JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

Anesth Analg 2009; 109:451-460
© 2009 International Anesthesia Research Society
doi: 10.1213/ane.0b013e3181aa9550
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Chakkarapani, E.
Right arrow Articles by Dingley, J.
PubMed
Right arrow Articles by Chakkarapani, E.
Right arrow Articles by Dingley, J.
Related Collections
Right arrow Drug Delivery
Right arrow Technology
Right arrow Pharmacology

TECHNOLOGY, COMPUTING, AND SIMULATION

A Closed-Circuit Neonatal Xenon Delivery System: A Technical and Practical Neuroprotection Feasibility Study in Newborn Pigs

Ela Chakkarapani, MRCPCH*, Marianne Thoresen, MD, PhD, FRCPCH*, Catherine E. Hobbs, PhD*, Kristian Aquilina, FRCS*, Xun Liu, PhD*, and John Dingley, MD{dagger}

From the *Department of Clinical Sciences at South Bristol, University of Bristol, Bristol; and {dagger}Division of Anaesthesia and Intensive Care, The Clinical School, University of Wales, Swansea, UK.

Address correspondence and reprint requests to Dr. J. Dingley, Department of Anaesthetics and Intensive Care Medicine, Morriston Hospital, Swansea SA6 6NL, UK. Address e-mail to j.dingley{at}swansea.ac.uk.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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 µV), 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 (<$2/h at $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.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Xenon (Xe) is a rare noble gas with anesthetic properties, also showing great promise as a neuroprotectant in both in vitro and in vivo experimental studies.1–8 Its mechanisms include preconditioning,8 antagonism of the N-methyl-d-aspartate subtype of glutamate receptor,9,10 and reduction of neurotransmitter release,1,11 among others.12 Severe hypoxic-ischemic (HI) brain injury occurs in 1–2/1000 live human births at term with permanent disability or death rates of 60%–70%.13 Brain injury develops after a destructive cascade lasting hours or days that includes "excitotoxic" apoptosis by prolonged activation of N-methyl-d-aspartate receptors,14 and this raises the possibility that an after insult therapy for newborn infants might be developed to limit the eventual damage. Currently, hypothermia (HT) is the only intervention that improves neurological outcome after HI injury both experimentally15–18 and clinically.19–21 Six infants must be treated with HT for one to derive a clear benefit (i.e., the "number needed to treat" is 6),19 so potential adjunctive therapies are of great interest.

Xe is an attractive adjunct to cooling due to its lack of chemical reactivity, minimal side effects,22,23 and ease of reversibility. Xe is not fetotoxic24,25 and has been used safely, although briefly, in newborns.26 The expense and scarcity are currently obstacles to widespread anesthetic use and need to be resolved if this gas is to enter clinical practice.

Both Xe and HT are antiexcitotoxic4,27,28 and antiapoptotic.4,29 The optimum Xe administration period required to maximize neuroprotection in the newborn is unclear, although HT is currently used clinically for up to 72 h. In our previous rodent studies, we found that 3 h of Xe inhalation had an additive neuroprotective effect with HT, increasing neuroprotection from 37% (HT only) to 76% when HT was combined with 50% inhaled Xe.7 Other rodent studies have suggested synergism between HT and Xe.4 The next step is to perform in vivo experiments more representative of the human neonate, and for this we need to develop and evaluate a suitably economical Xe delivery system.

Xe is extracted during industrial oxygen production from liquefaction of air at a relatively fixed rate of approximately 9–12 million L/yr. For Xe procurement alone, air liquefaction would be prohibitively expensive. The need to use Xe efficiently is therefore due not only to its expense but also to its scarcity and effectively fixed annual production. This cost, often quoted as $10/L,30 has led to the suggestion that despite "ideal anesthetic" characteristics, Xe could never enter clinical use.31 However, the paucity of effective neuroprotective interventions in the newborn and the promise of Xe in this regard caused us to consider how this potential drug might be used efficiently.

Xe is a relatively insoluble gas32 so, after initial loading or "wash-in," a state of near-equilibrium is rapidly attained. Subsequent patient uptake is thereafter very low (typically 2.5–4 L/h) in the human adult,33,34 suggesting that a cost-efficient clinical delivery system should be technically possible.35

A low-flow circle might appear a reasonable solution; however, if a 70% Xe anesthetic is administered for 2 h in an adult with a total fresh gas flow as low as 0.5 L/min, <20% of this Xe will be taken up, with more than 80% still being spilled as waste.30 Russian researchers have been obliged to use Xe recovery methods to mitigate losses with breathing systems of this type.36 The low-Xe uptake of the patient favors the use of closed-circuit (minimal flow) breathing systems for greatest efficiency, economy, and responsible use of this limited resource.

The primary objectives of this study were to (a) design an optimally gas-efficient closed-circuit Xe/O2 delivery system suitable, in principle, for use in ventilated neonates, (b) provide inherent safety against hypoxic gas mixtures without use of complex control systems, (c) evaluate its technical and practical feasibility with and without simultaneous HT in a previously described model approximating the real human clinical scenario of global neonatal HI injury, prolonged Xe delivery, subsequent neonatal intensive care unit (NICU) management, and tracheal extubation. Secondarily, we explored the effects of HT on Xe consumption.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The protocol was conducted under Home Office license in accordance with United Kingdom guidelines in Large White Landrace pigs <24 h old. To determine whether it was possible to deliver Xe alone and with cooling by this method in neonates after a global HI insult, two groups of eight animals were maintained and monitored before (baseline period), during (HI insult), and after (16 h Xe delivery) a severe, transient global HI insult produced using a previously described technique.17 During the after insult Xe delivery period, one group was maintained at normothermia, whereas the other was additionally cooled to a target temperature of 33.5°C. From pilot data, the selection of n = 16 animals led to a power of 0.8 for detecting a 20% difference between groups in Xe consumption, using an {alpha} of 0.05.

