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Introduction: Venous gas emboli (VGE) are widely used as a surrogate endpoint instead of decompression sickness (DCS) in studies of decompression procedures. Peak post-dive VGE grades vary widely following repeated identical dives but little is known about how much of the variability in VGE grades is proportioned between-diver and within-diver., Methods: A retrospective analysis of 834 man-dives on six dive profiles with post-dive VGE measurements was conducted under controlled laboratory conditions. Among these data, 151 divers did repeated dives on the same profile on two to nine occasions separated by at least one week (total of 693 man-dives). Data were analysed for between- and within-diver variability in peak post-dive VGE grades using mixed-effect models with diver as the random variable and associated intraclass correlation coefficients., Results: Most divers produced a wide range of VGE grades after repeated dives on the same profile. The intraclass correlation coefficient (repeatability) was 0.33 indicating that 33% of the variability in VGE grades is between-diver variability; correspondingly, 67% of variability in VGE grades is within-diver variability. DCS cases were associated with an individual diver's highest VGE grades and not with their lower VGE grades., Conclusions: These data demonstrate large within-diver variability in VGE grades following repeated dives on the same dive profile and suggest there is substantial within-diver variability in susceptibility to DCS. Post-dive VGE grades are not useful for evaluating decompression practice for individual divers., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Inner ear decompression sickness (IEDCS) may occur after upward or downward excursions in saturation diving. Previous studies in nonsaturation diving strongly suggest that IEDCS is caused by arterialization of small venous bubbles across intracardiac or intrapulmonary right-to-left shunts and bubble growth through inward diffusion of supersaturated gas when they arrive in the inner ear. The present study used published saturation diving data and models of inner ear inert gas kinetics and bubble dynamics in arterial conditions to assess whether IEDCS after saturation excursions could also be explained by arterialization of venous bubbles and whether such bubbles might survive longer and be more likely to reach the inner ear under deep saturation diving conditions. Previous data show that saturation excursions produce venous bubbles. Modeling shows that gas supersaturation in the inner ear persists longer than in the brain after such excursions, explaining why the inner ear would be more vulnerable to injury by arriving bubbles. Estimated survival of arterialized bubbles is significantly prolonged at high ambient pressure such that bubbles large enough to be filtered by pulmonary capillaries but able to cross right-to-left shunts are more likely to survive transit to the inner ear than at the surface. IEDCS after saturation excursions is plausibly caused by arterialization of venous bubbles whose prolonged arterial survival at deep depths suggests that larger bubbles in greater numbers reach the inner ear. NEW & NOTEWORTHY Inner ear decompression sickness that occurs during deep saturation diving is explained by arterialization of venous bubbles across intracardiac or intrapulmonary right-to-left shunts and growth of these bubbles if they arrive in the inner ear. Bubbles in arterial blood have prolonged lifetimes at hyperbaric pressures compared with at sea level. This can explain why inner ear decompression sickness is more characteristic of rapid decompressions at great depths than of decompression at sea level.

Introduction: The US Navy air decompression table was promulgated in 2008, and a revised version, calculated with the VVal-79 Thalmann algorithm, was promulgated in 2016. The Swedish Armed Forces conducted a laboratory dive trial using the 2008 air decompression table and 32 dives to 40 metres' seawater for 20 minutes bottom time resulted in two cases of decompression sickness (DCS) and high venous gas emboli (VGE) grades. These results motivated an examination of current US Navy air decompression schedules., Methods: An air decompression schedule to 132 feet seawater (fsw; 506 kPa) for 20 minutes bottom time with a 9-minute stop at 20 fsw was computed with the VVal-79 Thalmann algorithm. Dives were conducted in 29°C water in the ocean simulation facility at the Navy Experimental Diving Unit. Divers dressed in shorts and t-shirts performed approximately 90 watts cycle ergometer work on the bottom and rested during decompression. VGE were monitored with 2-D echocardiography at 20-minute intervals for two hours post-dive., Results: Ninety-six man-dives were completed, resulting in no cases of DCS. The median (IQR) peak VGE grades were 3 (2-3) at rest and 3 (3-3) with limb flexion. VGE grades remained elevated two hours post-dive with median grades 1 (1-3) at rest and 3 (1-3) with movement., Conclusions: Testing of a short, deep air decompression schedule computed with the VVal-79 Thalmann algorithm, tested under diving conditions similar to earlier US Navy dive trials, resulted in a low incidence of DCS., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Divers suspected of suffering decompression illness (DCI) in locations remote from a recompression chamber are sometimes treated with in-water recompression (IWR). There are no data that establish the benefits of IWR compared to conventional first aid with surface oxygen and transport to the nearest chamber. However, the theoretical benefit of IWR is that it can be initiated with a very short delay to recompression after onset of manifestations of DCI. Retrospective analyses of the effect on outcome of increasing delay generally do not capture this very short delay achievable with IWR. However, in military training and experimental diving, delay to recompression is typically less than two hours and more than 90% of cases have complete resolution of manifestations during the first treatment, often within minutes of recompression. A major risk of IWR is that of an oxygen convulsion resulting in drowning. As a result, typical IWR oxygen-breathing protocols use shallower maximum depths (9 metres' sea water (msw), 191 kPa) and are shorter (1-3 hours) than standard recompression protocols for the initial treatment of DCI (e.g., US Navy Treatment Tables 5 and 6). There has been no experimentation with initial treatment of DCI at pressures less than 285 kPa since the original development of these treatment tables, when no differences in outcomes were seen between maximum pressures of 203 kPa (10 msw) and 285 kPa (18 msw) or deeper. These data and case series suggest that recompression treatment comprising pressures and durations similar to IWR protocols can be effective. The risk of IWR is not justified for treatment of mild symptoms likely to resolve spontaneously or for divers so functionally compromised that they would not be safe in the water. However, IWR conducted by properly trained and equipped divers may be justified for manifestations that are life or limb threatening where timely recompression is unavailable., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

