John Dingley

Xenon and Hypothermia Combine Additively, Offering Long-Term Functional and Histopathologic Neuroprotection After Neonatal Hypoxia/Ischemia

Background and Purpose— Hypoxic/ischemic (HI) brain injury affects 1 to 6 per 1000 live human births, with a mortality of 15% to 20%. A quarter of survivors have permanent disabilities. Hypothermia is the only intervention that improves outcome; however, further improvements might be obtained by combining hypothermia with additional treatments. Xenon is a noble anesthetic gas with an excellent safety profile, showing great promise in vitro and in vivo as a neuroprotectant. We investigated combinations of 50% xenon (Xe50%) and hypothermia of 32°C (HT32°C) as a post-HI therapy. Methods— An established neonatal rat HI model was used. Serial functional neurologic testing into adulthood 10 weeks after injury was performed, followed by global and regional brain histopathology evaluation. Results— In the combination Xe50%HT32°C group, complete restoration of long-term functional outcomes was seen. Hypothermia produced improvement on short- (P<0.001) and long- (P<0.001) term functional testing, whereas Xe50% alone predominantly improved long-term function (P<0.05), suggesting that short-term testing does not always predict eventual outcome. Similarly, the Xe50%HT32°C combination produced the greatest (71%) improvement in global histopathology scores, a pattern mirrored in the regional scores, whereas Xe50% and HT32°C individually produced smaller improvements (P<0.05 and P<0.001, respectively). The interaction between the 2 treatments was additive. Conclusions— The xenon/hypothermia combination additively confers greater protection after HI than either treatment alone. The functional improvement is almost complete, is sustained long term, and is accompanied by greatly improved histopathology. The unique safety profile differentiates xenon as an attractive combination therapy with hypothermia to improve the otherwise bleak outcome from neonatal HI.

Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia.

Hypothermia (HT) improves outcome after neonatal hypoxia–ischemia. Combination therapy may extend neuroprotection. The noble anesthetic gas xenon (Xe) has an excellent safety profile. We have shown earlier that 3 h of 50% Xe plus HT (32°C) additively gives more protection (72%) than either alone (HT = 31.1%, Xe = 10.2%). Factors limiting clinical use include high-cost and specialist administration requirements. Thus, combinations of 1 h of 50% Xe were administered concurrently for either the first (1 hImmediateXe) or last (1 hDelayedXe) of 3 h of posthypoxic–ischemic HT as compared with 3 h of 50% Xe/HT to investigate how brief Xe exposure with a delay would affect efficacy. An established neonatal rat hypoxia–ischemia model was used. Serial functional neurologic testing into adulthood was performed, followed by neuropathological examination. Xenon with HT was more effective with longer Xe duration (3 h versus 1 h) (P = 0.015). However, 1 h Xe/3 h HT resulted in better neuroprotection than 3 h HT alone (P = 0.03), this significant effect was also present with 1 h Xe after a 2-h delay. One (immediate or with a delay) or 3 h Xe also significantly improved motor function (P= 0.024). Females had significantly better motor scores than males, but no sex-dependent difference in pathology results. The neuroprotection of short, delayed Xe treatment would allow transport to specialist facilities to receive Xe.

Xenon Enhances Hypothermic Neuroprotection in Asphyxiated Newborn Pigs

To investigate whether inhaling 50% xenon during hypothermia (HT) offers better neuroprotection than xenon or HT alone.

Exploration of xenon as a potential cardiostable sedative: a comparison with propofol after cardiac surgery

Xenon anaesthesia is thought to have minimal haemodynamic side‐effects. It is, however, expensive and requires special delivery systems for economic use. In this randomised cross‐over study, we: (i) investigated the haemodynamic profile and recovery characteristics of xenon compared with propofol sedation in postoperative cardiac surgery patients, and (ii) evaluated a fully closed breathing system to minimise xenon consumption. We demonstrated a significantly faster recovery from xenon (3 min 11 s) than propofol sedation (25 min 23 s). Relative to propofol, xenon sedation produced no change in heart rate or mean arterial pressure and there were significantly higher mean values for central venous pressure (10.6 vs. 8.9 mmHg), pulmonary artery occlusion pressure (11.2 vs. 9.5 mmHg), mean pulmonary artery pressure (20.1 vs. 18.3 mmHg) and systemic vascular resistance index (2170 vs. 1896 dyn.s.cm−5.m−2). The haemodynamic profile seen with propofol reflected its known vasodilator effects. This was supported by the almost identical left ventricular stroke work indexes seen with both methods of sedation.

Xenon: recent developments

Xenon is the Greek word for stranger. The gas was discovered by Ramsay and Travers in 1898 in the residue left after evaporating liquid air components. It was originally labelled, with others, an inert gas but after discovery of some compounds this group was renamed the noble gases in 1962. It is the heaviest stable gas in this group and the only one which is anaesthetic under normobaric conditions [1]. Xenon constitutes 0.0000087% of the atmosphere, which is estimated to contain around 400 million tonnes. An average room contains about 4 ml. Based on the assumption that the relative distribution of all elements on all planets in the solar system is roughly the same, the earth’s atmosphere contains about 2000 times less than expected. It is manufactured by fractional distillation of air, costing around 2000 times as much as nitrous oxide. Where possible it is recycled, e.g. from old computer displays. It is used in lasers, high-intensity lamps, flash bulbs, space applications, X-ray tubes and medicine (imaging, anaesthesia). As an anaesthetic it exhibits many of the features of the ideal agent. Xenon has been used for routine clinical anaesthesia in Russia, Germany, the Netherlands and