Equipment Design, Selection, and Technical Considerations
Three machines and monitoring systems were constructed for this study.

The Breathing System
If no fresh O2 is supplied to a conventional anesthesia circle system, the patient will consume all O2 present until a hypoxic mixture develops. Therefore, in a closed-circle system, fresh gases must be added at a rate exactly matching patient uptake of each gas. There are various ways to achieve this. In the simplest of closed underwater diving systems, the user will breathe pure O2 around a circuit similar to an anesthesia circle. In time, by metabolic O2 consumption, the reservoir bag will completely collapse part-way through an inspired breath. At this point, by continued inspiratory effort, a demand valve on an attached O2 cylinder will open, providing the missing volume of O2 to complete the inspiration phase. If we now imagine this circle to contain a mixture of Xe (slow uptake) and O2 (metabolic uptake), a different situation develops. It can be envisioned that substitution of these two uptake volumes with pure O2 at each end-inspiration would produce a slowly increasing inspired O2 fraction (Fio2). It was our intention to incorporate these concepts into a ventilator driven closed circuit in which a standard ventilator, set to deliver 100% O2 in each breath to the circuit, provided not only the motive power but also, via a special volume substitution valve, the required O2 replenishment in place of the demand valve in the diving example. When delivering a Xe/O2 mixture, there would then be a background tendency for the Fio2 to slowly increase, whereas the inspired Xe concentration would decrease at a similar rate. This would provide a degree of hypoxic mixture protection without use of O2 sensors, servo loops, or electronic valves, any of which could fail and produce a life-threatening situation. Xe could then be delivered to the circle by computer or manual control to offset this trend, replacing the minimal patient Xe uptake. The design of a circuit to achieve these design aims is described in Figures 1 and 2. All components of this closed-circuit breathing system are original designs with the exception of the flexible bag and patient connector (Intersurgical, Wokingham, UK).


Figure 126
View larger version (50K):
[in this window]
[in a new window]

  		Figure 1. Full neonatal closed-circuit assembly (overall height 122 cm). A neonatal ventilator set to deliver 100% O2 is attached to lower chamber of the circuit. During inspiration, bag (A) is compressed. Gas passes to upper part of machine, cannot pass through expiratory valve (B) so passes through soda lime (C), via inspiratory hose (D) and inspiratory valve (E) to patient connection (F) inflating the lungs. Gas monitoring includes xenon/O2 analyzer (G), auxiliary O2 analyzer (H), O2 cells for these analyzers (I,J), and a xenon sensor (K). Bag (A) fully empties before end-inspiration due to patient uptake of gas from circle during the previous breath cycle, at this moment O2 substitution valve (L) opens to replenish this volume deficit with O2. During expiratory cycle gas passes through expiratory valve (B) into bag (A). Aliquots of xenon from flexible bag (M) are manually added via a valve arrangement by pressing flexible bulb (N).

 


Figure 226
View larger version (34K):
[in this window]
[in a new window]

  		Figure 2. Mechanism of operation. Labeling matches Figure 1. Although pressure-controlled ventilation was used in the study, it is easier to describe mechanism in terms of volume-controlled ventilation. End-expiration (left): Lungs deflated, exhaled gas into bag (A) via expiratory valve (B). Bag only partially full (exaggerated in diagram). Gas volume in (A) slightly less than tidal volume set on ventilator due to gas uptake by patient during previous breathing cycle. Mid-inspiration (center): Bag A deflating, gas passing through soda lime, hose, inspiratory valve to lungs. Oxygen from ventilator entering lower chamber through an elongated port. This, by an entrainment effect on surrounding gas, creates a mild pressure reduction beneath the O2 substitution valve (L) ensuring it remains closed until end-inspiration without spring-loading. End-inspiration (right): Ventilator delivers remainder of tidal volume to lower chamber. Bag (A) is already empty so small aliquot of O2 driven through O2 substitution valve (L) into closed circuit so replacing gas volume consumed by patient. A safety valve spills gas from upper chamber to the lower if circle is overfilled for any reason (not shown).

 
The Xe delivery system is designed to be fitted between a conventional NICU mechanical ventilator (SLE 2000, SLE, South Croydon, UK) and the tracheal tube. The latex-free bag in the lower chamber has a volume of 500 mL, larger than a neonatal tidal volume, providing free space to accommodate added Xe bolus volumes without overspill. The removable soda lime canister has a volume of 800 mL permitting long periods of ventilation without replacement. The inspiratory and expiratory hoses are made of smooth bore medical polyurethane. Relative to conventional corrugated hoses these had minimal compliance and formed reliable leak-free connections.

In this design, a small aliquot of O2 enters the closed circle upper part of the circuit at each end-inspiration from a lower bag-in-bottle chamber (where it is present as the driving gas from the ventilator) via a dedicated O2 substitution valve.

