JOURNAL
Vol.
41,
OF
APPLIED
PHYSIOLOGY
No. 3, September
1976.
Printed
in U.S.A.
Decompressian-induced decrease elimination rate in awake dogs B. G. D’AOUST, K. H. SMITH, Virginia Mason Research Center,
in nitrogen
AND H. T. SWANSON Seattle, Washington 98101
D’AOUST, B. G., K. H. SMITH, AND H. T. SWANSON. Decompression-induced decrease in nitrogen elimination rate in awake dogs. J. Appl. Physiol. 41(3): 348-355. 1976. -Formulation of safe decompression procedures still requires unproven assumptions regarding both gas equilibration rates and the associated ascent criteria. Although the assumption of symmetry of uptake and elimination rates has been suspect for several years, few data are available. Measurements of actual mixed venous blood nitrogen content [TN21 during compression and following decompression in chronically catheterized awake dogs have clearly demonstrated that desaturation is markedly slower than saturation, and that this effect can be imposed by decompression. The disappearance of arteriovenous nitrogen concentration differences during desaturation following a decompression that produced decompression sickness indicates that cardiopulmonary and cardiovascular changes induced by mechanisms associated with decompression per se can potentiate its deleterious effects. Current US practices do not provide for such asymmetry, while those used in the UK have incorporated this in their models for the last decade. gas uptake and elimination; decompression sickness; bends; ascent criteria; diving; supersaturation; asymmetry; inert gas
TIME SPENT UNDER PRESSURE must be repaid. Although
saturation diving presents the more extreme decompression problem, it is often less dangerous in practice because by maintaining crews under pressure for many days adequate decompression is more cost effective. On the other hand, with short nonsaturation deep dives, for which there is an increasing need in undersea exploration, there remains a challenge to physiologists to provide both safe and efficient decompression procedures. Viewed physiologically, there are two basic problems: prediction of saturation and desaturation rates, and prediction or calculation of critical conditions for bubble production or phase separation. Solution of both problems rests on measurements as yet inaccessible to us. Reliable measurements of tissue inert gas tension under hyperbaric conditions are only just beginning to be measured in animals and man (1, 4) since up until recently measurements of dissolved gas tension in vivo have been impossible. Thus only a gross picture is available of the combinations of time, depth, supersaturation, and hydrostatic pressure that allow gas phase initiation and bubble growth (10, 23, 33). Since 1968, however, it has been repeatedly demon-
strated (12, 25-27, 29, 30) that symptom-free dives can still produce vascular and avascular bubbles. This places in doubt not only the assumptions regarding the degree of supersaturation tolerated, but also the assumption of symmetry of gas uptake and elimination. In fact, recent studies report direct observation of phenomena which argue against the symmetry assumption. Heimbecker et al. (16) saw capillary stasis following decompression in the hamster cheek pouch and in dog mesentery, both tissues being completely saturated with gas. Buckles (6) observed the same result in the hamster cheek pouch upon decompression from a time/ depth profile that did not induce observable bubbles. More recently Bove et al. (5) have observed the same phenomena in the epidural vertebral venous system, but with the presence of bubble emboli. While it appears that the assumption that tissues can sustain a certain but still unknown degree of supersaturation is justified, it is unlikely that a well-stirred or mechanically active tissue such as blood or muscle under exercise would tolerate as great a supersaturation for as long a time as “unstirred” tissue. More information is required regarding the time period over which a given degree of supersaturation may be tolerated without the appearance of a gas phase. There is more than enough evidence then that decompression per se is not without its physiological effects. It is therefore of interest to directly determine the mixed venous blood content of inert gas during desaturation following decompression. If bubble formation or vascular changes or both occur during decompression, gas elimination must follow a different curve (19, 20). Since decompression immediately precedes desaturation in the diving situation, it is desirable to check its effect on gas elimination. Most measurements of the rates of desaturation of man have revealed “compartments” having half-times ranging from 3 to 310 min (2); such studies have been carried out at ambient pressure of 1 atm or in altitude chambers. This has been considered supporting evidence for the use in diving table calculations of a multiple parallel compartment model. Further, studies of animals under pressure have usually used anesthesia. To our knowledge, no data concerning the time course of change of mixed venous blood inert gas content or tension in awake animals under pressure or following decompression have been reported; however, recent work by Groom et al. (15) at atmospheric pressure has indicated that the unanesthetized dog eliminates half its
348
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DECOMPRESSION-INDUCED
DECREASE
IN
N,
349
ELIMINATION
total N, store in one quarter the time of the anesthetized dog To a first approximation, mixed venous blood inert gas content reflects the average state of saturation of the body’s tissues during saturation and desaturation, neglecting spatial and temporal changes in perfusion. Thus, changes in desaturation rate should first be reflected in mixed venous blood nitrogen content. Such analyses form the basis of this study. METHODS