(Mitchell SJ, Bennett MH, Bryson P, Butler FK, Doolette DJ, Holm JR, Kot J, Lafère P. Pre-hospital management of decompression illness: expert review of key principles and controversies. Diving and Hyperbaric Medicine. 2018 March;48(1):45е.doi.10.28920/dhm48.1.45-55.) Guidelines for the pre-hospital management of decompression illness (DCI) had not been formally revised since the 2004 Divers Alert Network/Undersea and Hyperbaric Medical Society workshop held in Sydney, entitled "Management of mild or marginal decompression illness in remote locations." A contemporary review was initiated by the Divers Alert Network and undertaken by a multinational committee with members from Australasia, the USA and Europe. The process began with literature reviews by designated committee members on: the diagnosis of DCI; first aid strategies for DCI; remote triage of possible DCI victims by diving medicine experts; evacuation of DCI victims; effect of delay to recompression in DCI; pitfalls in management when DCI victims present at hospitals without diving medicine expertise and in-water recompression. This was followed by presentation of those reviews at a dedicated workshop at the 2017 UHMS Annual Scientific Meeting, discussion by registrants at that workshop and, finally, several committee meetings to formulate statements addressing points considered of prime importance to the management of DCI in the field. The committee placed particular emphasis on resolving controversies around the definition of "mild DCI" arising over 12 years of practical application of the 2004 workshop's findings, and on the controversial issue of in-water recompression. The guideline statements are promulgated in this paper. The full workshop proceedings are in preparation for publication., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (This article is the copyright of the authors who grant Diving and Hyperbaric Medicine and Undersea and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Guidelines for the pre-hospital management of decompression illness (DCI) had not been formally revised since the 2004 Divers Alert Network/Undersea and Hyperbaric Medical Society workshop held in Sydney, entitled "Management of mild or marginal decompression illness in remote locations". A contemporary review was initiated by the Diver's Alert Network and undertaken by a multinational committee with members from Australasia, the USA and Europe. The process began with literature reviews by designated committee members on: the diagnosis of DCI; first aid strategies for DCI; remote triage of possible DCI victims by diving medicine experts; evacuation of DCI victims; effect of delay to recompression in DCI; pitfalls in management when DCI victims present at hospitals without diving medicine expertise and in-water recompression. This was followed by presentation of those reviews at a dedicated workshop at the 2017 UHMS Annual Meeting, discussion by registrants at that workshop and finally several committee meetings to formulate statements addressing points considered of prime importance to the management of DCI in the field. The committee placed particular emphasis on resolving controversies around the definition of "mild DCI" arising over 12 years of practical application of the 2004 workshop's findings, and on the controversial issue of in-water recompression. The guideline statements are promulgated in this paper. The full workshop proceedings are in preparation for publication., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Decompression sickness (DCS) can be experienced following a reduction in ambient pressure; such as that associated with diving or ascent to high altitudes. DCS is believed to result when supersaturated inert gas dissolved in biological tissues exits solution and forms bubbles. Models to predict the probability of DCS are typically based on nitrogen and/or helium gas uptake and washout in several theoretical tissues, each represented by a single perfusion-limited compartment. It has been previously shown that coupled perfusion-diffusion compartments are better descriptors than solely perfusion-based models of nitrogen and helium uptake and elimination kinetics observed in the brain and skeletal muscle of sheep. In this work, we examine the application of these coupled pharmacokinetic structures with at least one diffusion compartment to the prediction of the incidence of decompression sickness in humans. We compare these models to LEM-NMRI98, a well-described U.S. Navy gas content model, consisting of three uncoupled perfusion-limited compartments incorporating oxygen and linear-exponential kinetics. Pharmacokinetic gas content models with a diffusion component describe the probability of DCS in human bounce dives made with air, single non-air bounce dives, and oxygen decompression dives better than LEM-NMRI98. However, for the full data set, LEM-NMRI98 remains the best descriptor of the data., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Inside chamber attendants rescuing survivors from a pressurised, distressed submarine may themselves accumulate a decompression obligation which may exceed the limits of Defense and Civil Institute of Environmental Medicine tables presently used by the Royal Australian Navy. This study assessed the probability of decompression sickness (P DCS ) for medical attendants supervising survivors undergoing oxygen-accelerated saturation decompression according to the National Oceanic and Atmospheric Administration (NOAA) 17.11 table., Methods: Estimated probability of decompression sickness (P DCS ), the units pulmonary oxygen toxicity dose (UPTD) and the volume of oxygen required were calculated for attendants breathing air during the NOAA table compared with the introduction of various periods of oxygen breathing., Results: The P DCS in medical attendants breathing air whilst supervising survivors receiving NOAA decompression is up to 4.5%. For the longest predicted profile (830 minutes at 253 kPa) oxygen breathing at 30, 60 and 90 minutes at 132 kPa partial pressure of oxygen reduced the air-breathing-associated P DCS to less than 3.1 %, 2.1% and 1.4% respectively., Conclusions: The probability of at least one incident of DCS among attendants, with consequent strain on resources, is high if attendants breathe air throughout their exposure. The introduction of 90 minutes of oxygen breathing greatly reduces the probability of this interruption to rescue operations.

Introduction: Personnel rescuing survivors from a pressurized, distressed Royal Australian Navy (RAN) submarine may themselves accumulate a decompression obligation, which may exceed the bottom time limits of the Defense and Civil Institute of Environmental Medicine (DCIEM) Air and In-Water Oxygen Decompression tables (DCIEM Table 1 and 2) presently used by the RAN. This study compared DCIEM Table 2 with alternative decompression tables with longer bottom times: United States Navy XVALSS_DISSUB 7, VVAL-18M and Royal Navy 14 Modified tables., Methods: Estimated probability of decompression sickness (P DCS ), the units pulmonary oxygen toxicity dose (UPTD), the volume of oxygen required and the total decompression time were calculated for hypothetical single and repetitive exposures to 253 kPa air pressure for various bottom times and prescribed decompression schedules., Results: Compared to DCIEM Table 2, XVALSS_DISSUB 7 single and repetitive schedules had lower estimated P DCS , which came at the cost of longer oxygen decompressions. For single exposures, DCIEM schedules had P DCS estimates ranging from 1.8% to 6.4% with 0 to 101 UPTD and XVALSS_DISSUB 7 schedules had P DCS of less than 3.1%, with 36 to 350 UPTD., Conclusions: The XVALSS_DISSUB 7 table was specifically designed for submarine rescue and, unlike DCIEM Table 2, has schedules for the estimated maximum required bottom times at 253 kPa. Adopting these tables may negate the requirement for saturation decompression of rescue personnel exceeding DCIEM limits.

