NEW ANAESTHETIC STRATEGIES FOR PAEDIATRIC AND FOETAL INTERVENTIONS TO IMPROVE HAEMODYNAMIC STABILITY AND NEUROCOGNITIVE OUTCOME

General anesthesia in young children has reached such a level of safety in terms of immediate outcome that indications are growing disproportionally. General anesthesia is increasingly used to provide not only ideal and safe conditions for invasive surgical interventions, but also for diagnostic and interventional procedures. With the advances in prenatal diagnosis and therapy, the indications for fetal surgery continue to expand, and anesthesia is even applied to the unborn fetus.

Unfortunately, even modern anesthetic agents have important side effects in the pediatric and fetal population, including eventual neurotoxicity and hemodynamic depression. Neurotoxicity has been repeatedly described for all commonly used anesthetics in mammalian models, including rodents, piglets and non-human primates. Animals exposed to anesthetics during the brain growth spurt showed an increase in neuronal apoptosis, and neonatal exposure has been associated with detrimental effects on short- and long-term neurodevelopmental outcome.(1)Several retrospective studies in humans have yielded inconclusive results, but suggest a strong association between exposure to anesthesia in early infancy and deterioration in neurodevelopmental outcomes.(2-5)Potential neuroprotective strategies against anesthesia-induced toxicity in the developing brain are to be identified. In pre-clinical studies, several pharmacological agents (magnesium, melatonin, xenon,…) have been described to protect the developing brain from harm. The clinical relevance of these experimental findings is difficult to determine, since translation from observations in animals to clinical practice in humans remains complex. As a second matter of concern, all commonly used volatile anesthetic agents (VA) have dose-dependent negative inotropic effects.VA cross the placenta rapidly and have a direct depressant effect on the fetal cardiovascular system. Low concentrations (1-1,5 minimal alveolar concentration (MAC)) have minimal fetal effects in animal models, but high concentrations may result in fetal acidosis.(6)During human fetal surgery, Rychik et al reported marked cardiac changes (decreased cardiac output, depressed systolic ventricular function, and tricuspid and mitral valve insufficiencies) in fetuses with an otherwise normal cardiovascular system. The authors concluded that the impairment of myocardial performance was most probably owing to the high levels of (2 MAC) VA administered to the mother.(7)Moreover, increased sensibility to VA during pregnancy and the high-dose VA used to ensure appropriate uterine relaxation lead to a decrease of maternal cardiac output and a subsequent decrease of uterine blood flow, reduced cardiac function and bradycardia in the fetus. 

In this perspective, we want to test whether using the noble gas XENONas adjuvant to other anesthetics can reduce neurotoxicity and improve cardiovascular stability in PEDIATRICand FETAL ANESTHESIA. 

Since xenon has repeatedly been demonstrated to offer neuroprotection in various models of neuronal injury, xenon-anesthesia could be of particular interest in pediatric and fetal anesthesia.(8-15)Even in the context of anesthetic-induced neurotoxicity, xenon has been demonstrated to exhibit specific neuroprotective properties by attenuating isoflurane-induced neurodegeneration in rats.(16,17)

In addition and in contrast to the majority of conventionally used general anaesthetics, xenon is virtually devoid of negative inotropic effects.(18-20)Furthermore, xenon was shown to have only minimal hemodynamic side effects when compared to VA or intravenous anaesthetics.(21)Xenon’s unique hemodynamic profile is most probably due to the fact that xenon exhibits less sympathicolysis than other anaesthetics, resulting in a better preservation of cardiac contractility, preload and afterload.(18,22-25)This could be of primordial relevance for children undergoing specific interventions known to be associated with a particular risk for intra-procedural hemodynamic instability and during fetal interventions in order not to jeopardize maternal, placental and fetal hemodynamics.

Until now, clinical data on the use of xenon in children are scarce. There is however no indication that xenon is associated with detrimental effects in children. In contrast, there is increasing evidence that xenon is remarkably safe also in the neonatal/pediatric population. Numerous studies have proven that xenon offers long-term functional and histopathologic neuroprotection in rodents after neonatal hypoxia/ischemia. 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-ischemic encephalopathy (NCT01545271). A second trial assesses whether following perinatal asphyxia a combination therapy of inhaled xenon and hypothermia can preserve cerebral metabolism and structure (NCT00934700). In order to guarantee the administration of at least 30% oxygen, xenon can be administered in concentrations of maximally 60-70%. Due to its low potency, these concentrations are sub-anesthetic in children. Hence, xenon will have to be delivered 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 hemodynamic compromise.(26-28)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.(26)And a last advantage of adding xenon to sevoflurane is the reduction of xenon consumption and associated costs without compromising xenon’s organ protective effects, because due to the scarcity of xenon (air contains only 87 ppb xenon), xenon is extremely costly. 

Up to now, however, xenon has not been tested in human pediatric anesthesia or in the context of fetal surgery (neither in animals nor in humans). The proposed project will therefore deliver original and first-ever data.