Modern NICU ventilators maintain a bias gas flow throughout the breathing cycle. At end-expiration, this displaces any residual CO2 from the "Y" connector, reducing CO2 rebreathing. However, with a closed circuit, the absence of a bias flow combined with small neonatal tidal volumes means that an efficient self-closing, leak-free, low-opening pressure inspiratory valve was required to prevent rebreathing. Our inspiratory valve was derived from a military design (IDA71 diving rebreather, Russian Navy)*. A very thin valve disc was, by virtue of its negligible mass, adequately retained by a very fine coil-spring to provide the desired low opening pressure while retaining the ability to function in any orientation—important in this application as we sited it in the inspiratory hose close to the tracheal tube. Although reusable in this study (Fig. 1), the breathing system was designed to allow possible redevelopment as a molded single-use device, explaining, for example, the selection of a low-cost hanging bag rather than a vertical bellows. The compressible volumes of the complete upper closed circuit with soda lime and the lower bag-in-bottle chamber were 1100 and 2100 mL, respectively. These volumes were mainly dictated by the diameters of polycarbonate tubing available for construction, giving an overall system compliance of 3 mL/cm H2O. The design aims were that it should (a) be driven by a standard NICU ventilator, (b) avoid the need to develop a specialized Xe-specific ventilator, (c) have inherent hypoxic mixture prevention properties not dependent on electronics, (d) reduce misassembly risk, and (e) provide the user with the most intuitive treatment reversal method: reconnection of the neonate directly to the NICU ventilator.

Gas Delivery to Breathing System
This also followed the single-use concept. The slow-rising Fio2 tendency was deliberately offset by occasional manual delivery of Xe boluses to maintain the target Xe concentration; the combination of closed circuit, low patient weight, and low-Xe uptake suggest that these boluses should be infrequent. We have previously delivered Xe using high-pressure Xe cylinders with electronic valves actuated by both computer37 and manual control.23 After using servo control in the past, we realized that, because of the slow uptake of Xe, manual addition of Xe boluses should not be particularly onerous,23 facilitating a much simpler design devoid of any computer control systems. In this study with neonatal subjects, we anticipated a very low-Xe uptake and therefore adopted a manual method. On this occasion, it was designed to function at ambient pressure for additional simplicity and safety, eliminating any risk of the circle "flooding" with Xe due to a cylinder/regulator/electronic malfunction (Fig. 3).


Figure 326
View larger version (50K):
[in this window]
[in a new window]

  		Figure 3. Xenon delivery to closed circuit. Xenon cylinder is completely discharged (5 L Xe) into the flexible ambient pressure reservoir bag via stopcock (A) and self-sealing unidirectional valve (B). Flexible bulb (C) refills itself from the reservoir bag via unidirectional valve (D) and then by manual pressure on bulb (C) 50 mL xenon boluses can be delivered via unidirectional valve (E) into the breathing system as required.

 

This design, in turn, facilitated the use of small low-pressure cylinders of 5-L Xe to fill an ambient pressure Xe reservoir bag, thus eliminating the need for a large high-pressure Xe cylinder with its attendant risk of costly accidental gas loss. A flexible bulb and valve arrangement allowed manual addition of approximately 50 mL Xe boluses from reservoir bag to breathing system. These were added to the expiratory limb of the circuit to allow maximum mixing with existing gases in the circle before entering the lungs. The flexible bulb volume of 50 mL was selected not only because of the paucity of suitable designs available but also because its slow refill properties and small volume ensured more even gas mixing within the circle, as it was impossible to rapidly add larger xenon boluses. Erring on the side of caution, our circuit was primed with O2. During the first few minutes of Xe delivery, the Fio2 was increased by tolerating some overspill of circle gas as it was added. Once the target Xe concentration had been reached, the system was allowed to run in a steady closed state by the O2 substitution valve mechanism and then only occasional Xe boluses were required. The Xe/O2 monitors were constantly observed as would be the case during the conduct of a conventional anesthetic. Deviations in Xe concentration of more than 2%–4% from target were corrected by the operator adding Xe to the circuit, each bolus typically producing a 2% increase in Xe concentration. These corrections offset the inherent tendency of this circuit design to generate a very slowly increasing O2 concentration (O2 + minimal Xe consumptions being replaced with equal volume of O2 via substitution valve). The total (cumulative) Xe consumption pattern in each experiment was derived from a record of the number and timing of each bolus.

Leak Test Procedure
Before use, an infant test lung (Imtmedical, Switzerland) was fitted to the tracheal tube connector and the ventilator started. A small volume of gas (approximately 100 mL) was added to the breathing system; at end-expiration, the hanging bag would then contain this exact volume of gas and, in the absence of leaks, this volume would not decrease with time.

Circuit Priming Before Use
One liter per minute of O2 was delivered to the ventilator connector port on the lower chamber. The O2 entered the lower chamber, collapsed the hanging bag, flowed upward via the O2 substitution valve through the soda lime, and out via the inspiratory hose, substantially replacing all contained gases with O2, which we confirmed by examination of the O2 analyzer displays.

Gas Monitoring
Concentrations of Xe/O2 in the breathing gas and ETco2 concentration needed to be measured for safety and to guide manual Xe administration. Our previous experience with closed circuits and side-stream monitors highlighted problems with sample line occlusion, humidity-induced unreliability, gas leakage, and nitrogen contamination of gas returning to the circuit. We therefore used mainstream monitoring wherever possible. A mainstream Xe/O2 anesthesia analyzer (GKM-03-INSOVT, Moscow, Russia obtained via Alfa-Impex Oy, Finland) was used and 22-mm female taper fittings in the upper chamber of the breathing system were created to accept the two sensors of this monitor (Fig. 4). This analyzer was designed for anesthesia in Russia, where Xe has been licensed since 2002 and used in approximately 3000 anesthetics (personal communication with supplier). It has a conventional electrochemical O2 cell and, possibly uniquely, a similarly shaped Xe sensor operating on the principle of thermal conductivity. Xe concentration is difficult to measure at acceptable cost as it is almost completely unreactive, does not absorb light, and is not paramagnetic. This sensor works on the principle that, in a mixture of gases in which one has a very different thermal conductivity to the others, its relative concentration can be derived. The thermal conductivity of Xe is almost five times lower than that of O2 or nitrogen, which is similar, and this anomaly favors Xe measurement by this method.