Decompression sickness (DCS) is a disease caused by gas bubbles forming in body tissues following a reduction in ambient pressure, such as occurs in scuba diving. Probabilistic models for quantifying the risk of DCS are typically composed of a collection of independent, perfusion-limited theoretical tissue compartments which describe gas content or bubble volume within these compartments. It has been previously shown that 'pharmacokinetic' gas content models, with compartments coupled in series, show promise as predictors of the incidence of DCS. The mechanism of coupling can be through perfusion or diffusion. This work examines the application of five novel pharmacokinetic structures with compartments coupled by perfusion to the prediction of the probability and time of onset of DCS in humans. We optimize these models against a training set of human dive trial data consisting of 4335 exposures with 223 DCS cases. Further, we examine the extrapolation quality of the models on an additional set of human dive trial data consisting of 3140 exposures with 147 DCS cases. We find that pharmacokinetic models describe the incidence of DCS for single air bounce dives better than a single-compartment, perfusion-limited model. We further find the U.S. Navy LEM-NMRI98 is a better predictor of DCS risk for the entire training set than any of our pharmacokinetic models. However, one of the pharmacokinetic models we consider, the CS2T3 model, is a better predictor of DCS risk for single air bounce dives and oxygen decompression dives. Additionally, we find that LEM-NMRI98 outperforms CS2T3 on the extrapolation data., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The International Meeting on Ultrasound for Diving Research produced expert consensus recommendations for ultrasound detection of vascular gas bubbles and the analysis, interpretation and reporting of such data. Recommendations for standardization of techniques to allow comparison between studies included bubble monitoring site selection, frequency and duration of monitoring, and use of the Spencer, Kisman-Masurel or Eftedal-Brubakk scales. Recommendations for reporting of results included description of subject posture and provocation manoeuvres during monitoring, reporting of untransformed data and the appropriate use of statistics. These guidelines are available from www.dhmjournal.com.

Introduction: In studies of decompression procedures, ultrasonically detected venous gas emboli (VGE) are commonly used as a surrogate endpoint for decompression sickness (DCS). However, VGE have not been rigorously validated as a surrogate endpoint for DCS., Methods: A data set for validation of VGE as a surrogate endpoint for DCS was retrospectively assembled comprising maximum VGE grades measured using two-dimensional echocardiography and DCS outcome following 868 laboratory man-dives. Dives were conducted according to only ten different experimental interventions such that the ten cumulative incidences of DCS (0-22%) provide relatively precise point estimates of the probability of DCS, P(DCS). Logistic models relating the P(DCS) to VGE grade and intervention were fitted to these validation data. Assessment of the models was used to evaluate the Prentice criteria for validating a surrogate endpoint., Results: The P(DCS)) increased with increasing VGE grade. However, the difference in the P(DCS) between interventions was larger than explained by differences in VGE grades. Therefore, VGE grades did not largely capture the intervention effect on the true endpoint (DCS) in accord with the Prentice definition of a surrogate endpoint., Conclusions: VGE can be used for comparisons of decompression procedures in samples of subjects but must be interpreted cautiously. A significant difference in VGE grade probably indicates a difference in the P(DCS). However, failure to find a significant difference in VGE grades does not necessarily indicate no difference in P(DCS).

Inner-ear decompression sickness (inner ear DCS) may occur in isolation ('pure' inner-ear DCS), or as part of a multisystem DCS presentation. Symptoms may develop during decompression from deep, mixed-gas dives or after surfacing from recreational air dives. Modelling of inner-ear inert gas kinetics suggests that onset during decompression results from supersaturation of the inner-ear tissue and in-situ bubble formation. This supersaturation may be augmented by inert gas counterdiffusion following helium to nitrogen gas switches, but such switches are unlikely, of themselves, to precipitate inner-ear DCS. Presentations after surfacing from air dives are frequently the 'pure' form of inner ear DCS with short symptom latency following dives to moderate depth, and the vestibular end organ appears more vulnerable than is the cochlea. A large right-to-left shunt (usually a persistent foramen ovale) is found in a disproportionate number of cases, suggesting that shunted venous gas emboli (VGE) cause injury to the inner-ear. However, this seems an incomplete explanation for the relationship between inner-ear DCS and right-to-left shunt. The brain must concomitantly be exposed to larger numbers of VGE, yet inner-ear DCS frequently occurs in the absence of cerebral symptoms. This may be explained by slower inert gas washout in the inner ear than in the brain. Thus, there is a window after surfacing within which VGE arriving in the inner-ear (but not the brain) would grow due to inward diffusion of supersaturated inert gas. A similar difference in gas kinetics may explain the different susceptibilities of cochlear and vestibular tissue within the inner-ear itself. The cochlea has greater perfusion and a smaller tissue volume, implying faster inert gas washout. It may be susceptible to injury by incoming arterial bubbles for a shorter time after surfacing than the vestibular organ.

In underwater diving, decompression schedules are based on compartmental models of nitrogen and helium tissue kinetics. However, these models are not based on direct measurements of nitrogen and helium kinetics. In isoflurane-anesthetized sheep, nitrogen and helium kinetics in the hind limb (n = 5) and brain (n = 5) were determined during helium-oxygen breathing and after return to nitrogen-oxygen breathing. Nitrogen and helium concentrations in arterial, femoral vein, and sagittal sinus blood samples were determined using headspace gas chromatography, and venous blood flows were monitored continuously using ultrasonic Doppler. The experiment was repeated at different states of hind limb blood flow and cerebral blood flow. Using arterial blood gas concentrations and blood flows as input, parameters and model selection criteria of various compartmental models of hind limb and brain were estimated by fitting to the observed venous gas concentrations. In both the hind limb and brain, nitrogen and helium kinetics were best fit by models with multiexponential kinetics. In the brain, there were no differences in nitrogen and helium kinetics. Hind limb models fit separately to the two gases indicated that nitrogen kinetics were slightly faster than helium, but models with the same kinetics for both gases fit the data well. In the hind limb and brain, the blood:tissue exchange of nitrogen is similar to that of helium. On the basis of these results, it is inappropriate to assign substantially different time constants for nitrogen and helium in all compartments in decompression algorithms., (Copyright © 2015 the American Physiological Society.)

Introduction: In studies of decompression procedures, ultrasonically detected venous gas emboli (VGE) are commonly used as a surrogate outcome if decompression sickness (DCS) is unlikely to be observed. There is substantial variability in observed VGE grades, and studies should be designed with sufficient power to detect an important effect., Methods: Data for estimating sample size requirements for studies using VGE as an outcome is provided by a comparison of two decompression schedules that found corresponding differences in DCS incidence (3/192 [DCS/dives] vs. 10/198) and median maximum VGE grade (2 vs. 3, P < 0.0001, Wilcoxon test). Sixty-two subjects dived each schedule at least once, accounting for 183 and 180 man-dives on each schedule. From these data, the frequency with which 10,000 randomly resampled, paired samples of maximum VGE grade were significantly different (paired Wilcoxon test, one-sided P ⋜ 0.05 or 0.025) in the same direction as the VGE grades of the full data set were counted (estimated power). Resampling was also used to estimate power of a Bayesian method that ranks two samples based on DCS risks estimated from the VGE grades., Results: Paired sample sizes of 50 subjects yielded about 80% power, but the power dropped to less than 50% with fewer than 30 subjects., Conclusions: Comparisons of VGE grades that fail to find a difference between paired sample sizes of 30 or fewer must be interpreted cautiously. Studies can be considered well powered if the sample size is 50 even if only a one-grade difference in median VGE grade is of interest.

