Anaesthesia 2013, 68, 9951009

Editorial

Editorial
Prophylactic use of oxytocin at caesarean section: where are the guidelines?
Oxytocin, a polypeptide hormone produced by the posterior pituitary gland, was rst synthesised by Vincent du Vigneaud, an American biochemist in the 1950s [1]. He was subsequently awarded the Nobel Prize for Chemistry for this and other work. Syntocinon, its synthetic analogue, was introduced into medical practice in the late 1950s and its dose, administration and clinical applications have been the subject of debate ever since. The ndings of a UK-wide survey into the administration of oxytocin, published in this issue of the Journal, highlights continued variation in practice throughout the UK, and the authors call for national protocols to guide dosing [2]. Postpartum haemorrhage remains a signicant cause of maternal morbidity [3] and the use of oxytocin has reduced maternal morbidity worldwide [4]. However, use of oxytocin is not without its own problems as it can cause signicant maternal side effects [5, 6]. Hypotension and tachycardia are common, and electrocardiographic changes suggestive of myocardial ischaemia may occur [7]. Maternal death related to oxytocin administration is documented in the Con1006

dential Enquiries into Maternal Deaths, 199799 [8]. The varied oxytocin dosing regimens used throughout the UK have been a subject of increased interest over the last decade. In 2001, a national survey found that 87% of responding UK lead obstetric anaesthetists were using a dose of 10 IU oxytocin, 50% by rapid intravenous bolus [9]. A repeat of the same survey a year later indicated that only 15% of respondents were using a 10-IU dose, and only 23% of these by rapid bolus [9]. A welcome nding of this current survey by West et al. is that an initial 10-IU oxytocin bolus has completely disappeared from UK practice. Current guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG) [10] and the British National Formulary [11] recommend the use of 5 IU oxytocin as a slow bolus, although the timescale over which it should be administered is not specied. Bolus dosing is associated with signicantly more cardiovascular sideeffects than if administered over 5 minutes, for both 5 IU and 3 IU oxytocin [12, 13]. Reducing the dose of the oxytocin bolus may not be the key to reducing side-effects:

even doses between 0.5 IU and 3 IU have been shown to produce hypotension in 20-30% of patients when given as a bolus [14]. It may be that reducing the speed of drug delivery is the most important factor for reducing potentially dangerous side-effects, and this is especially important in those at high risk due to cardiac disease or hypovolaemia. Some centres do not use a traditional bolus of oxytocin but commence a prophylactic oxytocin infusion. A Canadian study of 40 patients found that the ED90 of oxytocin infusion required to produce adequate uterine contraction three minutes after delivery was 0.29 IU.min1 in a low-risk population undergoing elective caesarean delivery [15]. What evidence base is there to guide oxytocin doses? In the mid2000s, two studies published data on a range of oxytocin doses used at caesarean section and estimated a minimum effective dose (ED90) for oxytocin after both elective caesarean section [16] and caesarean after labour [17]. The primary endpoint used was uterine tone, subjectively assessed by a blinded obstetrician. The ED90 of oxytocin at elective caesarean was calculated as 0.35 IU

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Anaesthesia 2013, 68, 9951009

and after labour as 3 IU. The variation in dose between the elective and emergency patients may be related to oxytocin receptor desensitisation from use of oxytocin in labour. This is seen at a cellular level with oxytocin exposure of just over 4 hours [18]. In 2010, additional data from a study looking at reduced oxytocin doses at caesarean delivery suggested that between 0.5 and 3 IU oxytocin was enough to achieve adequate uterine tone after elective caesarean section [14]. However, these studies were small, with 30 [17], 40 [16] and 75 [14] patients, respectively, and they did not look at outcomes after leaving the operating room. They were thus underpowered to look at clinically signicant outcomes such as reduction in postoperative haematocrit and the risk of major postpartum haemorrhage. In addition, all patients received prophylactic oxytocin infusion after the bolus dose, which is not standard practice throughout the UK (used routinely in 23% of responding units in West et al.s survey [2]). We must be careful not to extrapolate from these dose-nding studies and assume that lower doses of oxytocin are adequate if a prophylactic infusion is not subsequently administered. However, the introduction of routine oxytocin infusion after caesarean section would have a major impact on delivery suites in the UK. Many postnatal wards in the UK do not manage women with oxytocin infusions and so discharge from the delivery suite may be delayed, signicantly impacting on the throughput of work. A large (2069 patients) randomised con-

