Xenon Antiaggregant Effects.

In in vitro model of short-term therapeutic inhalation of Xe/O2 mixture, xenon in millimolar concentrations led to a pronounced decrease in induced platelet aggregation in the platelet-enriched blood plasma. The maximum and statistically significant decrease occurred in response to induction by collagen (by ≈30%, p≤0.01) and ADP (by ≈25%, p≤0.01). A slightly weaker but statistically significant reduction in aggregation appeared in response to ristocetin (by ≈12%, p≤0.01) and epinephrine (by ≈9%, p≤0.01). It should be noted that the spontaneous aggregation exceeded the reference values in the control group. Nevertheless, even at minimal absolute values, spontaneous platelet aggregation decreased by 2 times in response to xenon (p≤0.01). The reasons for the decrease of spontaneous and induced aggregation are xenon accumulation in the lipid bilayer of the membrane with subsequent nonspecific (mechanical) disassociation of membrane platelet structures and specific block of its distinct from neuronal NMDA receptor.

Combining a noble gas with radiotherapy: glutamate receptor antagonist xenon may act as a radiosensitizer in glioblastoma.

BACKGROUND: Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as a radiosensitizer in GB. METHODS: We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine. RESULTS: The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Indications for the presence of glutamate receptor subunits were present in glioblastoma-derived and HeLa cells. Significantly reduced clonogenic survival by xenon was shown in U87 and U251 at irradiation doses of 4-8 Gy and 2, 6 and 8 Gy, respectively (p < 0.05). Clonogenic survival was further reduced by the addition of memantine, showing a significant effect at 2-8 Gy for both glioblastoma cell lines (p < 0.05). Xenon did not significantly reduce the surviving fraction of HeLa cells until a radiation dose of 8 Gy. CONCLUSION: The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled indications of radiosensitizing properties of xenon gas in glioblastoma.

Effects of xenon anesthesia on postoperative neurocognitive disorders: a systematic review and meta-analysis.

The latest clinical trials have reported conflicting outcomes regarding the effectiveness of xenon anesthesia in preventing postoperative neurocognitive dysfunction; thus, this study assessed the existing evidence. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases from inception to April 9, 2023, for randomized controlled trials of xenon anesthesia in postoperative patients. We included English-language randomized controlled studies of adult patients undergoing surgery with xenon anesthesia that compared its effects to those of other anesthetics. Duplicate studies, pediatric studies, and ongoing clinical trials were excluded. Nine studies with 754 participants were identified. A forest plot revealed that the incidence of postoperative neurocognitive dysfunction did not differ between the xenon anesthesia and control groups (P = 0.43). Additionally, xenon anesthesia significantly shortened the emergence time for time to opening eyes (P < 0.001), time to extubation (P < 0.001), time to react on demand (P = 0.01), and time to time and spatial orientation (P = 0.04). However, the Aldrete score significantly increased with xenon anesthesia (P = 0.005). Postoperative complications did not differ between the anesthesia groups. Egger's test for bias showed no small-study effect, and a trim-and-fill analysis showed no apparent publication bias. In conclusion, xenon anesthesia probably did not affect the occurrence of postoperative neurocognitive dysfunction. However, xenon anesthesia may effectively shorten the emergence time of certain parameters without adverse effects.

Protein Kinase A Is Responsible for the Presynaptic Inhibition of Glycinergic and Glutamatergic Transmissions by Xenon in Rat Spinal Cord and Hippocampal CA3 Neurons.

