To the Editor: 

Intranasal application of low-dose xenon has recently been reported to have beneficial effects on perioperative analgesia in patients undergoing abdominal hysterectomy.1This is a novel route of xenon application that could help to circumvent the problem of its high cost and allow wider use of this gaseous anesthetic. However, we have several concerns regarding the pharmacokinetics and route of action of intranasally applied xenon suggested by the authors.

As shown by blood gas analysis undertaken by the authors in two healthy volunteers, a steady-state concentration of approximately 500 nl/ml xenon was reached in the blood of the internal jugular vein (IJV) within 10 min after commencement of intranasal delivery of xenon at 1 l/h. Simultaneously, as stated by the authors, samples of peripheral venous blood were ⩽20 nl/ml xenon. The authors consider the concentration of xenon in the IJV to be a reflection of xenon content in cranial blood and target brain tissue.

Here, as well as in their previous work,2the authors advocate a direct delivery route of xenon from the nose to brain that is supposedly accountable for the beneficial effects of xenon on pain. Although it is not clearly explained in their article, the authors previously suggested that xenon could reach brain tissue by diffusion from the venous sinuses of the cranial cavity.2 

A portion of nasal venous blood is indeed diverted to intracranial veins via  direct communication between the ophthalmic veins, pterygoid plexus, and cavernous sinus, but the other portion of blood is drained extracranially by facial veins directly into the IJV. Stated differently, the cavernous sinus receives only a portion of xenon-enriched blood from the nasal space, but the IJV collects almost all the blood from it. Therefore, a steady concentration of xenon in the IJV 10 min after intranasal application in volunteers is more a reflection of saturation of the nasal mucosa and nasal (not cranial) venous vascular beds with xenon. The actual concentration of xenon in the cavernous sinus is probably less than 500 nl/ml because the latter collects only a portion of nasal venous blood. Furthermore, although the cavernous sinus does communicate with basilar and superficial cortical veins, it is a “blood collector” that is ultimately drained into the IJV, and retrograde flow of xenon-containing blood toward cortical matter is very unlikely. Diffusion from the sinus itself to surrounding brain tissue and then to the rest of the brain is also unlikely.

Therefore, a likely explanation of how xenon was delivered to the brain, and possibly the spinal cord, to mediate its analgesic effects would be transport with arterial blood from the left heart.

Blood collected from the IJV in the right heart passes through the lungs, so the larger part of xenon will be rapidly exchanged with alveolar air and eventually lost with exhaled gas in spontaneously breathing volunteers or in study subjects mechanically ventilated with relatively high minute volumes. Indeed, as evidenced by a pharmacokinetic study undertaken by the same research team in anesthetized pigs (minute volume, about 5 l/min), arterial blood levels of xenon were ⩽20 nl/ml in this setting.3Clearly, and considering that clinically relevant anesthetic concentrations of xenon are in the micromolar range, the likelihood of such concentrations of xenon exerting clinically significant effects is very unlikely. Hence, the next question would be how intranasally delivered xenon could have reached target tissues at concentrations capable of improving (though only minimally) intraoperative analgesia and reduced postoperative pain reported in their article? Here, in our view, is one feasible explanation.

Given the usage of endotracheal tubes with inflatable cuffs impermeable to xenon, the authors allege that direct pulmonary contamination with xenon was avoided. However, did they consider that xenon-containing central venous blood would be diverted to the lungs? Here, xenon would readily escape into the alveolar space by diffusion because of its very low blood-gas partition coefficient4and would accumulate in the anesthetic circuit operated in the minimal-flow ventilation (oxygen flow, 300 ml/min) mode that the authors used. In our view, what the authors intended to present as solely intranasal delivery of anesthetic gas turned into inhalational anesthesia with rebreathed low-dose xenon. We think that the authors should not have limited the pharmacokinetic study to volunteers only; xenon concentrations in the anesthetic gas mixture and in the arterial blood of study subjects should also have been determined.

Finally, if the beneficial effects of low-dose xenon described in their article are indeed clinically significant and if our assumption is correct, then there is probably no need to complicate the anesthetic procedure and administer xenon intranasally. A conventional inhalational route of low-dose xenon (e.g. , 15–20 ml/min) implemented as a part of low- or minimal-flow, closed-circuit anesthesia should be more than sufficient to benefit from xenon as an addition to the anesthetic protocol.

Xenon is a valuable anesthetic and we appreciate the authors' efforts to overcome the limitation of its high cost by administering it at low-dose to use it more widely in clinical practice. However, would low-dose xenon result in better analgesia compared with inhalational anesthetics applied at conventional doses (not at 0.5 minimal alveolar concentration desflurane, as tested in their article) or in combination with nitrous oxide; or would the difference be insignificant if xenon is applied at a low dose? These are the questions that have to be answered in the future.

Holsträter TF, Georgieff M, Föhr KJ, Klingler W, Uhl ME, Walker T, Köster S, Grön G, Adolph O: Intranasal application of xenon reduces opioid requirement and postoperative pain in patients undergoing major abdominal surgery: A randomized controlled trial. ANESTHESIOLOGY 2011; 115:398–407
Adolph O, Köster S, Georgieff M, Bäder S, Föhr KJ, Kammer T, Herrnberger B, Grön G: Xenon-induced changes in CNS sensitization to pain. Neuroimage 2010; 49:720–30
Froeba G, Georgieff M, Linder EM, Föhr KJ, Weigt HU, Holsträter TF, Kölle MA, Adolph O: Intranasal application of xenon: Describing the pharmacokinetics in experimental animals and the increased pain tolerance within a placebo-controlled experimental human study. Br J Anaesth 2010; 104:351–8
Goto T, Suwa K, Uezono S, Ichinose F, Uchiyama M, Morita S: The blood-gas partition coefficient of xenon may be lower than generally accepted. Br J Anaesth 1998; 80:255–6