Safety and feasibility of xenon as an adjuvant to sevoflurane anaesthesia in children undergoing interventional or diagnostic cardiac catheterization: study protocol for a randomised controlled trial

Despite originally being described as chemically inert, noble gases including xenon, argon and helium have been repeatedly demonstrated to exhibit remarkable biological properties. In 1939, Behnke and Yarbrough observed narcotic effects of argon in humans at pressures from 4 to 10 atm [1]. In 1946, Lawrence reported anaesthetic properties of normobaric xenon in mice [2]. The first use of xenon for anaesthesia in humans was performed by Cullen and Gross in 1951 [2,3]. However, only the development of closed-circuit anaesthesia machines in the 1990s has made xenon available to a broader spectrum of patients. Xenon is described as having many of the characteristics of an ideal inhalational anaesthetic agent. It is non-flammable, non-explosive, non-toxic, devoid of teratogenic effects and does not contribute to the greenhouse effect. Due to the lowest blood/gas partition coefficient of all known anaesthetics, xenon provides rapid induction and emergence from anaesthesia. Moreover, xenon affects haemodynamics, myocardial performance and the neurohumoral system less than other anaesthetic agents [4].

Since the ‘re-introduction’ of xenon into clinical anaesthesia by Lachmann and colleagues in 1990 [5], xenon has been repeatedly demonstrated in experimental and clinical studies to produce only minimal haemodynamic side effects when compared to volatile or intravenous anaesthetics, even when used in heart failure conditions [6-9]. This inert haemodynamic profile may be owing to the fact that xenon anaesthesia is associated with significantly less sympathicolysis than known from other anaesthetics [10]. Meanwhile, these initial observations could be confirmed in two European multi-centre randomised controlled trials in which xenon was compared to isoflurane and found to slightly decrease heart rate and to preserve or moderately increase arterial pressures [11,12]. Moreover, recent evidence indicates that - in contrast to the majority of conventionally used general anaesthetics - xenon is virtually devoid of negative inotropic effects [12-15]. Furthermore, and adding to the culminating evidence that noble gases exert organ-protective effects in various conditions, xenon was found to induce both early and late pharmacological preconditioning in experimental models of myocardial ischemia [16].

Several clinical trials have been specifically performed in patients at increased cardiovascular risk or during cardiac surgery [17-20]. In this high-risk group, xenon anaesthesia was devoid of negative haemodynamic side effects, but instead showed a preservation of pre-anaesthetic haemodynamic parameters during the procedure.

The effects of xenon on right ventricular afterload are controversial. One study reported an increase in pulmonary arterial elastance in pigs that received xenon in addition to a baseline anaesthesia with pentobarbital and fentanyl [21]. In contrast, other investigators described xenon as not affecting pulmonary vascular resistance (PVR) in pigs [22]. Accordingly, Goto observed no changes in PVR in patients undergoing xenon anaesthesia [23]. Likewise, Bedi and co-workers found PVR did not change in critically ill patients who were sedated with xenon during their stay in the intensive care unit [24]. Our group also did not observe any effects of xenon on PVR in patients undergoing open-heart surgery [25].

From the present literature, there is hence no hint for a safety risk of xenon in patients with cardiac co-morbidity.

Apart from its beneficial effects on the cardiovascular system, xenon has been repeatedly demonstrated to offer neuroprotection in various animal models and models of neuronal injury, including neuronal ischemia, hypoxia, traumatic brain injury, neonatal asphyxia, cardiopulmonary bypass-associated neuronal injury and postoperative cognitive dysfunction (POCD) [26-33].

Xenon-mediated neuroprotection could be of particular interest in paediatric anaesthesia because epidemiologic studies have recently documented a correlation between anaesthetic exposure at a young age and subsequent learning difficulties and specific neurologic deficits [34-37]. Of note, xenon has been demonstrated to attenuate isoflurane-induced neuro-degeneration in rats [38,39]. In paediatric anaesthesia, exposure to sevoflurane is a well-known risk factor for the occurrence of emergence delirium after general anaesthesia in preschool children. Emergence delirium occurs in up to 80% of the anaesthetized children, has been associated with a prolonged stay in the postoperative care unit, can result in self-injury and has been linked to maladaptive behavioural changes during the late post-operative period. As the addition of xenon helps to reduce the sevoflurane concentrations and as the mechanism of anaesthesia of xenon is fundamentally different from that of sevoflurane, the incidence of emergence delirium could therefore be reduced [40].

The efficacy and safety of xenon for general anaesthesia has been repeatedly demonstrated in clinical trials, resulting in the medicolegal approval by the European Medicines Agency (EMA) in 2007.

Unfortunately, xenon has not been approved yet as an anaesthetic for children 0 to 18 years of age, most probably due to a paucity of clinical data that are required for a marketing approval. Up to now, there is no indication that xenon is associated with detrimental effects in children. In contrast, there is increasing evidence that xenon is also remarkably safe in the neonatal/paediatric population. Numerous studies have proven that xenon offers long-term functional and histopathologic neuroprotection in rodents after neonatal hypoxia/ischemia [26-28]. Also, in asphyxiated new-born pigs, xenon enhances hypothermic neuroprotection and offers stable haemodynamics [41,42]. Based on these animal data, two clinical trials are currently recruiting human neonates in the UK: one in which the effect of inhaled xenon (combined with therapeutic hypothermia) is evaluated in new-born infants with hypoxic-ischaemic encephalopathy (NCT01545271) and a second trial assessing whether following perinatal asphyxia, a combination therapy of inhaled xenon and hypothermia can preserve cerebral metabolism and structure (NCT00934700).

Up to now, the minimum alveolar concentration (MAC) of xenon required to produce anaesthesia in children is unknown. In adults, the MAC of xenon has been determined to be 63% [43]. It has to be assumed that - in accordance with other volatile or gaseous anaesthetics - the MAC of xenon in children is higher than in adults. Given a minimum requirement of 30% inhaled oxygen in ventilated patients, xenon mono-anaesthesia will be difficult to achieve in the paediatric population. Hence, xenon administration to children probably will have to be performed with sub-anaesthetic doses that will be applied in adjunction to the established anaesthetic sevoflurane. Such a strategy is associated with several advantages:

It has been repeatedly demonstrated that xenon interacts additively with other anaesthetics, which allows a significant dose reduction of the anaesthetics to which xenon is added and results in less haemodynamic compromise [44,45]. Further, in the majority of animal experiments, xenon has been demonstrated to exert its cardio- and neuroprotective effects already in sub-anaesthetic concentrations [0.25-0.5 MAC], suggesting that organ protection can be achieved independently from anaesthetic effects. In rats, it has been shown that the combination of xenon and sevoflurane preconditioning induces long-term neuroprotection in neonatal asphyxia [46]. Due to the scarcity of xenon (air contains only 87 ppb xenon), xenon anaesthesia is extremely costly. The combination of xenon with sevoflurane may be suited to reduce xenon consumption and associated costs without compromising xenon’s organ protective effects.