The effects of a general anesthetic xenon (Xe) on spontaneous, miniature, electrically evoked synaptic transmissions were examined using the "synapse bouton preparation," with which we can clearly evaluate pure synaptic responses and accurately quantify pre- and postsynaptic transmissions. Glycinergic and glutamatergic transmissions were investigated in rat spinal sacral dorsal commissural nucleus and hippocampal CA3 neurons, respectively. Xe presynaptically inhibited spontaneous glycinergic transmission, the effect of which was resistant to tetrodotoxin, Cd2+, extracellular Ca2+, thapsigargin (a selective sarcoplasmic/endoplasmic reticulum Ca2+-ATPase inhibitor), SQ22536 (an adenylate cyclase inhibitor), 8-Br-cAMP (membrane-permeable cAMP analog), ZD7288 (an hyperpolarization-activated cyclic nucleotide-gated channel blocker), chelerythrine (a PKC inhibitor), and KN-93 (a CaMKII inhibitor) while being sensitive to PKA inhibitors (H-89, KT5720, and Rp-cAMPS). Moreover, Xe inhibited evoked glycinergic transmission, which was canceled by KT5720. Like glycinergic transmission, spontaneous and evoked glutamatergic transmissions were also inhibited by Xe in a KT5720-sensitive manner. Our results suggest that Xe decreases glycinergic and glutamatergic spontaneous and evoked transmissions at the presynaptic level in a PKA-dependent manner. These presynaptic responses are independent of Ca2+ dynamics. We conclude that PKA can be the main molecular target of Xe in the inhibitory effects on both inhibitory and excitatory neurotransmitter release. SIGNIFICANCE STATEMENT: Spontaneous and evoked glycinergic and glutamatergic transmissions were investigated using the whole-cell patch clamp technique in rat spinal sacral dorsal commissural nucleus and hippocampal CA3 neurons, respectively. Xenon (Xe) significantly inhibited glycinergic and glutamatergic transmission presynaptically. As a signaling mechanism, protein kinase A was responsible for the inhibitory effects of Xe on both glycine and glutamate release. These results may help understand how Xe modulates neurotransmitter release and exerts its excellent anesthetic properties.

Xenon's Sedative Effect Is Mediated by Interaction with the Cyclic Nucleotide-Binding Domain (CNBD) of HCN2 Channels Expressed by Thalamocortical Neurons of the Ventrobasal Nucleus in Mice.

Previous studies have shown that xenon reduces hyperpolarization-activated cyclic nucleotide-gated channels type-2 (HCN2) channel-mediated current (Ih) amplitude and shifts the half-maximal activation voltage (V1/2) in thalamocortical circuits of acute brain slices to more hyperpolarized potentials. HCN2 channels are dually gated by the membrane voltage and via cyclic nucleotides binding to the cyclic nucleotide-binding domain (CNBD) on the channel. In this study, we hypothesize that xenon interferes with the HCN2 CNBD to mediate its effect. Using the transgenic mice model HCN2EA, in which the binding of cAMP to HCN2 was abolished by two amino acid mutations (R591E, T592A), we performed ex-vivo patch-clamp recordings and in-vivo open-field test to prove this hypothesis. Our data showed that xenon (1.9 mM) application to brain slices shifts the V1/2 of Ih to more hyperpolarized potentials in wild-type thalamocortical neurons (TC) (V1/2: -97.09 [-99.56--95.04] mV compared to control -85.67 [-94.47--82.10] mV; p = 0.0005). These effects were abolished in HCN2EA neurons (TC), whereby the V1/2 reached only -92.56 [-93.16- -89.68] mV with xenon compared to -90.03 [-98.99--84.59] mV in the control (p = 0.84). After application of a xenon mixture (70% xenon, 30% O2), wild-type mice activity in the open-field test decreased to 5 [2-10] while in HCN2EA mice it remained at 30 [15-42]%, (p = 0.0006). In conclusion, we show that xenon impairs HCN2 channel function by interfering with the HCN2 CNBD site and provide in-vivo evidence that this mechanism contributes to xenon-mediated hypnotic properties.

[Xenon post-conditioning protects against spinal cord ischemia-reperfusion injury in rats by downregulating mTOR pathway and inhibiting endoplasmic reticulum stress-induced neuronal apoptosis].