Technical divers perform deep, mixed-gas 'bounce' dives, which are inherently inefficient because even a short duration at the target depth results in lengthy decompression. Technical divers use decompression schedules generated from modified versions of decompression algorithms originally developed for other types of diving. Many modifications ostensibly produce shorter and/or safer decompression, but have generally been driven by anecdote. Scientific evidence relevant to many of these modifications exists, but is often difficult to locate. This review assembles and examines scientific evidence relevant to technical diving decompression practice. There is a widespread belief that bubble algorithms, which redistribute decompression in favour of deeper decompression stops, are more efficient than traditional, shallow-stop, gas-content algorithms, but recent laboratory data support the opposite view. It seems unlikely that switches from helium- to nitrogen-based breathing gases during ascent will accelerate decompression from typical technical bounce dives. However, there is evidence for a higher prevalence of neurological decompression sickness (DCS) after dives conducted breathing only helium-oxygen than those with nitrogen-oxygen. There is also weak evidence suggesting less neurological DCS occurs if helium-oxygen breathing gas is switched to air during decompression than if no switch is made. On the other hand, helium-to-nitrogen breathing gas switches are implicated in the development of inner-ear DCS arising during decompression. Inner-ear DCS is difficult to predict, but strategies to minimize the risk include adequate initial decompression, delaying helium-to-nitrogen switches until relatively shallow, and the use of the maximum safe fraction of inspired oxygen during decompression.

Technical divers use gases other than air and advanced equipment configurations to conduct dives that are deeper and/or longer than typical recreational air dives. The use of oxygen-nitrogen (nitrox) mixes with oxygen fractions higher than air results in longer no-decompression limits for shallow diving, and faster decompression from deeper dives. For depths beyond the air-diving range, technical divers mix helium, a light non-narcotic gas, with nitrogen and oxygen to produce 'trimix'. These blends are tailored to the depth of intended use with a fraction of oxygen calculated to produce an inspired oxygen partial pressure unlikely to cause cerebral oxygen toxicity and a nitrogen fraction calculated to produce a tolerable degree of nitrogen narcosis. A typical deep technical dive will involve the use of trimix at the target depth with changes to gases containing more oxygen and less inert gas during the decompression. Open-circuit scuba may be used to carry and utilise such gases, but this is very wasteful of expensive helium. There is increasing use of closed-circuit 'rebreather' devices. These recycle expired gas and potentially limit gas consumption to a small amount of inert gas to maintain the volume of the breathing circuit during descent and the amount of oxygen metabolised by the diver. This paper reviews the basic approach to planning and execution of dives using these methods to better inform physicians of the physical demands and risks.

The Diving Committee of the Undersea and Hyperbaric Medical Society has reviewed available evidence in relation to the medical aspects of rescuing a submerged unresponsive compressed-gas diver. The rescue process has been subdivided into three phases, and relevant questions have been addressed as follows. Phase 1, preparation for ascent: If the regulator is out of the mouth, should it be replaced? If the diver is in the tonic or clonic phase of a seizure, should the ascent be delayed until the clonic phase has subsided? Are there any special considerations for rescuing rebreather divers? Phase 2, retrieval to the surface: What is a "safe" ascent rate? If the rescuer has a decompression obligation, should they take the victim to the surface? If the regulator is in the mouth and the victim is breathing, does this change the ascent procedures? If the regulator is in the mouth, the victim is breathing, and the victim has a decompression obligation, does this change the ascent procedures? Is it necessary to hold the victim's head in a particular position? Is it necessary to press on the victim's chest to ensure exhalation? Are there any special considerations for rescuing rebreather divers? Phase 3, procedure at the surface: Is it possible to make an assessment of breathing in the water? Can effective rescue breaths be delivered in the water? What is the likelihood of persistent circulation after respiratory arrest? Does the recent advocacy for "compression-only resuscitation" suggest that rescue breaths should not be administered to a non-breathing diver? What rules should guide the relative priority of in-water rescue breaths over accessing surface support where definitive CPR can be started? A "best practice" decision tree for submerged diver rescue has been proposed.

Exposure to elevated ambient pressure (hyperbaric conditions) occurs most commonly in underwater diving, during which respired gas density and partial pressures, work of breathing, and physiological dead space are all increased. There is a tendency toward hypercapnia during diving, with several potential causes. Most importantly, there may be reduced responsiveness of the respiratory controller to rising arterial CO₂, leading to hypoventilation and CO₂ retention. Contributory factors may include elevated arterial PO₂, inert gas narcosis and an innate (but variable) tendency of the respiratory controller to sacrifice tight control of arterial CO₂ when work of breathing increases. Oxygen is usually breathed at elevated partial pressure under hyperbaric conditions. Oxygen breathing at modest hyperbaric pressure is used therapeutically in hyperbaric chambers to increase arterial carriage of oxygen and diffusion into tissues. However, to avoid cerebral and pulmonary oxygen toxicity during underwater diving, both the magnitude and duration of oxygen exposure must be managed. Therefore, most underwater diving is conducted breathing mixtures of oxygen and inert gases such as nitrogen or helium, often simply air. At hyperbaric pressure, tissues equilibrate over time with high inspired inert gas partial pressure. Subsequent decompression may reduce ambient pressure below the sum of tissue gas partial pressures (supersaturation) which can result in tissue gas bubble formation and potential injury (decompression sickness). Risk of decompression sickness is minimized by scheduling time at depth and decompression rate to limit tissue supersaturation or size and profusion of bubbles in accord with models of tissue gas kinetics and bubble formation and growth., (© 2011 American Physiological Society.)

Inner ear decompression sickness has been strongly associated with the presence of right-to-left shunts. The implied involvement of intravascular bubbles shunted from venous to arterial circulations is inconsistent with the frequent absence of cerebral symptoms in these cases. If arterial bubbles reach the labyrinthine artery, they must also be distributing widely in the brain. This discrepancy could be explained by slower inert gas washout from the inner ear after diving and the consequent tendency for arterial bubbles entering this supersaturated territory to grow because of inward diffusion of gas. Published models for inner ear and brain inert gas kinetics were used to predict tissue gas tensions after an air dive to 4 atm absolute for 25 min. The models predict half-times for nitrogen washout of 8.8 min and 1.2 min for the inner ear and brain, respectively. The inner ear remains supersaturated with nitrogen for longer after diving than the brain, and in the simulated dive, for a period that corresponds with the latency of typical cases. It is therefore plausible that prolonged inner ear inert gas supersaturation contributes to the selective vulnerability of the inner ear to short latency decompression sickness in divers with right-to-left shunt.