Figure 426
View larger version (112K):
[in this window]
[in a new window]

  		Figure 4. Gas analyzer and sensor connections. The xenon/oxygen analyzer is shown (A). Upper surface of breathing system contains main (B), auxiliary (C) electrochemical oxygen cells, and the thermal conductivity xenon sensor (D). Handle (E) is used to disassemble the main components of the upper structure.

 

For safety, a secondary battery-powered anesthesia O2 analyzer (Teledyne, Viamed, West Yorkshire, UK) was used with an electrochemical sensor, which was also mounted on the top of the breathing system. ETco2 concentration was measured with a mainstream infrared analyzer (Tidal WaveTM, Respironics UK, Chichester, UK), specifically chosen for its low dead space neonatal tracheal tube connector to minimize CO2 rebreathing.

Xe Uptake Modeling
To investigate the proportion of our experimental Xe consumption rates attributable to uptake by the piglets (i.e., uptake by tissues) versus that due to losses by leaks and diffusion, we used the computer simulation program "Narkup 2000" (D C White, Northwick Park Hospital, Middlesex, UK and G Lockwood, Hammersmith Hospital, London, UK) to predict the Xe uptake by the piglets.38 This was first programmed with neonatal cardiorespiratory values (weight 1.8 kg, cardiac output 250 mL/min, minute ventilation 310 mL/min, 35% dead space, 7% shunt), and typical adult tissue compartment parameters (the relative content of each tissue type within the body). The simulation was then repeated using neonatal tissue compartment parameters derived from anatomical tables39 in case the lower fat content of neonates had any major effect on the predicted Xe uptake.

Conduct of Experiment
Anesthesia/Ventilation
Unrestrained animals were anesthetized with halothane/O2/nitrous oxide followed by orotracheal intubation with cuffed 3-mm internal diameter tubes (Mallinckrodt Medical, Athlone, Ireland) and mechanical ventilation (SLE 2000, SLE) commenced. The cuff was inflated with air during ventilation until an audible leak just ceased. The animals were not paralyzed. Vascular access was obtained and monitoring of core temperature, electrocardiogram, and amplitude integrated electroencephalogram (aEEG) was established. aEEG (CFM 6000, Olympic Medical, Seattle, WA and BrainZTM, BrainZ instruments Limited, Auckland, New Zealand) was required as a monitoring tool during the HI insult.40 Ventilation settings were adjusted to maintain an ETco2 between 35 and 45 mm Hg, confirmed by intermittent blood gas analyses during the study, except during the insult. Before and after the HI insult, the Fio2 was adjusted to maintain a saturation on pulse oximetry of >95%.

Fluid Management
A 3.75% dextrose/0.45% saline maintenance infusion was commenced at 15 mL · kg–1 · h–1 before the insult, after which 5% dextrose/0.45% saline was run at 10 mL · kg–1 · h–1.

Temperature Control
The piglets were kept in purpose-built neonatal incubators. During the initial baseline period and HI insult periods, the normal piglet core temperature of 39°C ± 0.2°C was maintained with a radiant warmer. HT was induced to a rectal temperature of 33.5°C ± 0.2°C as required, using a clinical cooling mattress (Tecotherm, TecCom, GmbH, Munich, Germany).

Cardiac Monitoring
Continuous mean arterial blood pressure (MAP) was measured from an umbilical artery catheter and three-lead electrocardiogram monitoring (Passport 2, Datascope, Montvale, NJ) was undertaken. During the insult, no lower limit for MAP was set, unless followed by bradycardia (<80 bpm); otherwise, a MAP less than 40 mm Hg during the study period was treated with a 10 mL/kg bolus of 0.9% saline followed by a second identical bolus if still unsatisfactory. If hypotension persisted or bradycardia developed, inotropic support was commenced with dopamine (range, 5–20 µg · kg–1 · min–1) plus, if necessary, noradrenaline (range, 0.1–1 µg · kg–1 · min–1).

After placement of all monitoring equipment, the piglet was laid prone and rested for 60 min under anesthesia after which a 45 min global HI insult was applied.41

HI Insult and Resuscitation
Briefly, the Fio2 was reduced abruptly to 4%–6% for 45 min to reduce the aEEG background amplitude to <7 µV with an inspired halothane concentration of 0.7%–1.0%.41 The piglet was then resuscitated for 30 min in air or the lowest inspired O2 concentration required to achieve an O2 saturation of more than 95%, and anesthesia was being maintained using a total IV technique comprising a 4 mg/kg propofol bolus, propofol (4–12 mg · kg–1 · h–1), and remifentanil (3–20 µg · kg–1 · h–1). Although an air/O2 mix helped remove any residual volatile anesthetics, 100% O2 would have been theoretically better, allowing formal denitrogenation before closed circuit use. This was, however, undesirable in terms of reperfusion injury immediately after such a severe insult. We had also discovered from pilot work that the small piglet nitrogen content versus the volume of the closed circuit meant that the lack of a denitrogenation maneuver did not, in practice, present a nitrogen accumulation problem.

After insult, the pigs were randomized to receive Xe while normo or hypothermic: 16 h 50% Xe at Trectal 39.0°C for 16 h, or 16 h 50% Xe at Trectal33.5°C for 12 h, followed by rewarming, respectively.