OBJECTIVE: The purpose of this study was to determine whether xenon post-conditioning affects mTOR signaling as well as endoplasmic reticulum stress (ERS)-apoptosis pathway in rats with spinal cord ischemia/reperfusion injury. METHODS: Fifty male rats were randomized equally into sham-operated group (Sham group), I/R model group (I/R group), I/R model+ xenon post-conditioning group (Xe group), I/R model+rapamycin (a mTOR signaling pathway inhibitor) treatment group (I/R+ Rapa group), and I/R model + xenon post- conditioning with rapamycin treatment group (Xe + Rapa group).. In the latter 4 groups, SCIRI was induced by clamping the abdominal aorta for 85 min followed by reperfusion for 4 h. Rapamycin (or vehicle) was administered by daily intraperitoneal injection (4 mg/kg) for 3 days before SCIRI, and xenon post-conditioning by inhalation of 1∶1 mixture of xenon and oxygen for 1 h at 1 h after initiation of reperfusion; the rats without xenon post-conditioning were given inhalation of nitrogen and oxygen (1∶ 1). After the reperfusion, motor function and histopathologic changes in the rats were examined. Western blotting and real-time PCR were used to detect the protein and mRNA expressions of GRP78, ATF6, IRE1α, PERK, mTOR, p-mTOR, Bax, Bcl-2 and caspase-3 in the spinal cord. RESULTS: The rats showed significantly lowered hind limb motor function following SCIRI (P < 0.01) with a decreased count of normal neurons, increased mRNA and protein expressions of GRP78, ATF6, IRE1α, PERK, and caspase-3, and elevated p-mTOR/mTOR ratio and Bax/Bcl-2 ratio (P < 0.01). Xenon post-conditioning significantly decreased the mRNA and protein levels of GRP78, ATF6, IRE1α, PERK and caspase-3 (P < 0.05 or 0.01) and reduced p-mTOR/mTOR and Bax/Bcl-2 ratios (P < 0.01) in rats with SCIRI; the mRNA contents and protein levels of GRP78 and ATF6 were significantly decreased in I/R+Rapa group (P < 0.01). Compared with those in Xe group, the rats in I/R+Rapa group and Xe+Rapa had significantly lowered BBB and Tarlov scores of the hind legs (P < 0.01), and caspase-3 protein level and Bax/Bcl-2 ratio were significantly lowered in Xe+Rapa group (P < 0.05 or 0.01). CONCLUSION: By inhibiting ERS and neuronal apoptosis, xenon post- conditioning may have protective effects against SCIRI in rats. The mTOR signaling pathway is partially involved in this process.

Hyperbaric treatment of platelets extends in vitro storage to 14 days.

BACKGROUND: Platelets for transfusion have a storage time of 5-7 days at 22°C-24°C, which results in a strain on the supply chain and supply shortages. We describe a novel method to extend platelet storage using xenon (Xe) gas under high pressure and refrigeration. STUDY DESIGN AND METHODS: Apheresis platelets (APU) prepared in 65% platelet additive solution (PAS) were stored under standard conditions (SC) at 20°C-24°C to Day 5. Paired APUs were prepared with Xe and stored to Day 14 at 2°C-6°C under hyperbaric conditions (XHC). A standard panel of in vitro assays was conducted. RESULTS: XHC platelets were viable out to Day 14. The average pH of Day 14 platelets was 6.58, and 86% maintained some degree of swirl compared with 7.02 and 100% swirl for Day 5 SC platelets. The rate of glycolysis was reduced under XHC storage with less glucose consumption and lactate generation. Activation levels for Day 14 platelets, while increased, did not prevent response to agonists in vitro, including epinephrine + Adenosine 5-Diphosphate (EPI/ADP) and thrombin receptor-activating peptide (TRAP) aggregation. Thromboelastogram (TEG) assessment showed 80% or greater conservation of platelet function for Day 14 xenon stored platelets compared with Day 5 SC platelets. DISCUSSION: Platelet storage with the Xe/hyperbaric/cold method is a feasible candidate for extension of storage to 14 days based on in vitro characteristics. In vivo recovery and survival studies are indicated. The capability to extend platelet storage to 14 days would make large strides toward resolving issues of platelet outdating for prophylactic use.

Medical Gas Therapy for Tissue, Organ, and CNS Protection: A Systematic Review of Effects, Mechanisms, and Challenges.

Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable "biological gas" (CO, H2 , H2 S, NO, O2 , O3 , and N2 O) or "noble gas" (He, Ar, and Xe) treatment may preserve cells against common pathologies by regulating oxidative, inflammatory, apoptotic, survival, and/or repair processes. Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO-CO, HIF-1α/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF-1α/ERK activation. Primary findings also reveal that the need to utilize cutting-edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad-spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma.