Aims: This study evaluated the relative importance of perfusion and diffusion mechanisms in compartmental models of blood : tissue helium exchange in a predominantly skeletal muscle tissue bed in the sheep hind limb. Helium has different physiochemical properties from previously studied gases and is a common diluent gas in underwater diving where decompression schedules are based on theoretical models of inert gas kinetics., Methods: Helium kinetics across skeletal muscle were determined during and after 20 min of helium inhalation, at separate resting and low steady-states of femoral vein blood flow in six sheep under isoflurane anaesthesia. Helium concentrations in arterial and femoral vein blood were determined using gas chromatographic analysis and femoral vein blood flow was monitored continuously. Parameters and model selection criteria of various perfusion-limited or perfusion-diffusion compartmental models of skeletal muscle were estimated by simultaneous fitting of the models to the femoral vein helium concentrations for both blood flow states., Results: A model comprising two parallel perfusion-limited compartment models fitted the data well but required a 51-fold difference in relative compartment perfusion that did not seem physiologically plausible. Models that allowed a countercurrent diffusion exchange of helium between arterial and venous vessels outside of the tissue compartments provided better overall fit of the data and credible parameter estimates., Conclusions: These results suggest a role of arterial-venous diffusion in blood : tissue helium equilibration in skeletal muscle.

1. Perfluorocarbon emulsions have potential medical applications, particularly as temporary oxygen carriers and are likely to be coadministered with other intravenous drugs. It is possible that perfluorocarbon emulsions may alter the disposition of other drugs in the body. 2. In the present study, we examined the brain pharmacokinetics of a 5 min infusion of 100 mg lignocaine in three chronically instrumented sheep before and after the administration of a new investigational perflurocarbon emulsion (Oxygent; Alliance Pharmaceutical, San Diego, CA, USA). 3. The rate constant for the blood : brain equilibration of lignocaine was larger after perflubron administration. This change could not be attributed to a change in brain blood flow and, therefore, may be the result of a change in the free fraction of lignocaine in the blood.

This study evaluated the relative importance of perfusion and diffusion mechanisms in compartmental models of blood:tissue helium exchange in the brain. Helium has different physiochemical properties from previously studied gases, and is a common diluent gas in underwater diving where decompression schedules are based on theoretical models of inert gas kinetics. Helium kinetics across the cerebrum were determined during and after 15 min of helium inhalation, at separate low and high steady states of cerebral blood flow in seven sheep under isoflurane anaesthesia. Helium concentrations in arterial and sagittal sinus venous blood were determined using gas chromatographic analysis, and sagittal sinus blood flow was monitored continuously. Parameters and model selection criteria of various perfusion-limited or perfusion-diffusion compartmental models of the brain were estimated by simultaneous fitting of the models to the sagittal sinus helium concentrations for both blood flow states. Purely perfusion-limited models fitted the data poorly. Models that allowed a diffusion-limited exchange of helium between a perfusion-limited tissue compartment and an unperfused deep compartment provided better overall fit of the data and credible parameter estimates. Fit to the data was also improved by allowing countercurrent diffusion shunt of helium between arterial and venous blood. These results suggest a role of diffusion in blood:tissue helium equilibration in brain.

Many divers report less fatigue following diving breathing oxygen rich N2-O2 mixtures compared with breathing air. In this double blinded, randomized controlled study 11 divers breathed either air or Enriched Air Nitrox 36% (oxygen 36%, nitrogen 64%) during an 18 msw (281 kPa(a)) dry chamber dive for a bottom time of 40 minutes. Two periods of exercise were performed during the dive. Divers were assessed before and after each dive using the Multidimensional Fatigue Inventory-20, a visual analogue scale, Digit Span Tests, Stroop Tests, and Divers Health Survey (DHS). Diving to 18m produced no measurable difference in fatigue, attention levels, ability to concentrate or DHS scores, following dives using either breathing gas.

Isolated inner ear decompression sickness (DCS) is recognized in deep diving involving breathing of helium-oxygen mixtures, particularly when breathing gas is switched to a nitrogen-rich mixture during decompression. The biophysical basis for this selective vulnerability of the inner ear to DCS has not been established. A compartmental model of inert gas kinetics in the human inner ear was constructed from anatomical and physiological parameters described in the literature and used to simulate inert gas tensions in the inner ear during deep dives and breathing-gas substitutions that have been reported to cause inner ear DCS. The model predicts considerable supersaturation, and therefore possible bubble formation, during the initial phase of a conventional decompression. Counterdiffusion of helium and nitrogen from the perilymph may produce supersaturation in the membranous labyrinth and endolymph after switching to a nitrogen-rich breathing mixture even without decompression. Conventional decompression algorithms may result in inadequate decompression for the inner ear for deep dives. Breathing-gas switches should be scheduled deep or shallow to avoid the period of maximum supersaturation resulting from decompression.

Acclimatization to decompression stress has been reported in caisson workers and helium-oxygen divers; however the alternative notion that the risk of decompression sickness increases with successive days of diving is widespread. We examined 201 multi-day series of 2 to 29 diving days identified retrospectively in a database of occupational air dives for evidence of acclimatization or sensitization. Decompression related health status was measured using a self-administered diver health survey; resulting scores were analyzed by linear modelling. Daily diving consisted of 1-3 dives each to mean maximum depth of 17.2 (SD 3.9) meters seawater for a mean duration of 23 (SD 17) min. Daily diver health scores increased with calculated daily risk of decompression sickness but were not influenced by the order of dives in multi-day series. Poor health outcome indicated by treated decompression sickness and diver health scores > 8 occurred early in multi-day series. There was no evidence of sensitization to decompression stress whereas the timing of poor health outcomes suggests an element of acclimatization.

Background: Many occupational diving groups have substantially different diving patterns to those for which decompression schedules are validated., Aims: To evaluate tuna farm occupational diving practice against existing decompression models and describe a method for collecting and modelling self reported field decompression data., Methods: Machine readable objective depth/time profiles were obtained from depth/time recorders worn by tuna farm occupational divers. Divers' health status was measured at the end of each working day using a self administered health survey that produces an interval diver health score (DHS) with possible values ranging from 0 to 30. Depth/time profiles were analysed according to existing decompression models. The contribution of diving exposure and between diver variability to DHS was evaluated using linear regression., Results: The mean risk of decompression sickness was calculated as 0.005 (SD 0.003, n = 383). The mean DHS following diving was 3 (SD 2, n = 383) and following non-diving activities was 1 (SD 1, n = 41). After accounting for between diver variability in intercept, DHS was found to increase one unit for every 1% increase in the risk of decompression sickness., Conclusions: A method has been established for the collection and analysis of self reported objective decompression data from occupational diving groups that can potentially be used as the basis for development of purpose designed occupational diving decompression schedules.

