The use of remifentanil for labour analgesia has grown over 12 years, from a few carefully selected cases  to being available in over a third of units in the UK . As interest among the anaesthetic community has grown, articles have appeared in journals with increasing regularity. This issue of Anaesthesia contains three reports on the use of remifentanil during labour. Two are concerned with establishing the best method of administration: Shen et al. compare patient-controlled analgesia (PCA) with continuous infusion , and Jost et al. demonstrate a novel approach of a patient-altered variable PCA dose . The third article is a case report of cardio-respiratory arrest associated with remifentanil PCA . This is now the fourth case report of respiratory and/or cardiac arrest related to remifentanil in obstetrics published in the last year [5-8]. Why the sudden flurry? Has familiarity bred complacency? And where does this leave remifentanil within our armoury of labour analgesic techniques?
Remifentanil has a substantial body of evidence that supports its use for labour analgesia. It is an ultra-short acting opioid that is rapidly and efficiently metabolised by both mother and fetus [9, 10]. A recent meta-analysis confirms that it is a more effective labour analgesic than other parenteral and inhalational alternatives . Whilst epidurals might provide better pain relief, remifentanil PCA is popular with parturients and both share similar satisfaction scores [11, 12]. It has euphoric side-effects that may contribute to its acceptability with labouring women, with some studies demonstrating similar pain relief scores to epidural analgesia . Several units have published safe use in hundreds of cases [14-16], and its application within the UK and beyond has grown rapidly [2, 17, 18]. Some hospitals have developed remifentanil analgesia either for women with contraindications to regional analgesia or where an ‘epidural on demand’ service is not provided . Others allow remifentanil as a routine analgesic option, which has been so popular with women as to lead to a reduction in the overall uptake of regional analgesia .
On the other hand, other evidence suggests that remifentanil only offers modest analgesia for labour [11, 12]. The optimum bolus dose, duration of bolus delivery, lockout interval and suitability of a background infusion all remain unknown . One dose-finding study found that some women required an eight-fold higher dose than others to provide comparable analgesia . Many of the regimens described allow doses similar to those given during general anaesthesia . Indeed, using the most popular PCA settings in the UK of a 40-μg bolus with a two-minute lockout , during any given three-minute period a parturient weighing between 60 and 80 kg could readily receive 0.33–0.44 μg.kg.min−1. Despite the potentially large doses used, patients can still rapidly develop tolerance, with several studies showing a reduction in efficacy after 60 minutes of use [3, 22, 23]. To take account for such wide variation, Jost et al. have developed a variable dose regimen whereby the parturient can increase the dose administered by pressing the demand button for longer .
Neuraxial analgesia is currently the only method that potentially provides absolute relief from contraction pain, whereas all others provide partial pain relief. Labour pain is unique in the regular cycling between intense pain and none. The doses of long-acting analgesics such as pethidine and diamorphine have to be balanced to provide analgesia during contractions without excessive effect between contractions. The ideal for analgesic methods with a short duration is to provide an effect only when needed. In this respect, TENS – with its instant onset and offset – is best, although unfortunately it has low efficacy. Nitrous oxide is next best, with rapid uptake in the alveoli and a short journey from the lungs to the brain. However, to be used effectively the inhalation has to start immediately the contraction is perceived . With remifentanil, a dose given at the start of a contraction will not provide analgesia for that contraction, but will have an analgesic effect 1–3 minutes later [3, 9, 12], and a respiratory depressant effect 2-4 minutes later . We therefore question whether linking the size of a bolus to the intensity of the current contraction, as Jost et al. describe, is conceptually erroneous because of this delayed effect . The safety of such an approach would have to be carefully evaluated.
It is the respiratory depressant potential of remifentanil that is the most concerning. Virtually all investigators have described ventilatory depression during their studies ; indeed, one of the earliest trials examining the use of remifentanil in labour was discontinued after four patients due to unacceptable respiratory side-effects . The frequency and severity of the ventilatory depression that have been described vary; however, a recent appraisal of the literature suggests that 32% of patients in published studies had some degree of ventilatory depression  and that patients using remifentanil PCA spend 5% of the time with arterial oxygen saturations below 90% [27, 28]. Most published studies have concentrated on the efficacy of remi-fentanil rather than its safety; one of very few that specifically looked at maternal side-effects did not include continuous monitoring of oxygen saturation . However, it is examining outcomes in the real world, rather than in tightly controlled clinical trials, that is arguably more revealing. One audit of 612 women in labour demonstrated oxygen saturations below 90% in 17.7% of parturients, with 0.8% having the PCA withdrawn due to persistent desaturation despite oxygen therapy . Other audits show levels of desaturation or oxygen supplementation of between 6% and 27% [15, 16, 29].
Why does this frequent ventilatory depression progress only rarely to respiratory or cardiac arrest? In the recently published cases, the precipitating factors were sometimes clear, such as a drug dilution error that resulted in an accidental ten-fold dose increase  or the recent administration of other strong opioids . Other factors are speculative and include the possibility of sequestration of drug within the arm veins because of compression from a blood pressure cuff or arm flexion, with the subsequent central release of multiple doses . One common factor in two recent cases is that the patients were receiving remifentanil PCA following an intrauterine death [5, 8]. In this circumstance there might be a natural desire to avoid excessive levels of monitoring and staff presence, and the fetal heart rate as an indirect indicator of maternal cardio-respiratory function is absent. Clearly, the cardiac arrest that occurred in Marr et al.'s case is of greatest concern . Was it a primary ventilatory arrest followed by a vagally-mediated bradycardia, aggravated by orthostatic hypotension while sitting? Whatever the cause, unrelieved inferior vena cava compression once supine would certainly have contributed to the ensuing cardiovascular collapse.