Xenon treatment after severe traumatic brain injury improves locomotor outcome, reduces acute neuronal loss and enhances early beneficial neuroinflammation: a randomized, blinded, controlled animal study.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of morbidity and mortality, but there are no clinically proven treatments that specifically target neuronal loss and secondary injury development following TBI. In this study, we evaluate the effect of xenon treatment on functional outcome, lesion volume, neuronal loss and neuroinflammation after severe TBI in rats. METHODS: Young adult male Sprague Dawley rats were subjected to controlled cortical impact (CCI) brain trauma or sham surgery followed by treatment with either 50% xenon:25% oxygen balance nitrogen, or control gas 75% nitrogen:25% oxygen. Locomotor function was assessed using Catwalk-XT automated gait analysis at baseline and 24 h after injury. Histological outcomes were assessed following perfusion fixation at 15 min or 24 h after injury or sham procedure. RESULTS: Xenon treatment reduced lesion volume, reduced early locomotor deficits, and attenuated neuronal loss in clinically relevant cortical and subcortical areas. Xenon treatment resulted in significant increases in Iba1-positive microglia and GFAP-positive reactive astrocytes that was associated with neuronal preservation. CONCLUSIONS: Our findings demonstrate that xenon improves functional outcome and reduces neuronal loss after brain trauma in rats. Neuronal preservation was associated with a xenon-induced enhancement of microglial cell numbers and astrocyte activation, consistent with a role for early beneficial neuroinflammation in xenon's neuroprotective effect. These findings suggest that xenon may be a first-line clinical treatment for brain trauma.

Effects of xenon gas on human airway epithelial cells during hyperoxia and hypothermia.

BACKGROUND: Hypothermia with xenon gas has been used to reduce brain injury and disability rate after perinatal hypoxia-ischemia. We evaluated xenon gas therapy effects in an in vitro model with or without hypothermia on cultured human airway epithelial cells (Calu-3). METHODS: Calu-3 monolayers were grown at an air-liquid interface and exposed to one of the following conditions: 1) 21% FiO2 at 37°C (control); 2) 45% FiO2 and 50% xenon at 37°C; 3) 21% FiO2 and 50% xenon at 32°C; 4) 45% FiO2 and 50% xenon at 32°C for 24 hours. Transepithelial resistance (TER) measurements were performed and apical surface fluids were collected and assayed for total protein, IL-6, and IL-8. Three monolayers were used for immunofluorescence localization of zonula occludens-1 (ZO-1). The data were analyzed by one-way ANOVA. RESULTS: TER decreased at 24 hours in all treatment groups. Xenon with hyperoxia and hypothermia resulted in greatest decrease in TER compared with other groups. Immunofluorescence localization of ZO-1 (XY) showed reduced density of ZO-1 rings and incomplete ring-like staining in the 45% FiO2- 50% xenon group at 32°C compared with other groups. Secretion of total protein was not different among groups. Secretion of IL-6 in 21% FiO2 with xenon group at 32°C was less than that of the control group. The secretion of IL-8 in 45% FiO2 with xenon at 32°C was greater than that of other groups. CONCLUSION: Hyperoxia and hypothermia result in detrimental epithelial cell function and inflammation over 24-hour exposure. Xenon gas did not affect cell function or reduce inflammation.

Flow path system of ultraviolet C irradiation from xenon flash to reduce bacteria survival in platelet products containing a platelet additive solution.