Introduction: Hysteresis plots can be used to examine pharmacokinetic data in which there is a transport delay between drug concentrations at two sites in the body (e.g., in blood entering and leaving an organ). However, the area enclosed by the hysteresis "loop" does not provide quantitative information about the magnitude of the delay., Methods: A quick, graphical, and model independent alternative to the hysteresis plot (an "area fraction plot") was developed for a spreadsheet program on a personal computer. It has the advantage that the area enclosed by the "loop" is the mean transit time (MTT) of the transport delay. The method was based on plotting the cumulative area under the concentration-time curve as a fraction of the total area under curve for each site, and is a type of moment analysis. The method is described and was validated by application to simulated data sets. It was also applied to previously published data to calculate the MTT of lidocaine in the lungs and hindquarters of conscious, instrumented sheep., Results: The validation process showed the area fraction plot was relatively insensitive to integration errors even with moderately noisy data sets. However, failing to analyse the data up to the time point where pseudo-equilibrium was re-established could result in potentially large underestimates of the transit time. The MTT of lidocaine (mean+/-S.E.M.) in the lungs of five sheep was rapid (0.61+/-0.15 min), and 14.2+/-3.1% of the lidocaine was retained in the lungs. The values were in good agreement with values obtained via structural modelling of the same data. The MTT of lidocaine in the hindquarters was 10.6+/-0.9 min, and the retention was 25.2+/-3.1%., Discussion: The method can be used in the same situations as a hysteresis plot, but provides additional quantitative information about the transport delay causing the hysteresis.

1. The effects of cerebral arterial gas embolism on cerebral blood flow and systemic cardiovascular parameters were assessed in anaesthetized sheep. 2. Six sheep received a 2.5 mL injection of air simultaneously into each common carotid artery over 5 s. Mean arterial blood pressure, heart rate, end-tidal carbon dioxide and an ultrasonic Doppler index of cerebral blood flow were monitored continuously. Cardiac output was determined by periodic thermodilution. 3. Intracarotid injection of air produced an immediate drop in mean cerebral blood flow. This drop was transient and mean cerebral blood flow subsequently increased to 151% before declining slowly to baseline. Coincident with the increased cerebral blood flow was a sustained increase in mean cardiac output to 161% of baseline. Mean arterial blood pressure, heart rate and end-tidal carbon dioxide were not significantly altered by the intracarotid injection of air. 4. The increased cardiac output is a pathological response to impact of arterial air bubbles on the brain, possibly the brainstem. The increased cerebral blood flow is probably the result of the increased cardiac output and dilation of cerebral resistance vessels caused by the passage of air bubbles.

This study evaluated the relative importance of perfusion and diffusion mechanisms in compartmental models of blood : tissue inert gas exchange in skeletal muscle. Nitrous oxide kinetics in a hind limb skeletal muscle bed were determined during and after 20 min of nitrous oxide inhalation, at separate low and high steady states of hind limb blood flow in five sheep under halothane anaesthesia. Nitrous oxide concentrations in arterial and femoral vein blood were determined using gas chromatographic analysis and femoral vein blood flow was monitored continuously. Parameters and model selection criteria of various perfusion- or diffusion-limited structural models of skeletal muscle were estimated by simultaneous fitting of the models to the mean observed femoral vein nitrous oxide concentration for both blood flow states. Purely perfusion-limited models fit the data poorly. Models that allowed a diffusion-limited exchange of nitrous oxide between a perfusion-limited tissue compartment and an unperfused deep compartment provided better overall fit of the data and credible parameter estimates. The data was best described by allowing, in addition to diffusion-limited tissue equilibration, counter current diffusion of nitrous oxide between arterial and venous blood. The level of tissue blood flow modifies the magnitudes of both these diffusion effects. These results suggest a dual role of diffusion in blood : tissue inert gas equilibration in skeletal muscle.

Other authors have demonstrated an increase in tear film bubble counts following dry, compressed air dives. We examined the lower tear film meniscus for the presence of bubbles in 42 divers after compressed air dives on a single day and in 11 divers undergoing repetitive, multi-day diving exposures over 5 days. After diving, bubble counts increased significantly (P < 0.01) from predive values. From a predive median (inter-quartile range) of 0 (0-0.33) bubbles/eye, single-day divers reached a maximum bubble count at 48 h after diving of 1 (0-2.25) bubbles/eye. Similarly, from a predive count of 0.33 (0-1) bubbles/eye, multi-day divers had increased bubble counts from 24 h following their first dive until 24 h following their final dive when counts were 1.67 (0.92-3.08) bubbles/eye. Bubble counts were not significantly correlated with inert gas load, body mass index, age, or diving experience. We confirm that tear film bubble counts are raised after wet compressed air diving as previously described following dry diving.

Objectives: Much of the tuna harvested in South Australia since 1990 has involved "farming" techniques requiring the use of divers. From 1993 to 1995, 17 divers from this industry were treated for decompression illness (DCI). In response, the State Government introduced corrective strategies. A decrease in the number of divers presenting for treatment was subsequently recorded. Consequently, the hypothesis was tested that the government intervention resulted in a decrease in the incidence of DCI in the industry and an improved clinical outcome of divers with DCI., Methods: The incidence of treated DCI in tuna farm divers was estimated from the number of divers with DCI treated and the number of dives undertaken extrapolated from a survey of the industry in 1997-8. General health was measured in the tuna farm diving population by a valid and reliable self assessment questionnaire. The outcome of the divers treated for DCI was analysed with a modified clinical severity scoring system., Results: The apparent incidence of treated DCI has decreased in tuna farm divers since the government intervention. The evidence supports a truly decreased incidence rather than underreporting. The general health of the tuna farm divers was skewed towards the asymptomatic end of the range, although health scores indicative of DCI were reported after 1.7% of the dives that did not result in recognised DCI. The clinical outcome of the divers treated since the intervention has improved, possibly because of earlier recognition of the disease and hence less time spent diving while having DCI., Conclusions: The government intervention in the tuna industry in South Australia has resulted in a reduced incidence of DCI in the industry.

Decompression sickness (DCS) is a potentially crippling disease caused by intracorporeal bubble formation during or after decompression from a compressed gas underwater dive. Bubbles most commonly evolve from dissolved inert gas accumulated during the exposure to increased ambient pressure. Most diving is performed breathing air, and the inert gas of interest is nitrogen. Divers use algorithms based on nitrogen kinetic models to plan the duration and degree of exposure to increased ambient pressure and to control their ascent rate. However, even correct execution of dives planned using such algorithms often results in bubble formation and may result in DCS. This reflects the importance of idiosyncratic host factors that are difficult to model, and deficiencies in current nitrogen kinetic models. Models describing the exchange of nitrogen between tissues and blood may be based on distributed capillary units or lumped compartments, either of which may be perfusion- or diffusion-limited. However, such simplistic models are usually poor predictors of experimental nitrogen kinetics at the organ or tissue level, probably because they fail to account for factors such as heterogeneity in both tissue composition and blood perfusion and non-capillary exchange mechanisms. The modelling of safe decompression procedures is further complicated by incomplete understanding of the processes that determine bubble formation. Moreover, any formation of bubbles during decompression alters subsequent nitrogen kinetics. Although these factors mandate complex resolutions to account for the interaction between dissolved nitrogen kinetics and bubble formation and growth, most decompression schedules are based on relatively simple perfusion-limited lumped compartment models of blood: tissue nitrogen exchange. Not surprisingly, all models inevitably require empirical adjustment based on outcomes in the field. Improvements in the predictive power of decompression calculations are being achieved using probabilistic bubble models, but divers will always be subject to the possibility of developing DCS despite adherence to prescribed limits.