Xe Delivery After Insult
The closed-circuit Xe/O2 mixture was delivered for 16 h after insult. Once the 50% target Xe concentration had been reached, the propofol infusion was stopped and background remifentanil infusion continued. Pressure-controlled ventilation was used with inspiratory pressures of 18–20 cm H2O and positive end-expiratory pressure of 4 cm H2O, measured at the tracheal tube connector. After this, all anesthetics were stopped, analgesia was provided by IM buprenorphine (10–20 µg/kg every 12 h), the tracheal tube cuff deflated, the piglets were reconnected directly to the ventilator, gradually weaned, and tracheally extubated.

Analysis of Data
The data are mainly descriptive. Mean (95% CI) was used to describe normally distributed data, and median (nonparametric 95% CI) was used to describe skewed data. For statistical analysis, linear regression, and the Mann–Whitney test were used to explore differences between groups (SPSS 15.0 for windows, SPSS, Chicago, IL, and Minitab 15, Coventry, UK). With respect to Xe consumption data, linear regression was performed for each animal with cumulative Xe requirement as the dependent variable and time as the independent variable. A two-tailed P value <0.05 was considered significant.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The mean weight of the pigs was 1767 (1657–1877) g and 1818 (1662–1974) g for the Xe-NT and Xe-HT groups, respectively. The median age of the pigs in the Xe-NT group was 12.25 (2–23.39) h and 17.25 (11.9–23.84) h in the Xe-HT group.

During the Xe administration period, physiological variables were stable. Mean (95% CI) heart rates were 180 (165–195) and 148 (142–155) bpm (P < 0.0001) with MAPs of 54 (51–57) and 54 (49–59) mm Hg for the Xe-NT and Xe-HT groups, respectively. The O2 saturations on pulse oximetry for Xe-NT and Xe-HT were 99.3% (99–99.6) and 99.2% (98.8–99.5), respectively. CO2 removal was adequate with blood gas values of 41.3 (38.6–43.9) and 43.9 (36.1–51.8) mm Hg in the Xe-NT and Xe-HT groups. No animals died during the conduct of the experiment, with median (95% CI) times to successful weaning and tracheal extubation after cessation of the 16-h period of Xe administration of 3 (0.5–12.1) and 8.5 (2.5–40) h for each group, respectively. Except heart rate, none of these differences were significant.

The median (95% CI) Xe concentration in the circle was 52.3% (50.9–53.9) and 52.17% (50.9–53.5) in the Xe-NT and Xe-HT groups, respectively. O2 and nitrogen concentrations in the circle were 33.1% (32.1–34.5) and 13.4% (12.2–15.6), respectively, in the Xe-NT group. In Xe-HT group, O2 and calculated nitrogen concentrations were 34.7% (32.6%–36.9%) and 13.5% (11.2–15.1), respectively (Fig. 5).


Figure 526
View larger version (34K):
[in this window]
[in a new window]

  		Figure 5. Concentrations of oxygen, xenon, and nitrogen (calculated as 100 – O2% – Xe%) versus time. * = 30 min recovery period after insult.

 

The predicted tissue Xe uptake using NARKUP software programmed for a 1.8-kg patient with an adult tissue compartment distribution was 25.5 mL/h over the 16-h period. This decreased further to 16.1 mL/h when neonatal tissue compartment parameters were used.

The cumulative fresh Xe expenditure is shown in Figure 6. The overall median (95% CI) hourly Xe consumption was 0.19 (0.15–0.24) and 0.18 (0.16–0.21) L/h in the Xe-NT and Xe-HT groups, respectively, with an overall value for both groups of 0.18 (0.16–0.21) L/h. There was no significant difference between the slopes of the Xe consumption curves of the Xe-NT 0.0028 (0.0022–0.0053) and Xe-HT 0.0035 (0.0025–0.0056) groups (P = 0.5). Multiple linear regression showed that the temperature during Xe delivery, weight, age, or sex of an animal had no influence on the Xe requirement over time.


Figure 626
View larger version (14K):
[in this window]
[in a new window]

  		Figure 6. Cumulative xenon (XE) dose in both the Xe-normothermia and Xe-hypothermia groups during the 16 h of XE administration. Median (95% CI).

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Closed breathing systems may appear as an exotic method of anesthesia delivery; however, circle breathing systems with CO2 absorption for acetylene anesthesia were described by Carl Gauss as long ago as 1924/1925, and use of these systems "closed" with basal O2 flows is usually attributed to the anesthesiologist Brian Sword (CT) 4 yr later. Closed systems become particularly attractive whenever an expensive anesthetic is to be used, which has a low-patient uptake. This situation existed in the past with respect to cyclopropane, which was originally very expensive and the same principles apply now with respect to Xe. The advent of computer control systems has allowed production of closed circuit machines, which are easier to use, a current example being the Drager Zeus. A predecessor of this machine, the PhysioFlex (Physio, The Netherlands then Dräger, Lübeck, Germany), had a variant, the PhysioFlex-Xe, which was capable of closed-circuit Xe delivery.42 At least one computerized closed circuit machine for Xe anesthesia will be launched again soon in Europe. Closed systems have also been used successfully for many years in mine rescue, firefighting, military diving, and aerospace.

We sought to develop a relatively straightforward closed circuit delivery system suitable for cost-effective delivery of Xe to neonates as a potential neuroprotectant after perinatal asphyxia and to investigate its technical and practical feasibility in a realistic model of this clinical situation, which included the induced HT currently in clinical use.