Mongrel dogs, 15 kg, have been catheterized under anesthesia through the pulmonary artery by SwanGanz catheter. After at least a 24-h recovery period, they were serially &mpled while awake during either saturation to or desaturation from an additional pressure of 1, 2, or 3 atm (33, 66, or 99 ft of seawater [fsw]). Gas analyses were carried out by means of vacuum extraction with a volumetric Van Slyke and transfer of the sample into a gas chromatograph according to the method of Groom et al. (14). In our hands this method gave a sensitivity of kO.05 ~1 nitrogen (sTPn)/ml blood. To accomplish accurate analyses of mixed venous blood samples collected under pressure, a technique was needed to decompress the blood without bubble formation, which seriously decreases accuracy. By dilution of the blood sample with a quantity of gas-free saline previously loaded in the sample syringe, it has been possible to decompress blood samples from any pressure desired by simply adding enough gas-free saline to the blood samples to absorb the excess gas at depth without it becoming supersaturated (8). This technique was used successfully in all analyses of mixed venous and arterial blood, and provided a standard deviation of analyses of no more than 0.5 ,ul nitrogen/ml blood. Because the “no-decompression” profile at the 66- and 99-fsw depths allowed only a small amount of bottom time, few saturation data points were obtained. A longer desaturation sampling of mixed venous blood was carried out on the surface following the decompression. The experimental protocol was as follows: the awake animal was restrained in a standing position, the degree of restraint being the minimum required for strainrelieving the pulmonary artery catheter, but never seriously uncomfortable for the dog. When the animal had adjusted to this situation at surface pressure, the hatch was secured and pressurization begun at 60 ft/min to the test depth. Immediately on reaching the test depth, serial samples of blood were collected rapidly at first at geometrically increasing time intervals until the nodecompression limits (US Navy Tables l-11, 1970, 33) were almost reached for personnel in the chamber. At this point, if more samples were desired, another individual was “locked down” through the entry lock while the first “locked out.” Sampling in this manner during the saturation phase of the experiment was continued for up to 2 h in the 2-atm exposure and up to 1 h in the 4atm exposure. Most emphasis was placed on sampling thoroughly during the first 60 min following the compression and decompression, so as to accurately de-
pict the rapidly changing form of the venous blood nitrogen content curve. The animal was then left unrestrained in the chamber overnight at pressure and room temperature with adequate water. Decompression was carried out the next day with the same arrangement for restraining the animal and a similar sampling protocol. In both cases, compression at the rate of 60 ft/min and decompression at the rate of 25 ft/min, the pressure change was assumed to be essentially a step function, although it must be emphasized that such approximation can only be valid with respect to relatively longer time periods than required for compression and decompression. For studies of isobaric desaturation (Fig. 2), a tracheostomy was performed under general anesthesia 1 wk prior to the experiment and healing was complete. The same restraint was used as in the pressure studies, and the animals were standing (taking their own weight) inside the frame. The arrangement was satisfactory for both the experimental subject and the experimenter. Following collection, samples were stored for analysis under water so as to minimize contamination and analyzed by the above methods within 24 h. The results of all analyses of mixed venous blood nitrogen content [VNJ or arterial nitrogen content [aN,] were expressed as ~1 nitrogen/ml of blood. RESULTS
The average mixed venous nitrogen content found per atm of air was 9.86 ,ul N,/ml of blood which is computed from all initial precompression samples during the study. Consequently, this figure was used to compute the equilibrium values to which whole-body saturation or desaturation was approaching as a result of the pressure change imposed. The figure agrees well with that determined by Groom et al. (14) of 9.5 ,&ml. There are slight but significant differences in [iiNS] and [aN,] due to solubility differences; however, for the purposes of this study these differences were neglected. Figure 1 indicates a comparison of uptake and elimination in an awake dog when the pressure change was 2 atm (i.e., 66 fsw). Exponential constants are extracted from the saturation curve (solid line) by the graphical backward extrapolation method (14). The “slow” compartment of our saturation curve is similar to the slow components of the elimination curve reported by Groom et al. (14) (dotted line) which has been included for comparison. The “fast” component of our saturation curve, however, is much faster than the fast component of their elimination curve. This is an expected difference in gas kinetics between anesthetized and unanesthetized animals and supports our rationale that only awake animals should be used for such studies. It has recently been thoroughly documented by Groom et al. (15). A further implication from Fig. 1 is that uptake and elimination were indeed asymmetric, although our data shown in this curve for elimination is not suitable for graphical analyses. Further work used a least-squares analysis for extraction of constants. The projected values of initial and final [CN,3, based
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350
D’AOUST,
SMITH,
AND
SWANSON
100
EXPONENTIAL TO
AND
PLOT
OF SATURATION
DESATURATlON
horn
gt gl
FROM
66
f.sw.