Safeguards against respiratory depression exist; however, although 80% of units in the UK that used remifentanil PCA in 2005 monitored the respiratory rate (an intermittent form of monitoring), barely half the respondents reported that they monitored oxygen saturations . As this issue's case report  demonstrates, even when stringent local protocols are in place they cannot always be relied upon. Complacency can occur: the compliance with stipulated monitoring standards fell from 70% to 10% over time in one unit, and only after considerable and ongoing investment in training and a redesign of services did levels of monitoring exceed 90% . A recent survey of all UK labour wards showed that 11% of respondents reported critical incidents related to use of remifentanil, mostly respiratory depression. The common themes in every case were either incorrect drug preparation or reduced monitoring outwith the local protocols . It is likely that continuing and growing pressures on labour ward staffing and capacity will only serve to compound these latent threats.
What determines acceptable safety? Women should be consulted about risk, but risk is difficult to communicate at the best of times – let alone during painful labour [31, 32]. The information given to parturients needs to reflect the impact of these recent rare but catastrophic cases of cardiorespiratory arrest. We as a profession also need to consider how to manage these risks. The introduction of any new drug into the clinical environment involves a rigorous system of preclinical development, national and international licensing, and post-marketing surveillance. However, the process of translating the use of an existing drug or technology from its intended and licensed indication to another is far more haphazard. The tentative first small steps taken by innovative clinicians and researchers can soon become giant leaps in terms of the breadth of indication, and tolerances of safety, once in the clinical domain. This ‘mission creep’ is inevitable and its intentions laudable; however, some degree of oversight is required to manage this process safely. The Medicines and Healthcare products Regulatory Agency (MHRA) in the UK provides a ‘Yellow Card’ scheme to allow centralised reporting of adverse drug reactions, which helps undesirable trends affecting both new and established drugs to be rapidly identified. A similar scheme could be considered for novel drug indications in anaesthesia. By collating reports and spotting trends, such a scheme could allow patterns in adverse reactions to be picked up earlier, and through disseminating this information could prevent any reported near-misses from developing into serious incidents. A system has been established in Switzerland to monitor events relating to remifentanil in labour , and it now has data on over 1600 parturients. By expanding such databases to a large multinational or national level, valuable denominator data could be gathered, and with the National Audit Projects in the UK our speciality has demonstrated the feasibility and benefits of large-scale collaboration .
So what next for remifentanil in labour? After the case report of Bonner & McCylmont , Sneyd warned of the possibility of a maternal death and suggested that the use of remifentanil for labour analgesia cannot be justified , particularly given the lack of evidence to demonstrate its benefits over alternatives. By way of contrast, despite a patient's death, a recent editorial defended the continued use of regional nerve blocks on the grounds that all effective analgesic techniques carry some risk of disastrous complications . As previously mentioned, the number of cases in which remifentanil has been used for labour analgesia is increasing rapidly. Its routine use as a labour analgesic exposes more women to risk than selective use, although familiarity should help preserve safe management – provided high standards are maintained. The Belfast group introduced remifentanil for labour analgesia in 2004 and currently use it in approximately 1200 cases per year; as Hughes and Hodgkinson report, they have only encountered two cases of ventilatory depression in the last two years, both of which were responsive to stimulation by the midwife and oxygen administration . Belfast's tried and tested systems for safe management are built upon guidelines that are featured on (and available from) the Obstetric Anaesthetists’ Association website . As is common in medicine, it may be the new adopter or occasional user that puts their smaller number of patients at higher risk. Familiarity can breed complacency, but on the other hand unfamiliarity can breed errors.
We live and work in an imperfect world where, in spite everyone's best intentions, the provision of ideal levels of monitoring and supervision on labour wards cannot be relied upon. Despite our enthusiasm for popular and useful techniques, we all have to operate within the constraints of this reality, and our practice needs to reflect this. Epidural analgesia in labour is more effective than remifentanil and at least equally popular . The change to low-concentration local anaesthetic solutions for labour analgesia has reduced the risk of catastrophic complications such that there have been no deaths in the UK for several decades. Retaining epidural analgesia as the ‘gold standard’ of analgesia provided by anaesthetists would seem justified. However, remifentanil may have a role within the range of options for pain relief during labour as a potent analgesic that is not necessarily physician-led. But units that offer it must insist upon the continuous presence of a midwife or obstetric nurse, continuous oxygen saturation monitoring and, we would argue, continuous CTG monitoring which may be an indirect method of detecting global hypoxaemia with which midwives are far more familiar. The use of remifentanil for analgesia after intrauterine death, where its benefits over other opioids in terms of fetal effects are not a consideration, needs to be questioned. All units that offer remifentanil PCA on labour ward should closely examine their practice, and should discontinue the service if appropriate monitoring and supervision of patients cannot be guaranteed at all times.
The accumulated doses that PCA regimens can deliver and the lockout interval between doses need careful consideration. Early investigators warned against repeated boluses less than 2.5 minutes apart due to the risk of excessive respiratory depression . We would recommend that a three-minute lockout become the minimum standard, as shorter lockouts allow additional doses to be received before maximal side-effects – and peak analgesic effects – have occurred. Particular care is needed when other opioids have previously been administered. Ultimately, it will only be through a rigorous process of audit, appropriate supervision and co-ordinated adverse event monitoring that we can make remifentanil a safer option for women in labour.
Whatever our individual opinions of remifentanil in labour, the recent cases of respiratory and cardiac arrest are a timely reminder that nothing we do in anaesthesia is benign; risk is a constant companion to our practice, and must always be considered alongside any perceived benefits. Without due respect for the side-effects of remifentanil, we risk sleepwalking into a maternal death related to its use in the near future – we have been warned .