The overall Xe utilization rate was 0.18 L/h which, at approximately $10/L, equates to a running cost of under $2/h. This included some Xe losses incurred during the initial wash-in procedure to increase the inspired Xe fraction as rapidly as possible in which some gas overspill was tolerated. This initial loss could be avoided in the future by priming the circuit with a Xe/O2 mixture rather than with O2 alone. If, hypothetically, 1 million L/yr of the global Xe production could be set aside solely for medical use, then this would allow approximately 231,000 neonatal 24 h treatments to be provided for less than $45 Xe per treatment. In contrast, as an example, a very low-flow regime of 200 mL/min Xe would consume this entire supply within 3472 neonatal 24 h treatments at a Xe cost of $2,880 per treatment. We therefore believe our aim of effective cost containment for clinical practicality and responsible use of this scarce resource was achieved.

Satisfactory gas exchange was maintained in both groups during the 16 h after insult Xe delivery period. Our target Xe concentration was 50%, raising the possibility that the remaining gas in the circle could be 50% O2. In neonates with minimal lung damage, this might produce hyperoxia which, in addition to the well-known retinopathy, could be harmful after an HI insult via reperfusion injury and other mechanisms. In practice, babies with perinatal HI can have abnormal gas exchange from meconium aspiration, for example, and often do require an elevated Fio2. The residual nitrogen present in our breathing gas mixture advantageously helped reduce the Fio2 to approximately 34%. Maneuvers, if required, to attenuate an elevated Fio2 include increasing the Xe fraction or deliberately injecting of small volumes of air. In a human neonatal trial, there might be a precautionary requirement to flush the circuit at intervals of approximately 2 h to prevent accumulation of foreign gases emerging from the lungs, such as methane from gut fermentation and acetone from liver metabolism as the clinical effects of these gases, if any, are currently unclear. The clinical implications of this action are unclear. As the optimum therapeutic duration of Xe delivery is not currently known, our soda lime container was intended to last up to 72 h without replenishment as HT is currently being induced clinically for similar periods. The maximum volume of 800 mL that it can carry is probably excessive for such small subjects, especially if cooled. This volume will be reduced in future versions. If periodic circle flushes are considered necessary, any reductions in circuit volume would also be advantageous to minimize the Xe requirement of this maneuver.

We account for the reduced heart rate in the Xe-HT group relative to the Xe-normothermia group by the clinical observation that therapeutic HT in human neonates consistently decreases heart rate.43 Despite using cuffed tracheal tubes, weaning and tracheal extubation were possible without postextubation stridor. We used cuffed tracheal tubes (commercially available for human neonatal clinical use) to prevent excessive Xe loss via leakage at this point. We acknowledge past concerns over cuffed tubes in infants and potential airway edema. However, such tubes are now available in sizes as small as 2.5 mm internal diameter and finding a role in some centers with few reported problems.44 The effect of Xe diffusion into tracheal tube cuffs has been investigated by others and, although it does occur, the effect is much less pronounced than that seen with nitrous oxide.45

The predicted patient tissue Xe uptake using NARKUP software programmed for a 1.8-kg patient with an adult tissue compartment distribution was 0.026 L/h over the 16 h period, i.e., less than one seventh of our experimental measured Xe requirement. The uptake decreased even further to 0.016 L/h, i.e., 16 mL/h if neonatal tissue compartment parameters were used in the simulation, reflecting the lower proportion of body fat in neonates. In addition, our measured in vivo Xe requirement was linear with time rather than reaching an expected plateau as tissues saturated and was found to be unrelated to the weight of the animal. These observations collectively suggest that a steady, slight Xe loss from the breathing system was occurring in addition to this almost negligible predicted patient uptake. Despite being very low, we, therefore, suspect that a majority of our ongoing Xe requirements were still being expended replacing minor Xe losses. Because each machine was leak tested before use, we suggest that potential mechanisms of Xe loss might include diffusion through the silicone rubber hanging bag or minor leaks past the tracheal tube cuff. This is encouraging despite an overall Xe requirement of only 0.18 L/h (<$2/h), as it appears that with further development there may be the potential to reduce this even further.

The Xe consumption was sufficiently modest to render the concept of using gas cartridges a technically feasible method of refilling the Xe reservoir. Although we used small single-use gas cylinders in this study, we envision small pressurized gas cartridges containing 1–5 L Xe would be an ideal method of supply. Such cartridges already exist for carbonated drink (CO2) and food industry (N2O) use. One cartridge could provide sufficient Xe for an entire treatment of many hours duration.

The PhysioFlex-Xe was a closed system of 3.5 L volume, with small increments of O2 and other gases given by computer-controlled injection and excess gases evacuated as necessary. Inspired gases were measured as follows: O2, paramagnetic analyzer; carbon dioxide and volatile anesthetics, infrared spectrometer; Xe, thermal conductivity. The system incorporated a blower circulating the contents at 70 L/min, dual soda lime containers, a charcoal canister to produce rapid reductions in volatile and/or Xe concentrations as required, and four membrane chambers allowing controlled ventilation/system volume sensing. The system we describe is also a closed circuit. However, by design, it has no computerized gas-injection system (although it easily could), relying instead upon mechanical substitution of patient gas uptake with O2 to ensure a constant or slow-rising O2 concentration, offset by manual injections of Xe, which are infrequent at steady state due to the very low-Xe uptake of the neonate. It currently has a volume approximately 1/3 that of the PhysioFlex, which we intend to greatly reduce. Gas monitoring is by mainstream methods for reliability. As with the PhysioFlex, we measure Xe concentration by thermal conductivity electing to use a robust Russian device for this purpose having built and used Xe monitors of various designs in the past. It has no gas blower, membrane chambers, or computer, and the concept is that our unit could be redeveloped as a molded single-use circuit. Any compliant regions of compressible gas would be greatly reduced by molding the housings closely around the internal structures. A preassembled device has far fewer connections and seals, especially around the soda lime refill mechanism, all of which can leak. Leakage rates, which would normally be irrelevant in anesthesia practice could materially affect running costs in a circle system intended for Xe, explaining our great attention to this issue. As examples from current medical practice, cardiopulmonary bypass circuits are preassembled for safety and at least two single-use conventional anesthesia circles are also commercially available.