trolled trial from Ireland looked at the benet of adding a 4-h prophylactic infusion of oxytocin to all caesarean sections following an initial bolus of 5 IU. This showed that although a prophylactic infusion reduced the need for additional uterotonic agents, it did not affect the incidence of major obstetric haemorrhage (15.7% in the bolus and infusion group vs 16.0% with bolus only) [19]. There is also considerable variation in the rate of oxytocin infusions used, especially between UK and North American practice, and little evidence to recommend how long the infusion should be continued postoperatively. The difference in rates required between oxytocin infusion after bolus [19], instead of bolus [15] and for treatment of postpartum haemorrhage [10] can cause additional confusion. In the UK, the only recommendation available is from the RCOG green-top guideline which suggests 40 IU oxytocin in 500 ml saline 0.9% at a rate of 125 ml.h1 for the treatment, rather than the prophylaxis, of postpartum haemorrhage and uterine atony [10]. In UK practice, this is often the same infusion regimen used for prophylaxis in highrisk cases. The RCOG does not comment on the recommended duration of the infusion. Carbetocin is a newer drug that can potentially provide the benet of longer acting maintenance of uterine tone without the need for postoperative infusions. It is a synthetic derivative of oxytocin, and exerts its physiological effects on oxytocin receptors. It has a longer half-life of around 40 minutes [20],

compared with 410 minutes for oxytocin, and has been shown to reduce the need for additional oxytocics [21, 22] with no difference in the incidence of postpartum haemorrhage when compared with oxytocin [23]. It is currently licensed in the UK for prevention of uterine atony at a dose of 100 lg over 1 minute [24]. When comparing the cardiovascular side-effects, 100 lg carbetocin and 5 IU oxytocin injected over 1 minute produced statistically similar results in both groups for maternal heart rate and blood pressure [25]. West et al. call for a protocol to guide oxytocin dosing. The authors of a previous editorial in the International Journal of Obstetric Anesthesia, published after the dose-nding studies, attempted to offer just that. They proposed a protocol with a rule of threes for oxytocin: a 3 IU loading dose; 3-min assessment intervals; a total of three bolus doses (if rescue is required), a maintenance infusion of 3 IU.l1 run at 100 ml.h1; and the use of three alternative pharmacological agents if this regimen is inadequate (ergometrine, carboprost and misoprostol) [26]. However, there are additional key points that should be addressed. Tsen and Balkis proposed protocol did not mention the importance of speed of administration of the oxytocin bolus, or the evidence to suggest that there is a difference in dose requirements for oxytocin between elective caesarean sections and those performed after labour. Recent literature does appear to have already affected UK practice. West et al.s survey found that 5.3%
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Editorial

of lead obstetric anaesthetists are now using less than 5 IU oxytocin for prophylaxis at caesarean section. However, we must be cautious of how we interpret these recent studies. Although it has been shown that less than 5 IU oxytocin achieves adequate uterine tone after caesarean section, we need more information to show that this is not associated with an increased incidence of postpartum haemorrhage outside the operating room. If we are routinely to use a lower dose of oxytocin then it should be used with a prophylactic infusion. In the UK, an infusion over 4 hours is most commonly used [2] but the optimum duration is yet to determined. If we are using 5 IU oxytocin, there is evidence that a prophylactic infusion is not required. Any protocol developed needs to consider the impact on our routine practice in the UK, the growing evidence for carbetocin as an alternative agent, and the importance of speed of administration and previous oxytocin exposure, and therefore should not provide a one size ts all policy. Ultimately, we must ensure that the laudable aim of reducing complications from oxytocin administration does not lead to increased postoperative morbidity from postpartum haemorrhage.

Bristol, UK Email: Nicola.weale@nbt.nhs.uk

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References
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Competing interests
No external funding or competing interests declared. N. Weale C. Laxton Consultant Anaesthetists North Bristol NHS Trust Southmead Hospital
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after elective caesarean section in the Netherlands. Archives of Gynecology and Obstetrics 2013; 287: 11117. 23. Su LL, Chong YS, Samuel M. Carbetocin for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2012; 4: CD005457. 24. Joint Formulary Committee. British National Formulary. London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com/mc/bnf/current/ PHP4765-carbetocin.htm (accessed 15/04/2013). 25. Moertl MG, Friedrich S, Kraschl J, Wadsack C, Lang U, Schlembach D. Haemodynamic effects of carbetocin and oxytocin given as intravenous bolus on women undergoing caesarean delivery: a randomised trial. British Journal of

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Obstetrics and Gynaecology 2011; 118: 134956. 26. Tsen LC, Balki M. Oxytocin protocols during caesarean delivery: time to acknowledge the risk/benet ratio? International Journal of Obstetric Anesthesia 2010; 19: 2435. doi:10.1111/anae.12337

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