Background: Thiopental and propofol are highly lipid-soluble, and their entry into the brain often is assumed to be limited by cerebral blood flow rather than by a diffusion barrier. However, there is little direct experimental evidence for this assumption., Methods: The cerebral kinetics of thiopental and propofol were examined over a range of cerebral blood flows using five and six chronically instrumented sheep, respectively. Using anesthesia (2.0% halothane), three steady state levels of cerebral blood flow (low, medium, and high) were achieved in random order by altering arterial carbon dioxide tension. For each flow state, 250 mg thiopental or 100 mg propofol was infused intravenously over 2 min. To quantify cerebral kinetics, arterial and sagittal sinus blood was sampled rapidly for 20 min from the start of the infusion, and 1.5 h was allowed between consecutive infusions. Various models of cerebral kinetics were examined for their ability to account for the data., Results: The mean baseline cerebral blood flows for the "high" flow state were over threefold greater than those for the low. For the high-flow state the normalized arteriovenous concentration difference across the brain was smaller than for the low-flow state, for both drugs. The data were better described by a model with partial membrane limitation than those with only flow limitation or dispersion., Conclusions: The cerebral kinetics of thiopental and propofol after bolus injection were dependent on cerebral blood flow, despite partial diffusion limitation. Higher flows produce higher peak cerebral concentrations.

1. An acute in vivo hindlimb skeletal muscle preparation was developed in anaesthetized sheep in order to facilitate studies of the effects of altered blood flow states on drug kinetics in skeletal muscle. 2. A continuous index of blood flow was recorded via ultrasonic Doppler probes on the femoral artery and vein. Skeletal muscle effluent blood was sampled via a catheter in the femoral vein proximal to the probe. Low- and high-blood flow states were achieved by direct femoral artery infusion of adrenaline (0.002-0.006 mg/min) or magnesium (0.4-1 mmol/min), which produced mean (+/-SD) stable flow states of 25+/-12 and 185+/-56% (both n = 5) of baseline, respectively. The correlation coefficients between arterial and venous Doppler frequency shifts in five sheep during and after adrenaline infusion were 0.96 (indicating these vessels probably supplied and drained common tissue). 3. The venous Doppler frequency shifts were calibrated against timed collections of the femoral vein outflow to provide estimates of the low and normal blood flow states (mean flows of 2.8+/-1.7 and 9.3+/-5.7mL/100 g per min; both n = 3) and against an indirect Kety-Schmidt method during low- and high-blood flow states (mean flows of 2.2+/-1.3 and 18.2+/-7.0 mL/100 g per min; both n = 5). There was a generally good agreement between the two methods. 4. The tissue was neither hypoxic nor acidotic in the low- or high-flow states and altering the flow produced no change in muscle oxygen consumption, suggesting the flow changes were largely due to changes in resistance vessel tone. 5. Postmortem femoral artery dye injection and dissection of stained tissues showed the artery supplied 657+/-96 g (n = 5) of skeletal muscle and 42+/-20 g (n = 5) of other tissues. 6. It is concluded that the method is suitable for sampling predominantly muscle effluent blood at low- or high-blood flow states according to experimental requirements.

1. The present study compares the indirect Fick nitrous oxide equilibration method of Kety and Schmidt for cerebral blood flow (CBF) estimation with a direct ultrasonic Doppler index of venous outflow. 2. Cerebral blood flow was determined simultaneously by the direct measurement of sagittal sinus blood velocity and the indirect Kety and Schmidt method in five anaesthetized sheep during high and low steady states of CBF. High- and low-flow states were achieved by altering ventilation to produce hypercarbia and hypocarbia, respectively. 3. Four different sets of calculations were used to make the Kety and Schmidt estimations: arterial-venous nitrous oxide concentration differences during uptake or elution of the indicator and with or without extrapolation of arterial-venous differences to infinity. 4. During 15 min nitrous oxide administration, apparent blood:tissue equilibration of nitrous oxide was rapid in some data sets and slow in others. 5. There were no significant differences in CBF estimates between any of the four Kety and Schmidt calculations or the direct ultrasonic Doppler venous outflow method; however, CBF estimates based on nitrous oxide uptake correlated more strongly with the direct method than estimates based on nitrous oxide elution. 6. In the high-flow state, CBF estimates based on nitrous oxide uptake, but not those based on elution, distinguished between rapid and slow blood:tissue equilibration of nitrous oxide. 7. This provides validation of the Doppler sheep brain venous outflow method against the widely used Kety and Schmidt method.

The myocardial kinetics of meperidine and the relationship between these kinetics and the effect of meperidine on myocardial contractility (maximum positive rate of change of left ventricular pressure) were examined by analysis of previously published data collected in sheep after the i.v. injection of 100 mg of meperidine over 1 s. There was significant hysteresis between reductions in myocardial contractility and the arterial concentrations of meperidine, but not the coronary sinus blood (effluent from the heart) or calculated myocardial concentrations. The peak reduction in contractility occurred after the peak arterial concentration, at the time of the peak myocardial concentration, but before the peak coronary sinus concentration, suggesting that the site of drug action in the heart was not in equilibrium with either arterial blood or effluent blood from the heart. The most appropriate form of a dynamic model (a linear model with a threshold) was determined, without the need to assume a kinetic model, by directly fitting the observed reductions in myocardial contractility to the calculated myocardial concentrations. To determine the optimal kinetic and combined kinetic-dynamic models, a variety of one-, two-, and three-compartment models of the myocardium were fitted to the coronary sinus concentrations by using hybrid modeling. These included "tank in series" models that accounted well for drug dispersion and "peripheral compartment" models that accounted well for deep distribution. The most appropriate model was a "compilation" model, which incorporated features of both these extremes and was a better fit to the observed data than either a traditional single flow-limited compartment or a traditional membrane-limited model.

