In Reply

Abstract

In our recently published article, “Intranasal application of xenon reduces opioid requirement and postoperative pain in patients undergoing major abdominal surgery: A randomized controlled trial,”1we have reported data showing beneficial effects of intranasally applied xenon on intraoperative opioid requirement and postoperative analgesia in patients undergoing abdominal hysterectomy. Beside these main results we have also described the pharmacokinetic of intranasally applied xenon using blood gas analyses. We would like to thank Petrenko and Baba for their interest in our work. We are very pleased to provide additional information regarding our study results and are thankful for the opportunity to extend the discussion about the pharmacokinetic of intranasally applied xenon.In their letter to the editor, Petrenko and Baba question to what extent the xenon concentrations measured in the internal jugular vein of volunteers really reflect the xenon content in cranial blood and target brain tissue under clinical conditions. In addition, they raise the important question whether and in which way lipophilic drugs can reach the brain using a nose-to-brain bypass. Moreover, they discuss the probability that an accumulation of xenon in the anesthesia circuit might be essential for the analgesic effect described in our study.Concentrations of xenon measured in the venous blood of the sagittal sinus of seven anesthetized pigs2or the internal jugular vein (IJV) of two volunteers1reached a steady state of approximately 500 nl/ml after 10 min of intranasal application. There were no reliable differences between xenon concentrations in the venous blood comparing the intracranial sagittal sinus and the brain-draining IJV (fig. 1).A wealth of proof-of-principle studies have already reported nose-to-brain delivery of a range of different drugs in animal models and volunteers. Thus the various pathways that a drug can follow from the nasal cavity to reach the cerebrospinal fluid or the brain tissue have been discussed thoroughly.3,4It is suggested in the literature that a drug administered nasally is able to reach the central nervous system by neural (olfactory, trigeminal) pathways or the bloodstream. Nevertheless, the mechanisms of transport of drugs from the nose to the brain are not yet completely understood. Considering the monoatomic and highly lipophilic nature of xenon as well as the fast wash-in kinetic of nasally applied xenon, we favored a blood-based route of action. However, a neural-related pathway or a combination of different routes cannot be excluded.As stated in our article, the blood gas analyses in both species (pigs, volunteers) were accomplished under comparable conditions.1Blood gas analyses in volunteers served as a preparation of the clinical trial investigating patients undergoing abdominal surgery. To mimic the clinical conditions in the operation theater as closely as possible, the two volunteers were also anesthetized and mechanically ventilated during the blood gas assessment. Two different anesthesia workstations (Draeger Primus [Drägerwerk AG, Lübeck, Germany] for volunteers vs. Draeger Cicero [Drägerwerk AG] for pigs) and different ventilator settings (oxygen flow 300 ml/min for volunteers vs. 1,000 ml/min for pigs) were used in these studies. The concentrations of xenon measured in the blood of mechanically ventilated volunteers and pigs reached a plateau after a few minutes (IJV and sagittal sinus). In addition, under conditions that resemble the clinical setting, peripheral venous (volunteers) and arterial (pigs) xenon concentrations never exceeded 20 nl/ml.2,1Since the measured concentrations of xenon in the blood (IJV and sagittal sinus) of mechanically ventilated study subjects are obviously independent of the ventilator settings, and peripheral xenon concentrations barely reached the quantification limit, we conclude that a relevant accumulation of xenon in the anesthetic circuit is rather unlikely.Given that a relevant portion of xenon was rebreathed, as discussed by Petrenko and Baba, we would expect a continuous increase of xenon concentrations over time and a time-dependent increase of peripheral xenon concentrations. However, this was not the case. We also must consider that because of their defect in xenon tightness (e.g. , caused by silicon tubes), the employed anesthesia workstations are inappropriate for the inhalative application of xenon using an indirect xenon supply at a rate of only 1 l/h.Aside from the discussion about the pharmacokinetics, we would also like to emphasize that there is no evidence for the assumption that clinically relevant effects of xenon are generally limited to blood concentrations in the micromolar range. Note that even approximately 150 nl xenon/ml blood in the IJV are sufficient to suppress pain-related processes of central sensitization.5As mentioned by Petrenko and Baba, every additional application device will complicate the daily anesthetic procedure. Moreover, we have to keep in mind that the maximum amount of xenon uptake using this novel route of application is limited by the available surface of intranasal structures. Therefore we agree with the excellent suggestion that further studies are needed to evaluate the breakeven point between analgesic benefit and economic reality using inhalatively applied xenon in several subanesthetic concentrations.