and</strong>vomiting. 192. Carvalho JAC, et al. Oxytocin Requirements at Elective Cesarean Delivery: A Dose-Finding Study. Fortywomen having elective caesarean deliveries under spinal anaesthesia were studied <strong>and</strong> the ED 90 of oxytocinHyponatraemiaDespite the antidiuretic effect of oxytocin being much less pronounced compared with vasopressin, there is a smalleffect such that high doses, have been associated with water intoxication, due to increased water reabsorptionfrom the glomerular filtrate. Case reports usually also note an association with administration of large volumes of
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