I
ATA
AT
SURFACE
(1967)-anesthetized
Y = 782&
16.0;‘=
t+
582°0’30t
--‘) oL---‘_
---_
0
0
0 -a--
--
0
P---s-
O--O
dew
tumtion
Y = 75.0.e I j
lb i
20I
30
0101 -4,It 40
60 MINUTES
+ .25 e
6b
50I
701
FIG. 1. Semilogarithmic plot of saturation to and desaturation from 66 fsw of air. Arteriovenous difference is plotted as percent of total expected change in mixed venous nitrogen content [vN,] against time in min. Compression and decompression times are short in comparison to saturation and desaturation times and are considered as step function changes in PN~. Open circles (0) reflect desaturation; ( X) indicates saturation rate from which the lower expression for Y was arrived at graphically. Components a and b refer to the saturation curve (x) shown by the solid line. Data of Groom et al. (14) (0) are compared to the saturation curve. Differences in our data and their “fast” compartment are probably due to anesthesia (see Groom et al. (15)).
1. Exponential Surface
i deviation, % S* deviation, %
fsw
99 fsw
0.358
9.35
0.331 -0.1
Desaturation 0.682 0.0291 0.866 0.114 -1.03
0.52 0.12 0.73 0.26 -0.24
0.26 0.014 0.92 0.08 -0.07
0.341
15.3
4.2
0.65
0.011 0.669
B,
66
6.9
13.2
0.412
B2
fsw
0.21 -0.84
i deviation, % S* deviation, %
k2
33
0.446 0.004 0.733 0.266 - 0.04
h k2 B, B2
h
constants and coefficients* Saturation 0.344 0.0040 0.782 0.218 -0.26
0.003t 0.79
fit of all data to double exponential t Limitations of the data prelower than 0.003. Therefore this than an estimate of a low value.
on the known average venous blood N, solubility (above), were then used for curve fitting the data to a simple two-compartment exponential model given by Y = Ble-“lt + B2e-kd where Y equals the total fraction of saturation, B, and & are the coefficients characterizing the two compartments (blood flow in a perfusion limited model), and k 1and k, are the respective time constants. All results, with the exception of those shown in Fig. 1, were analyzed by a least-squares fit to this doubleexponential equation, modeling a two-compartment system. Essentially the same computer program used by Young et al. (36) was used for this analysis.
----_
--
I
1
90
120
FIG. 2. Isobaric desaturation of N, in a 12-kg tracheostomized awake dog as indicated by [iiN,] sampled from the pulmonary artery. A step function change in alveolar PN~ (neglecting lung washout) was accomplished by suddenly valving pure 0, into the trachea through an endotracheal tube. Results of two experiments are pooled. Curve and data points are also plotted (dotted line) in Figs. 3-5 for comparison. Ordinate: [VN,]; abscissa: time in min.
Constants extracted from the least-squares doubleexponential program (Table 1) were used to draw curves to the same fractional scale by a computer-plotter summarizing the data and reflecting only the apparent rate of saturation and desaturation of the tissues, as reflected by the nitrogen inert gas content of mixed venous blood. These curves are drawn in Figs. 2-5 which include the data points to which they are fitted. Figure 6 is a composite without the data points of the curves extracted from Figs. 2-5. Figures 2-5 are all drawn to the same fractional scale to facilitate comparison. Figure 2 represents an isobaric desaturation, i.e., no total pressure change, whereas Figs. 3-5 represent l-, 2-, and 3-atm pressure changes, respectively. Two prominent features of these data are illustrated in these figures. One is a greater degree of variability of [VNJ during initial saturation of the animal at any particular pressure, whether at 33, 66, or 99 fsw (2, 3, or 4 ATA). This probably reflects dynamic fluctuations in
.