BACKGROUND: Our previous study showed that ultraviolet C (UVC) from xenon (Xe) flash without any photoreactive compounds inactivated bacteria in platelet concentrates (PCs) with less damage to platelets (PLTs) as compared with Xe flash containing ultraviolet A, ultraviolet B, and visible light. Here, we report a UVC irradiation system for PCs under flow conditions consisting of a flow path-irradiation sheet, a peristaltic pump, and a collection bag. STUDY DESIGN AND METHODS: Platelet concentrates containing Ringer's solution (R-PCs) inoculated with bacteria were injected into a flow path sheet using a peristaltic pump, being irradiated with UVC from Xe flash. The quality of the irradiated PCs containing platelet additive solution (PAS-PCs) was assessed based on PC variables, PLT surface markers, and aggregation ability. RESULTS: Streptococcus dysgalactiae (12 tests) and Escherichia coli (11) were all negative on bacterial culture, while Staphylococcus aureus (12) and Klebsiella pneumoniae (14) grew in one and two R-PCs, respectively. Bacillus cereus spores were inactivated in 7 of 12 R-PCs. PC variables became significantly different between irradiated and nonirradiated PAS-PCs. P-selectin, first procaspase-activating compound (PAC-1) binding, and phosphatidylserine increased by irradiation. Aggregability stimulated by adenosine diphosphate, collagen, or thromboxane A2 increased in the irradiated PAS-PCs, while that by thrombin became smaller compared with nonirradiated controls. CONCLUSION: This newly developed system inactivated bacteria including spores in R-PCs. PAS-PCs irradiated by this system retained acceptable in vitro quality and aggregability. Usage of a peristaltic pump instead of agitator during irradiation may enable this system to be directly combined with an apheresis blood cell separator.

Effects of Xenon-Based Anesthetic Exposure on the Expression Levels of Polysialic Acid Neural Cell Adhesion Molecule (PSA-NCAM) on Human Neural Stem Cell-Derived Neurons.

Numerous studies suggest a long duration of anesthesia during the late gestation period and infancy is associated with an increased risk of neuronal damage and neurocognitive impairment. The noble gas xenon is an anesthetic that is reported to have neuroprotective effects in some circumstances at certain concentrations. Currently, the effects of xenon on the brain and its potential neuroprotective properties, and/or the effects of xenon used in combination with other anesthetics, are not clearly understood and some reported data appear contradictory. In the present study, human neural stem cells were employed as a human-relevant model to evaluate the effects of xenon when it was co-administered with propofol, a frequently used anesthetic in pediatric anesthesia, and to understand the mechanism(s). The expression of polysialic acid (PSA) neural cell adhesion molecule (NCAM) on human neural stem cell-differentiated neurons was investigated as a key target molecule. PSA is a specific marker of developing neurons. It is essential for neuronal viability and plasticity. Human neural stem cells were maintained in neural differentiation medium and directed to differentiate into neuronal and glial lineages, and were exposed to propofol (50 µM) for 16 h in the presence or absence of xenon (33%). The neural stem cell-derived neurons were characterized by labelling cells with PSA-NCAM, after 5 days of differentiation. Propofol- and/or xenon-induced neurotoxicities were determined by measuring PSA immunoreactivity. A time course study showed that neuronal cell surface PSA was clearly cleaved off from NCAM by endoneuraminidase N (Endo-N), and eliminated PSA immunostaining was not re-expressed 4, 8, or 16 h after Endo-N washout. However, in the presence of 33% xenon, intense PSA staining on neuronal cell surface and processes was evident 16 h after Endo-N washout. In addition, prolonged (16 h) propofol exposure significantly decreased the positive rate of PSA-labeled neurons. When combined with xenon, propofol's adverse effects on neurons were attenuated. This work, conducted on the human neural stem cell-derived models, has provided evidence of the beneficiary effects of xenon on neurons and helps develop xenon-based anesthesia regimens in the pediatric population.

The Effect of Xenon-Based Anesthesia on Somatosensory-Evoked Potentials in Patients Undergoing Carotid Endarterectomy.