This study aimed to evaluate the relative importance of diffusion-limited vs. perfusion-limited mechanisms in compartmental models of blood-tissue inert gas exchange in the brain. Nitrous oxide concentrations in arterial and brain efferent blood were determined using gas chromatographic analysis during and after 15 min of nitrous oxide inhalation, at separate low and high steady states of cerebral blood flow (CBF) in five sheep under halothane anesthesia. Parameters and model selection criteria of various perfusion- or diffusion-limited structural models of the brain were estimated by simultaneous fitting of the models to the mean observed brain effluent nitrous oxide concentration for both blood flow states. Perfusion-limited models returned precise, credible estimates of apparent brain volume but fit the low CBF data poorly. Diffusion-limited models provided better overall fit of the data, which was best described by exchange of nitrous oxide between a perfusion-limited brain compartment and an unperfused compartment. In individual animals, during the low CBF state, nitrous oxide kinetics displayed either fast, perfusion-limited behavior or slow, diffusion-limited behavior. This variability was exemplified in the different parameter estimates of the diffusion limited models fitted to the individual animal data sets. Results suggest that a diffusion limitation contributes to cerebral nitrous oxide kinetics.

The mechanism by which adenosine accumulates in the hippocampal slice during energy deprivation was investigated by examining the adenosine A1 receptor mediated depression of synaptically evoked field potentials in the CA1 area. Blocking of the mitochondrial electron transport chain with 200 microM sodium cyanide or mitochondrial uncoupling with 50 microM 2,4-dinitrophenol both produced a rapid depression of synaptic transmission that was antagonised by 1 microM 8-cyclopentyl-1, 3-dimethylxanthine, an adenosine A1 receptor antagonist. Cellular ATPase inhibition or elevation of cytosolic phosphocreatine failed to alter the 2,4-dinitrophenol induced depression of synaptic transmission. Attempts to block mitochondrial ATP synthesis with 3 microM oligomycin or 75 microM atractyloside did not cause depression of synaptic transmission. 100 microM iodotubercidin, an adenosine kinase inhibitor, alone produced a depression of synaptic transmission that was completely reversed by 1 microM 8-cyclopentyl-1,3-dimethylxanthine; however, a simultaneous or independent episode of hypoxia surmounted the adenosine A1 receptor antagonism and produced approximately 50% depression of synaptic transmission. Depression of synaptic transmission by hypoxia, cyanide or 2,4-dinitrophenol is a result of rapid adenosine accumulation and activation of extracellular adenosine A1 receptors. Although this early depression of synaptic transmission is a consequence of inhibition of normal mitochondrial function, it is not a result of depletion of cytosolic ATP, since attempts to preserve ATP did not maintain synaptic transmission during mitochondrial poisoning, and inhibitors of oxidative phosphorylation did not produce synaptic depression.

In the guinea-pig isolated ileum, (RS)-(+/-)-baclofen induced a depression of cholinergic twitch contractions, reversibly and competitively antagonised by (S)-2-hydroxysaclofen (pA2 = 5.2 +/- 0.2), but not by (R)-2-hyroxysaclofen. The depression of excitatory field potentials by baclofen ( 5 mu M) in rat CA1 hippocampal slices was antagonised by (S)-2-hydroxysaclofen (100 mu m) (pA2 = 4.3), whilst in rat neocortex, (S)-2-hyroxysaclofen (50-500 mu M) antagonised the baclofen (10 mu M)-induced suppression of spontaneous discharges, the (R)-enantiomer being inactive. These results show that (S)-2-hydroxysaclofen is the active antagonist at central and peripheral GABAB receptors.

Participation of adenosine receptors in the depression of synaptic transmission during hypoxia, and the production of multiple populations spikes in the pyramidal neurons following hypoxia, has been investigated in the CA1 area of the rat hippocampal slice. A method is presented for analysing such hyperexcitability, using input/output curves of the second population spike. This method provides evidence that rebound hyperexcitability following hypoxia or prolonged adenosine-mediated inhibition results from an increase in excitability of the CA1 pyramidal neurons rather than from an increase in excitatory neurotransmitter release. Hypoxia-induced depression of the synaptic components of evoked field potentials was blocked in a concentration dependent manner by the selective A1 receptor antagonist 8-cyclopentyltheophylline (8-CPT), demonstrating extracellular accumulation of adenosine during hypoxia. Upon reoxygenation of slices following 30 min hypoxia, multiple population spikes were evoked by a single orthodromic stimulus in slices that exhibited only a single population spike prior to hypoxia. Such post-hypoxic hyperexcitability was not prevented by superfusion of slices with 8-CPT during hypoxia. Depression of synaptic transmission by 30 min superfusion of slices with 50 microM adenosine was also followed, upon washout, by the appearance of multiple population spikes. However, such hyperexcitability could not be produced by superfusion with adenosine analogues selective for A1 receptors, cyclopentyladenosine, selective for A2a receptors, 2-p-(2-carboxyethyl)phenetheylamino-5'-ethylcarboxamidoadenosine (CGS 21680), or active at A2a and A2b receptors, N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine, suggesting that adenosine receptors other than the A1, A2a or A2b subtypes are involved in its generation.

The activity of the nitropropane analog of baclofen, 3-amino-2-(4-chlorophenyl)-nitropropane (N-BAC), has been examined at central and peripheral GABAB receptors. N-BAC was less potent than baclofen as a GABAB receptor agonist in depressing repetitive twitch contractions in the guinea-pig isolated ileum (IC50s for baclofen = 4.1 +/- 1.3 microM; N-BAC = 9.2 +/- 0.3 microM) and vas deferens (IC50s for baclofen = 30 microM; N-BAC = 100 microM), competitively antagonised by phaclofen, 2-hydroxysaclofen and CGP 35348 (3-aminopropyl-P-di-ethoxymethylphosphinic acid). In the ileum, the pA2 values for CGP 35348 with baclofen (4.7 +/- 0.2) and N-BAC (4.6 +/- 0.3) were not significantly different (P > 0.05), indicating that both agonists activate the same receptor type. By contrast, in rat neocortical slices, N-BAC was 20 times weaker than baclofen in attenuating spontaneous discharges, sensitive to CGP 35348, whilst it was 100 times less potent than baclofen in depressing evoked CA1 population spikes in the hippocampus. This new GABAB receptor agonist, N-BAC, is thus more active at peripheral than central GABAB receptors.

R-(-)-beta-phenyl-GABA has been compared at GABAB receptors using cortical and ileal preparations. R-(-)-beta-phenyl-GABA (EC50 = 25 microM) was a less potent full agonist than R,S-(+/-)-baclofen (EC50 = 2.5 microM), in depressing CA1 population spikes of rat hippocampal slices, and 5 times less potent in attenuating the spontaneous discharges of rat neocortex. However, R-(-)-beta-phenyl-GABA (100-400 microM) was only a weak partial agonist in the ileum. All these actions were sensitive to CGP 35348 (3-aminopropyl-(P-diethoxymethyl)-phosphinic acid) and therefore mediated by GABAB receptors.