Consensus guideline: Pre-hospital management of decompression illness: expert review of key principles and controversies.

(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.

Within-diver variability in venous gas emboli (VGE) following repeated dives.

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.

Extended lifetimes of bubbles at hyperbaric pressure may contribute to inner ear decompression sickness during saturation diving.

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.

Manned validation of a US Navy Diving Manual, Revision 7, VVal-79 schedule for short bottom time, deep air decompression diving.

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.

Selective vulnerability of the inner ear to decompression sickness in divers with right-to-left shunt: the role of tissue gas supersaturation.

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.

Gas micronuclei that underlie decompression bubbles and decompression sickness have not been identified.

Gas micronuclei are gas-filled voids in liquids from which bubbles can form at low gas supersaturation. If water is depleted of gas micronuclei, high gas supersaturation is required for bubble formation. This high gas supersaturation is required in part to overcome the Laplace pressure at the point of transition from dissolved gas to a bubble of perhaps nanometer-scale radius. The sum of gas and vapour partial pressures inside a spherical bubble (Pbub) of radius r exceeds the ambient barometric pressure (Pamb) and is given by the Young-LaPlace equation: Pbub = Pamb + 2γ/r for a bubble not in contact with a solid surface. The second term on the right-hand side is the Laplace pressure across the gas-liquid interface due to surface tension (γ). For instance, for a surface tension characteristic of blood of 0.056 N·m⁻¹, de novo formation of a bubble of r = 10 nm requires gas supersaturation exceeding 2γ/r = 11.2 MPa. However, in humans, detectable venous gas bubbles follow decompression to sea level from as shallow as 138 kPa air saturation, implying gas supersaturation of only a few kPa are required for decompression bubble formation. It is widely accepted that bubbles that form at such low gas supersaturation grow from pre-existing, micron-scale gas micronuclei. For such gas micronuclei to already exist prior to gas supersaturation they cannot simply be small bubbles because positive feedback of Laplace pressure causes a micron radius bubble to dissolve in a fraction of a second. Theoretical candidates for gas micronuclei are bubbles coated in surfactants that counteract the Laplace pressure or crevices where gas voids assume shapes that negate the Laplace pressure. However, to date, the nature of gas micronuclei that underly decompression-induced bubbles and decompression sickness have yet to be identified. Consequently, I was intrigued that in two previous issues of Diving and Hyperbaric Medicine (2018 Volume 48, Issue 2, page 114 and Issue 3, page 197), letters from Ran Arieli to the Editor hypothesized a mechanism for decompression bubble formation in blood vessels and in the skin. Both letters stated "It is known that nanobubbles form spontaneously when a smooth hydrophobic surface is submerged in water containing dissolved gas. We have shown that nanobubbles are the gas micronuclei underlying decompression bubbles and decompression sickness". Surface nanobubbles have been extensively described in the physical chemistry literature, but the second sentence is supported by citation of an hypothesis article. The latter is based on experimental work (referenced therein) in which sections of large blood vessels from sheep were incubated in saline and compressed to 1.013 MPa for 18 hours then rapidly decompressed to the surface, whereupon macroscopic bubbles were photographed forming on the luminal surface of the vessels. The authors speculate that the bubbles were forming from surface nanobubbles on the vessel lumen, but no experimental or analytical evidence was presented that surface nanobubbles were present on the vessel lumen or were the precursors of the observed macroscopic bubbles. Surface nanobubbles form on atomically smooth, hard surfaces in gas supersaturated liquids and, imaged with atomic force microscopy, appear as spherical caps of gas. As far as I can determine, surface nanobubbles have not been reported on biological tissue surfaces. Surface nanobubbles typically have diameters less than 100 nanometers but have lifetimes that are orders of magnitude longer than would a bubble of similar dimensions. Surface nanobubbles do not grow into macroscopic bubbles when exposed to pressure waves sufficient to cause bubble formation from adventitious gas micronuclei elsewhere in the apparatus. This is surely not the last word in this new and active field of research into nanoscopic gas species; however, based on current evidence one must treat with skepticism speculation that unobserved surface nanobubbles are the gas micronuclei from which bubbles form in humans with low gas supersaturation and which underlie decompression sickness.

In-water recompression.

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.

Probabilistic pharmacokinetic models of decompression sickness in humans: Part 2, coupled perfusion-diffusion models.

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.

Pre-hospital management of decompression illness: expert review of key principles and controversies.

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.

Decompressing rescue personnel during Australian submarine 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 (PDCS), 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 PDCS, which came at the cost of longer oxygen decompressions. For single exposures, DCIEM schedules had PDCS estimates ranging from 1.8% to 6.4% with 0 to 101 UPTD and XVALSS_DISSUB 7 schedules had PDCS 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.

Decompressing recompression chamber attendants during Australian submarine rescue operations.

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 (PDCS) 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 (PDCS), 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 PDCS 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 PDCS 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.

Probabilistic pharmacokinetic models of decompression sickness in humans, part 1: Coupled perfusion-limited compartments.

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.

Venous gas emboli detected by two-dimensional echocardiography are an imperfect surrogate endpoint for decompression sickness.

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).

Consensus guidelines for the use of ultrasound for diving research.

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.

Pathophysiology of inner ear decompression sickness: potential role of the persistent foramen ovale.

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.

Altering blood flow does not reveal differences between nitrogen and helium kinetics in brain or in skeletal miracle in sheep.

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.

Biophysical basis for inner ear decompression sickness.

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.

A quantitative alternative to the hysteresis plot for measurement of drug transit time.

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.