OBJECTIVES: The aim of this study was to investigate the influence of xenon-based anesthesia on somatosensory-evoked potentials. DESIGN: Observational cohort study. SETTING: University hospital. PARTICIPANTS: Twenty subsequent adult patients undergoing elective carotid endarterectomy. INTERVENTIONS: Xenon-based anesthesia. MEASUREMENTS AND MAIN RESULTS: Cortical-evoked responses to median nerve stimulation were quantified by measurement of the amplitude and latency of the N20 wave, which are typically assessed during carotid surgery to detect intraoperative cerebral hypoperfusion and ischemia. Primary (N20 amplitude and latency) and secondary (mean arterial pressure, norepinephrine requirements and depth of anesthesia) were assessed during (1) propofol/remifentanil and (2) subsequent xenon/remifentanil anesthesia. Xenon at an inspiratory fraction of 62.5 ± 7% decreased norepinephrine requirement (0.067 ± 0.04 v 0.028 ± 0.02 µg/kg/min, p < 0.001), and mean arterial pressure was unchanged (90.6 ± 15.0 v 93.1 ± 9.6 mmHg, p = 0.40). Somatosensory-evoked potentials were available in all patients during xenon/remifentanil. Despite similar depth of anesthesia (Narcotrend index 38.4 ± 6.2 v 38.5 ± 5.8) during propofol and xenon, N20 amplitude was reduced after xenon wash-in from 3.7 ± 1.7 to 1.4 ± 2.8 µV, p < 0.001 on the surgical and 3.6 ± 1.6 to 1.4 ± 0.6 µV, p < 0.001 on the contralateral side. N20 latency remained unchanged during xenon (22.9 ± 2.1 v 22.5 ± 2.8 ms, p = 0.34 and 22.9 ± 2.0 v 22.9 ± 3.0, p = 0.97). CONCLUSIONS: Xenon influences somatosensory-evoked potentials measurement by reducing N20 wave amplitude but not latency. When xenon is considered as an anesthetic for carotid endarterectomy, wash-in needs to be completed before carotid surgery is commenced to provide stable baseline somatosensory-evoked potential measurement.

Noble gas neuroprotection: xenon and argon protect against hypoxic-ischaemic injury in rat hippocampus in vitro via distinct mechanisms.

BACKGROUND: Noble gases may provide novel treatments for neurological injuries such as ischaemic and traumatic brain injury. Few studies have evaluated the complete series of noble gases under identical conditions in the same model. METHODS: We used an in vitro model of hypoxia-ischaemia to evaluate the neuroprotective properties of the series of noble gases, helium, neon, argon, krypton, and xenon. Organotypic hippocampal brain slices from mice were subjected to oxygen-glucose deprivation, and injury was quantified using propidium iodide fluorescence. RESULTS: Both xenon and argon were equally effective neuroprotectants, with 0.5 atm of xenon or argon reducing injury by 96% (P<0.0001), whereas helium, neon, and krypton were devoid of any protective effect. Neuroprotection by xenon, but not argon, was reversed by elevated glycine. CONCLUSIONS: Xenon and argon are equally effective as neuroprotectants against hypoxia-ischaemia in vitro, with both gases preventing injury development. Although xenon's neuroprotective effect may be mediated by inhibition of the N-methyl-d-aspartate receptor at the glycine site, argon acts via a different mechanism. These findings may have important implications for their clinical use as neuroprotectants.

Better haemodynamic stability under xenon anaesthesia than under isoflurane anaesthesia during partial nephrectomy - a secondary analysis of a randomised controlled trial.

BACKGROUND: Renal dysfunction following intraoperative arterial hypotension is mainly caused by an insufficient renal blood flow. It is associated with higher mortality and morbidity rates. We hypothesised that the intraoperative haemodynamics are more stable during xenon anaesthesia than during isoflurane anaesthesia in patients undergoing partial nephrectomy. METHODS: We performed a secondary analysis of the haemodynamic variables collected during the randomised, single-blinded, single-centre PaNeX study, which analysed the postoperative renal function in 46 patients who underwent partial nephrectomy. The patients received either xenon or isoflurane anaesthesia with 1:1 allocation ratio. We analysed the duration of the intraoperative systolic blood pressure decrease by > 40% from baseline values and the cumulative duration of a mean arterial blood pressure (MAP) of < 65 mmHg as primary outcomes. The secondary outcomes were related to other blood pressure thresholds, the amount of administered norepinephrine, and the analysis of confounding factors on the haemodynamic stability. RESULTS: The periods of an MAP of < 65 mmHg were significantly shorter in the xenon group than in the isoflurane group. The medians [interquartile range] were 0 [0-10.0] and 25.0 [10.0-47.5] minutes, for the xenon and isoflurane group, respectively (P = 0.002). However, the cumulative duration of a systolic blood pressure decrease by > 40% did not significantly differ between the groups (P = 0.51). The periods with a systolic blood pressure decrease by 20% from baseline, MAP decrease to values < 60 mmHg, and the need for norepinephrine, as well as the cumulative dose of norepinephrine were significantly shorter and lower, respectively, in the xenon group. The confounding factors, such as demographic data, surgical technique, or anaesthesia data, were similar in the two groups. CONCLUSION: The patients undergoing xenon anaesthesia showed a better haemodynamic stability, which might be attributed to the xenon properties. The indirect effect of xenon anaesthesia might be of importance for the preservation of renal function during renal surgery and needs further elaboration. TRIAL REGISTRATION: ClinicalTrials.gov : NCT01839084. Registered 24 April 2013.