* Extracted from least-squares equation: Y = Ble+’ + B,e-‘+‘. vented calculation of constants value cannot be considered more
I
-0090 t
minutes
TABLE
30I
0
--we l
.
.
(N2)
.
2 ATA
751 0
FIG. 3. additional 8) following saturation Wang X-Y constants
I I5
I 30
I 45
I 60 MINUTES
33 FS.W.
I 75
1 90
I I05
1 120
Saturation (0) to and desaturation ( X) from 33 fsw (one atmosphere of compressed air) in awake 15kg dogs (N = compression and decompression at time 0. Isobaric de(0) is plotted for comparison. All curves were plotted by a plotter using the formula Y = B,eekl’ + Bp-“” and from Table 1.
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DECOMPRESSION-INDUCED
DECREASE
IN
N,
351
ELIMINATION
v (N2)
20
OESATURATION
(ISOBARK)
7 0 5J---,
I I5
30
r 45
I
I
I
I
60
75
90
105
3o
MINUTES
5. Same kind from a total pressure ance of the desaturation
45
60
75
90
105
I20
MINUTES
FIG. 4. Same kind of experiment as shown in Fig. 3 but to and from a total pressure change of 2 atm (N = 3). Note the much lower variance of the pooled data in the desaturation curve, suggesting a less dynamically varying state of the cardiovascular system.
FIG.
30
126
MINUTES
lN2)
15
of experiment as shown in Fig. 4 but to and change of 3 atm. Note the same narrow varicurve as compared to saturation N = 4.
total systemic blood flow and distribution, cardiac output, and tissue perfusion. In contrast, during desaturation the data show considerably less spread (except for decompression from the 33-ft exposures). The other and most significant feature of the results is an apparently more rapid decrease in [VN,] toward the final value of 9.86 ~1 NJml of blood following decompression than an increase toward the anticipated value of (P (in ATA) x 9.86 ml N, per ml of blood) following compression. This is evident in Figs. 2-4. Comparison of these elimination curves to the uptake curves suggests a) that the [VN,] is not a reliable index of either the rate or the state of body saturation following decompression; b) that providing cardiac output is not drastically changed throughout the 2-h sampling period following decompression, the elimination rate of N, from the body must be much reduced from the rate of uptake in the experimental situations studied. This result would be expected if the response observed by Heimbecker et al. (16) and Buckles (6) is happening in the capillary beds of these animals. Further, this assumption demands the corollary that considerable N,
FIG. 6. Composite plot to the same fractional scale as Figs. 2-5 showing basic similarity in uptake and elimination curve, regardless of the pressure change. Isobaric desaturation is also included. Note its greater similarity to the saturation curve than to the elimination curve. Also compare the constants in Table 1.
actually remains in the animal when the [VN,] is almost at ambient equilibrium. Although slight differences are clear in the curves of desaturation from 1, 2, and 3 ATA in Fig. 6, the data spread shown in Figs. 3-5 makes it clear that much more data would be required for significant comparison. We must assume, then, that during desaturation following decompression, the efficiency of transport of inert gases from the tissues to the venous blood has been decreased, and that much less nitrogen is being transferred from tissues to blood at any time after decompression than was transferred from the blood to tissues in the same period of time during saturation. This can be seen in the family of curves plotted in Fig. 6 which summarizes the essential asymmetry of saturation and desaturation following decompression. This difference is more clearly shown by comparison to the “isobaric desaturation” curve which shows the results of two experiments in which a tracheostomized, awake animal was suddenly allowed to breathe pure 02, a 0.7%atm sudden decrease in nitrogen tension effected without a hydrostatic pressure decrease. The latter curve is more nearly symmetrical with the hyperbaric saturation curves to 1, 2, and 3 additional atm of pressure as would be expected. The skin effect demonstrated by Groom et al. (13, 15) can contribute only a small amount to this curve which reflects chiefly the faster components. This indicates that it is decompression per se which by some as yet unknown mechanism imposes the asymmetry. The opposite control experiment, namely isobaric saturation, has not been carried out here because it obviously requires the experimentally difficult initial N, washout. Its absence is unimportant relative to the implications of the results, that uptake and elimination are not symmetrical under diving conditions. The fact that the desaturation curves plotted for the 66- and 99.ft dives exhibit considerably less variability as compared to their saturation counterparts is consistent with the conclusion that certain factors associated with decompression (possibly bubble formation, capillary stasis, or both) have severely limited the rate of transfer of tissue inert gas to the venous blood, interfer-