It is possible that an O2 substitution valve, if incorporated into a circle-based anesthesia machine might, by replenishing all the metabolic O2 uptake, improve upon the performance of the current antihypoxic mixture devices where at present even if the O2 rotameter is off, a residual flow of 50–100 mL/min O2 remains, which may not, however, meet a patient’s metabolic needs.

In summary, we have described and evaluated a closed-circuit Xe delivery system specifically intended for neonatal use, which automatically replenishes patient O2 consumption without complex control systems, has hypoxic mixture protection, and could be designed as a molded single-use device. The overall Xe requirement, and therefore running cost, was minimal at 0.18 L/h (<$2/h), permitting responsible use of a restricted global Xe supply in the maximum number of clinical cases per year. It is both technically and physiologically feasible to use this method of Xe delivery as a potential therapeutic intervention in neonates for prolonged periods, even after a severe HI injury, either with or without the cooling that might also be used. We have shown that economic Xe delivery is not only theoretically but also practically possible, even in this challenging clinical situation.


   Footnotes
 
*Additional information available at: www.therebreathersite.nl/Zuurstofrebreathers/Russian/ida-71.htm. Back

Accepted for publication February 2, 2009.

Supported by Programme grant 05 BTL 01 from the children’s medical research charity SPARKS, London, United Kingdom.

Dr. John Dingley is a Director of a University spin-out company, AOX Ltd., set up to develop delivery systems for gases, including xenon. The research group used technology from a patent held by AOX on part of the device described in this paper with the permission of AOX. AOX did not fund this study in any way.