A trial of pulsed xenon ultraviolet disinfection to reduce Clostridioides difficile infection.

BACKGROUND: An intervention was designed to test whether the addition of an ultraviolet (UV) disinfection step after terminal cleaning would be helpful in reducing Clostridium difficile infection (CDI) rates in a real-world situation. METHODS: This study was a quasi-experimental design using 3 units as intervention units for the intervention and 3 similar units as control units. Intervention units 2 hematology and bone marrow transplant units and one medical-surgical unit at a large teaching hospital in the Midwest. UV disinfection was added after patient discharge and terminal cleaning in the intervention units. RESULTS: At baseline, CDI rates in the intervention and control arms were similar. During the 6 months of UV disinfection, the CDI rate in the intervention units decreased to 11.2 per 10,000 patient days, compared with 28.7 per 10,000 patient days in the control units (P = .03). In addition, the intervention units also saw a reduction in vancomycin-resistant enterococci acquisition. CONCLUSIONS: The addition of UV disinfection to the terminal cleaning resulted in a reduction in CDI that has been sustained over several months 2 years.

Xenon Combined With Hypothermia in Perinatal Hypoxic-Ischemic Encephalopathy: A Noble Gas, a Noble Mission.

Perinatal hypoxia-ischemia is a major cause of neonatal morbidity. It generates primary neuronal damage of the neonatal brain and later secondary damage when reperfusion of the ischemic brain tissue causes a surge of oxygen free radicals and inflammation. This post-hypoxic-ischemic brain damage is a leading cause of motor and intellectual disabilities in survivors. Research worldwide has focused on mitigating this injury. Mild or moderate hypothermia is the standard treatment in many centers. However, its benefit is modest and the search for combinatorial effective neuroprotectants continues. This review focuses on xenon as one such agent. The use of mild to moderate hypothermia is reviewed first. Then promising results on the use of xenon to potentiate the effect of hypothermia in in vitro and in vivo animal experiments are discussed. In the first feasibility study on human neonates, researchers found a significant benefit of using 50% xenon for 18 hours in addition to 72 hours of hypothermia. Yet, this additional benefit of xenon was lacking in a larger cohort study, potentially because xenon was used beyond six hours of birth. The future of using xenon is promising, but further clinical studies are awaited to confirm the feasibility of its routine use and its optimal timing, concentration, and duration, for human neonatal hypoxia-ischemia.

Xenon-inhibition of the MscL mechano-sensitive channel and the CopB copper ATPase under different conditions suggests direct effects on these proteins.

Xenon is frequently used as a general anesthetic in humans, but the mechanism remains an issue of debate. While for some membrane proteins, a direct interaction of xenon with the protein has been shown to be the inhibitory mechanism, other membrane protein functions could be affected by changes of membrane properties due to partitioning of the gas into the lipid bilayer. Here, the effect of xenon on a mechanosensitive ion channel and a copper ion-translocating ATPase was compared under different conditions. Xenon inhibited spontaneous gating of the Escherichia coli mechano-sensitive mutant channel MscL-G22E, as shown by patch-clamp recording techniques. Under high hydrostatic pressure, MscL-inhibition was reversed. Similarly, the activity of the Enterococcus hirae CopB copper ATPase, reconstituted into proteoliposomes, was inhibited by xenon. However, the CopB ATPase activity was also inhibited by xenon when CopB was in a solubilized state. These findings suggest that xenon acts by directly interacting with these proteins, rather than via indirect effects by altering membrane properties. Also, inhibition of copper transport may be a novel effect of xenon that contributes to anesthesia.

Influence of xenon on pulmonary mechanics and lung aeration in patients with healthy lungs.