A comparative study of the incidence of sore throat with the laryngeal mask airway

In a prospective study of 150 patients randomly assigned to three groups, we have compared the incidence and duration of sore throat after a standard anaesthetic regimen using three different methods of airway management: facemask; laryngeal mask, and laryngeal mask with insertion aid. The insertion aid is currently being developed by Portex Ltd and is intended both to facilitate accurate placement of the laryngeal mask and to reduce trauma during insertion. All the patients were women undergoing short operative procedures requiring minimal postoperative analgesia. The incidence of sore throat was significantly less with a facemask (8%) than with the laryngeal mask when used without the insertion aid (28.5%) (p < 0.02). When using the insertion aid the incidence was 18% and this was not statistically different from the facemask. The presence of blood on the laryngeal mask (22%) was less likely when the insertion aid was used (4%) (p < 0.02).

Use of xenon as a sedative for patients receiving critical care

ObjectiveMany sedative regimens are used in the intensive care setting, but none are wholly without adverse effect. Xenon is a noble gas with sedative and analgesic properties. It has been used successfully as a general anesthetic and has many desirable properties, not least of which is a minimal effect on the myocardium. In theory, xenon may provide sedation without adverse effect for certain groups of critically ill patients. The objective of this study was to assess the feasibility of using xenon as an intensive care sedative. DesignDouble-blind, randomized study. SettingTertiary-level intensive care unit. SubjectsTwenty-one patients admitted to an intensive care unit following elective thoracic surgery. InterventionsA standard intensive care sedation regimen (intravenous propofol at 0–5 mg·kg−1·hr−1 and alfentanil 30 &mgr;g·kg−1·hr−1) was compared with a xenon sedation regimen delivered using a novel bellows-in-bottle delivery system. Measurements and Main ResultsEach sedative regimen was continued for 8 hrs. The hemodynamic effects, additional analgesic requirements, recovery from sedation, and effect on hematological and biochemical variables were compared for the two sedation regimens. All patients were successfully sedated during the xenon regimen. The mean ± sd end-tidal xenon concentration required to provide sedation throughout the duration of the study was 28 ± 9.0% (range, 9–62%). Arterial systolic, diastolic, and mean pressures showed a greater tendency for negative gradients in patients receiving the propofol regimen (p < .05, p < .1, and p < .01, respectively). Recovery following xenon was significantly faster than from the standard sedation regimen (p < .0001). Hematological and biochemical laboratory markers were within normal clinical limits in both groups. ConclusionsXenon provided satisfactory sedation in our group of patients. It was well tolerated with minimal hemodynamic effect. Recovery from this agent is extremely rapid. We have demonstrated the feasibility of using xenon within the critical care setting, without adverse effect.

A closed-circuit neonatal xenon delivery system: a technical and practical neuroprotection feasibility study in newborn pigs.

BACKGROUND: Asphyxia accounts for 23% of the 4 million annual global neonatal deaths. In developed countries, the incidence of death or severe disability after hypoxic-ischemic (HI) encephalopathy is 1–2/1000 infants born at term. Hypothermia (HT) benefits newborns post-HI and is rapidly entering clinical use. Xenon (Xe), a scarce and expensive anesthetic, combined with HT markedly increases neuroprotection in small animal HI models. The low-Xe uptake of the patient favors the use of closed-circuit breathing system for efficiency and economy. We developed a system for delivering Xe to mechanically ventilated neonates, then investigated its technical and practical feasibility in a previously described neonatal pig model approximating the clinical scenario of global HI injury, prolonged Xe delivery with and without HT as a potential therapy, subsequent neonatal intensive care unit management, and tracheal extubation. METHODS: Sixteen newborn pigs underwent a global 45 min HI insult (4%–6% inspired oxygen reducing the electroencephalogram amplitude to <7 &mgr;V), then received 16 h 50% inspired Xe during normothermia (39.0°C) or HT (33.5°C). A conventional neonatal ventilator provided breaths of oxygen to a lower chamber compressing a hanging bag within. This bag communicated with the upper closed part of the breathing system containing soda lime, unidirectional valves, Xe/oxygen analyzers, and a tracheal tube connection. At each end-inspiration, this bag emptied fully and a bolus of oxygen, the driving gas, crossed from the lower to upper chamber via an additional valve. This mechanically substituted the gas uptake from the circle during the previous breath cycle (oxygen + small volume of Xe) with an equivalent volume of oxygen creating a slow-rising inspired oxygen concentration. This was offset by manual injection of Xe boluses, infrequently at steady state, due to the low-Xe uptake of the patient. RESULTS: Total mean Xe usage was 0.18 (0.16–0.21) L/h with no differences between Xe-HT and Xe-NT groups, which had weights of 1767 (1657–1877) g and 1818 (1662–1974) g, respectively (95% CI). HT reduced heart rate in the cooled animals; 180 (165–195) vs 148 (142–155) bpm (P < 0.0001) with no differences in arterial blood pressure, oxygen saturation, arterial carbon dioxide tension, or weaning times between these groups. CONCLUSION: We describe a closed-circuit Xe delivery system with automatic mechanical oxygen replenishment, which could be developed as a single use device. Gas exchange was maintained while Xe consumption was minimal (<

Blood volume determination by the carbon monoxide method using a new delivery system: accuracy in critically ill humans and precision in an animal model.

2/h at

Insertion methods of the laryngeal mask airway. A survey of current practice in Wales.

10/L*). We have shown it is both feasible and cost-efficient to use this Xe delivery method in newborn pigs for up to 16 h with or without concurrent cooling after a severe HI insult.