*The price of xenon in nearly all previous papers on this subject has been quoted as $10/L. However, the authors would like to note that the price has now risen to approximately $30/L since this paper was written.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Petzelt C, Blom P, Schmehl W, Muller J, Kox WJ. Prevention of neurotoxicity in hypoxic cortical neurons by the noble gas xenon. Life Sci 2003;72:1909–18[Web of Science][Medline]
  2. Ma D, Wilhelm S, Maze M, Franks NP. Neuroprotective and neurotoxic properties of the ‘inert’ gas, xenon. Br J Anaesth 2002;89:739–46[Abstract/Free Full Text]
  3. Ma D, Yang H, Lynch J, Franks NP, Maze M, Grocott HP. Xenon attenuates cardiopulmonary bypass-induced neurologic and neurocognitive dysfunction in the rat. Anesthesiology 2003;98: 690–8[Web of Science][Medline]
  4. Ma D, Hossain M, Chow A, Arshad M, Battson RM, Sanders RD, Mehmet H, Edwards AD, Franks NP, Maze M. Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol 2005;58:182–93[Web of Science][Medline]
  5. Martin JL, Ma D, Hossain M, Xu J, Sanders RD, Franks NP, Maze M. Asynchronous administration of xenon and hypothermia significantly reduces brain infarction in the neonatal rat. Br J Anaesth 2007;98:236–40[Abstract/Free Full Text]
  6. Dingley J, Tooley J, Porter H, Thoresen M. Xenon provides short-term neuroprotection in neonatal rats when administered after hypoxia-ischemia. Stroke 2006;37:501–6[Abstract/Free Full Text]
  7. Hobbs C, Thoresen M, Tucker A, Aquilina K, Chakkarapani E, Dingley J. Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke 2008;39:1307–13[Abstract/Free Full Text]
  8. Ma D, Hossain M, Pettet GK, Luo Y, Lim T, Akimov S, Sanders RD, Franks NP, Maze M. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. J Cereb Blood Flow Metab 2006;26:199–208[Web of Science][Medline]
  9. Franks NP, Dickinson R, de Sousa SL, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature 1998;396:324[Medline]
  10. Natale G, Cattano D, Abramo A, Forfori F, Fulceri F, Fornai F, Paparelli A, Giunta F. Morphological evidence that xenon neuroprotects against N-methyl-dl-aspartic acid-induced damage in the rat arcuate nucleus: a time-dependent study. Ann N Y Acad Sci 2006;1074:650–8[Web of Science][Medline]
  11. Dinse A, Fohr KJ, Georgieff M, Beyer C, Bulling A, Weigt HU. Xenon reduces glutamate-, AMPA-, and kainate-induced membrane currents in cortical neurones. Br J Anaesth 2005;94:479–85[Abstract/Free Full Text]
  12. Gruss M, Bushell TJ, Bright DP, Lieb WR, Mathie A, Franks NP. Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol 2004;65:443–52[Abstract/Free Full Text]
  13. Finer NN, Robertson CM, Richards RT, Pinnell LE, Peters KL. Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome. J Pediatr 1981;98:112–7[Web of Science][Medline]
  14. Johnston MV. Excitotoxicity in neonatal hypoxia. Ment Retard Dev Disabil Res Rev 2001;7:229–34[Web of Science][Medline]
  15. Bona E, Hagberg H, Loberg EM, Bagenholm R, Thoresen M. Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome. Pediatr Res 1998;43:738–45[Web of Science][Medline]
  16. Ginsberg MD, Sternau LL, Globus MY, Dietrich WD, Busto R. Therapeutic modulation of brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev 1992;4: 189–225[Web of Science][Medline]
  17. Tooley JR, Satas S, Porter H, Silver IA, Thoresen M. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol 2003;53:65–72[Web of Science][Medline]
  18. Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx 2006;3:154–69[Medline]
  19. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365:663–70[Web of Science][Medline]
  20. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574–84[Abstract/Free Full Text]
  21. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, Horgan MJ, Languani S, Bhatia JJ, Givelichian LM, Sankaran K, Yager JY. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol 2005;32: 11–7[Web of Science][Medline]
  22. Rossaint R, Reyle-Hahn M, Schulte Am Esch J, Scholz J, Scherpereel P, Vallet B, Giunta F, Del Turco M, Erdmann W, Tenbrinck R, Hammerle AF, Nagele P; Xenon Study Group. Multicenter randomized comparison of the efficacy and safety of xenon and isoflurane in patients undergoing elective surgery. Anesthesiology 2003;98:6–13[Web of Science][Medline]
  23. Dingley J, King R, Hughes L, Terblanche C, Mahon S, Hepp M, Youhana A, Watkins A. Exploration of xenon as a potential cardiostable sedative: a comparison with propofol after cardiac surgery. Anaesthesia 2001;56:829–35[Web of Science][Medline]
  24. Lane GA, Nahrwold ML, Tait AR, Taylor-Busch M, Cohen PJ, Beaudoin AR. Anesthetics as teratogens: nitrous oxide is fetotoxic, xenon is not. Science 1980;210:899–901[Abstract/Free Full Text]
  25. Burov NE, Arzamastsev EV, Kornienko L, Kudimova LA. [Investigation of the teratogenic and embryotoxic action of xenon]. Anesteziol Reanimatol 2002:69–70
  26. Jayasinghe D, Gill AB, Levene MI. CBF reactivity in hypotensive and normotensive preterm infants. Pediatr Res 2003;54:848–53[Web of Science][Medline]
  27. Wilhelm S, Ma D, Maze M, Franks NP. Effects of xenon on in vitro and in vivo models of neuronal injury. Anesthesiology 2002;96:1485–91[Web of Science][Medline]
  28. Tymianski M, Sattler R, Zabramski JM, Spetzler RF. Characterization of neuroprotection from excitotoxicity by moderate and profound hypothermia in cultured cortical neurons unmasks a temperature-insensitive component of glutamate neurotoxicity. J Cereb Blood Flow Metab 1998;18:848–67[Web of Science][Medline]
  29. Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 1989;20:904–10[Abstract/Free Full Text]
  30. Lynch C III, Baum J, Tenbrinck R. Xenon anesthesia. Anesthesiology 2000;92:865–8[Web of Science][Medline]
  31. Nunn JF, Halsey MJ. Xenon in anaesthesia. Lancet 1990;336: 112–3[Web of Science][Medline]
  32. 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[Abstract/Free Full Text]
  33. Luttropp HH, Thomasson R, Dahm S, Persson J, Werner O. Clinical experience with minimal flow xenon anesthesia. Acta Anaesthesiol Scand 1994;38:121–5[Web of Science][Medline]
  34. Farrari A, Erdmann W, Del Tacca M, Formichi B, Volta C, Ferrari E, Bissolotti G, Giunta F. Xenon anesthesia: clinical results and recycling of gas. Appl Cardiopulm Pathophysiol 1998;7:153–5
  35. Baum JA. New and alternative delivery concepts and techniques. Best Pract Res Clin Anaesthesiol 2005;19:415–28[Medline]
  36. Burov NE, Molchanov IV, Nikolaev LL, Rashchupkin AB. [The method of low-flow xenon anesthesia]. Anesteziol Reanimatol 2003:31–4
  37. Dingley J, Findlay GP, Foex BA, Mecklenburgh J, Esmail M, Little RA. A closed xenon anesthesia delivery system. Anesthesiology 2001;94:173–6[Web of Science][Medline]
  38. Lockwood G, White DC. Measuring the costs of inhaled anaesthetics. Br J Anaesth 2001;87:559–63[Abstract/Free Full Text]
  39. ICRP. ICRP (International Commission on Radiological Protection) 2002. Basic anatomical and physiological data for use in radiological protection: reference values publication 89. Oxford: Pergamon, 2002
  40. Hellstrom-Westas L, Rosen I. Continuous brain function monitoring: state of the art in clinical practice. Semin Fetal Neonatal Med 2006;11:503–11[Web of Science][Medline]
  41. Thoresen M, Haaland K, Loberg EM, Whitelaw A, Apricena F, Hanko E, Steen PA. A piglet survival model of posthypoxic encephalopathy. Pediatr Res 1996;40:738–48[Web of Science][Medline]
  42. Nathan N, Sperandio M, Erdmann W, Westerkamp B, Van Dijk G, Scherpereel P, Feiss P. [PhysioFlex: a target-controlled self-regulating closed-circuit inhalation anesthesia regulator]. Ann Fr Anesth Reanim 1997;16:534–40[Web of Science][Medline]
  43. Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics 2000;106:92–9[Abstract/Free Full Text]
  44. Weiss M, Gerber AC. Cuffed tracheal tubes in children—things have changed. Pediatr Anesth 2008;16:1005–7
  45. Ishiguro Y, Saito H, Nakata Y, Goto T, Terui K, Niimi Y, Morita S. Effect of xenon on endotracheal tube cuff. J Clin Anesth 2000;12:371–3[Web of Science][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Chakkarapani, E.
Right arrow Articles by Dingley, J.
PubMed
Right arrow Articles by Chakkarapani, E.
Right arrow Articles by Dingley, J.
Related Collections
Right arrow Drug Delivery
Right arrow Technology
Right arrow Pharmacology

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2009 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press