BACKGROUND: The anaesthetic xenon shows potent organ-protective properties. Due to high density and dynamic viscosity, peak inspiratory pressure (Pmax) increases during xenon application. Thus, barotrauma may counteract organ protection. Accordingly, we investigated the influence of xenon on lung mechanics and lung aeration in patients with normal and reduced thoracic wall compliance. METHODS: After registration and ethical approval, 20 patients free of pulmonary disease undergoing routine xenon-based anaesthesia were mechanically ventilated. The primary outcome variable transpulmonary pressure (Ptp) was determined from plateau pressure and intraoesophageal pressure before and after xenon wash-in. We recorded Pmax, and calculated airway resistance (RAW), and static (Cstat) and dynamic (Cdyn) respiratory compliances. Finally, lung aeration was quantified by electrical impedance tomography-derived centre of ventilation index (CVI) and global inhomogeneity index (GI) in the awake state, before and during xenon. RESULTS: Xenon increased Pmax [20.8 (SD 3) vs 22.6 (3) cm H2O, P<0.001] and RAW [0.9 (0.2) vs 1.4 (0.3) cm H2O litre-1 s, P<0.001], without affecting Ptp [1.5 (4) vs 2.0 (4) cm H2O, P=0.15]. While Cstat remained unchanged, Cdyn was reduced [33.9 (7) vs 31.2 (6) ml (cm H2O)-1, P<0.001). A ventral tidal volume shift after anaesthesia induction [CVI 0.53 (0.03) vs 0.59 (0.04), P<0.001] was unaltered during xenon [CVI 0.59 (0.04), P=0.29]. Homogeneity of lung aeration was also unchanged during xenon [GI 0.37 (0.03) vs 0.37 (0.03), P=0.99]. There were no clinically meaningful differential BMI-related effects. CONCLUSIONS: Xenon increases calculated airway resistance and peak inspiratory pressure without affecting transpulmonary pressure, independent of BMI. CLINICAL TRIAL REGISTRATION: NCT02682758.

Postconditioning effects of argon or xenon on early graft function in a porcine model of kidney autotransplantation.

BACKGROUND: Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Preconditioning, reconditioning and postconditioning with argon and xenon protects against renal ischaemia-reperfusion injury in rodent models. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function in a porcine renal autotransplant model was tested. METHODS: Pigs (n = 6 per group) underwent left nephrectomy after 60 min of warm ischaemia (renal artery and vein clamping). The procured kidney was autotransplanted in a separate procedure after 18 h of cold storage, immediately after a right nephrectomy. Upon reperfusion, pigs were randomized to inhalation of control gas (70 per cent nitrogen and 30 per cent oxygen), argon (70 per cent and 30 per cent oxygen) or xenon (70 per cent and 30 per cent oxygen) for 2 h. The primary outcome parameter was peak plasma creatinine; secondary outcome parameters included further markers of graft function (creatinine course, urine output), graft injury (aspartate aminotransferase, heart-type fatty acid-binding protein, histology), apoptosis and autophagy (western blot, terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining), inflammatory mediators and markers of cell survival/growth (mRNA and tissue protein quantification), and animal survival. Results are presented as median (i.q.r.). ANOVA and Kruskal-Wallis tests were used where indicated. RESULTS: Peak plasma creatinine levels were similar between the groups: control 20·8 (16·4-23·1) mg/dl, argon 21·4 (17·1-24·9) mg/dl and xenon 19·4 (17·5-21·0) mg/dl (P = 0·607). Xenon was associated with an increase in autophagy and proapoptotic markers. Creatinine course, urine output, injury markers, histology, survival and inflammatory mediators were not affected by the intervention. CONCLUSION: Postconditioning with argon or xenon did not improve kidney graft function in this experimental model. Surgical relevance Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Based on mainly small animal experiments, noble gases (argon and xenon) have been proposed to minimize this ischaemia-reperfusion injury and improve outcomes after transplantation. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function was tested in a porcine kidney autotransplantation model. The peak plasma creatinine concentration was similar in the control, argon and xenon groups. No other secondary outcome parameters, including animal survival, were affected by the intervention. Xenon was associated with an increase in autophagy and proapoptotic markers. Despite promising results in small animal models, postconditioning with argon or xenon in a translational model of kidney autotransplantation was not beneficial. Clinical trials would require better results.