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352
D’AOUST,
ing with the dynamic control of tissue perfusion, thereby producing the apparently rapid desaturation of venous blood and yet at the same time leaving much inert gas still in the animal. It can be calculated on the basis of the total Nz store of the animal, the concentration of nitrogen in the venous blood and tissues and the coefficients and exponential constants computed in Table 1, that it would be impossible for the dog to completely desaturate by the time mixed venous blood nitrogen levels have decreased nearly to the value expected at one atmosphere. The amount of N, remaining and the degree of asymmetry imposed can be crudely estimated from this data and published values of the nitrogen store of dogs. Based on kinetic analysis of the body N,-washout curve in anesthetized dogs, Groom et al. (14) estimated an average N, concentration in the dog to be 22.5 ml kg-i atm+, although their values ranged between 17.9 and 34.7 ml=kg+ l atm? Their analysis used a-v differences throughout and assumed a [VN,] value of 9.5 pi/ml blood and a cardiac output (Q) of 115 ml mirP kg? Their value for cardiac output appears low, as compared with other measurements by us not in this study, whereas our values for [vN,], 9.86 ml STPD. ml blood-l atm-*, are similar to theirs. Except for the data shown in Fig. 1, our analysis uses only [TN,3 values and assumes that the v-a difference (during desaturation) is approximated by [vN,3 -9.86 ml l-l l atm-l and by PATA x 9.86 ml l-l atm-I[VNJ during saturation. Due to the unknown degree of physiological shunt, dead space errors, and difference in cardiac output in our own dogs versus those of Groom et al. (14), the results are not strictly comparable. However, the self-consistency of our results and the added interpretive advantage of work on awake animals justifies the following simple comparisons. Figure 7 illustrates an estimate of the “average supersaturation” sustained by our animals as a result of decompression (upper curves) compared to that expected if N, was eliminated according to the curve for “isobaric desaturation” shown in Fig. 5. The supersaturation was calculated on the basis of total nitrogen store, and N, removed at a given time, using the average value of 22.5 mlkg-* l atm+. It is clear that these supersaturation levels would not be sustained for very long; bubbles or a tissue gas phase would surely form in a short time. They represent the degree of decompression stress to which the animals have been subjected. On the other hand, the lower levels show less difference in supersaturation in spite of a threefold pressure difference. During saturation the [TN,] is subject to all the vascular inhomogeneities and nonlinearities which may occur as a result of shifts in cardiac output, vasodilation, capillary flow, and blood composition. One would normally expect similar fluctuations of venous blood inert gas content during desaturation since it is similarly affected by these same spatial and time-varying rates of blood-tissue inert gas transfer. The fact that this is not observed suggests that such effects are “masked” by the effects of the decompression itself. The results of other experiments carried out at 33 and 66 ft suggest that the degree of reduction of tissue to l
AND
SWANSON
MINUTES
l
l
l
SMITH,
l
7. A comparison of the residual “average” supersaturation levels remaining-in dogs decompressed from saturation at one, two and three atmospheres, assuming a) the elimination of N, proceeds according to the curve of “isobaric” desaturation, and b) that elimination oFN, has been limited according to the decompression desaturation curve. Supersaturations are computed as a) lower curves, remaining relative state of saturation as shown by the desaturation curve divided by ambient pressure; b) total N, store of the animal minus that amount of N, removed at time (t) divided by N, store at 1 atm. Both of these estimates are “average” total body values and therefore only comparable with M values in use for tissues with similar half-times. Note that residual supersaturations from l-, 2-, and 3-atm pressure change would be much less and also would differ less than those actually imposed by decompression (top three = a) “average” tissue saturation X curves). Supersaturation ratio pressure in atm + 1 atm (lower curves “isobaric desaturation”); b) total N, store per atm x pressure in atm minus (amount of N, removed as indicated by lowest curve in figure at time t) divided by N, store per atm. FIG.
blood inert gas transport during decompression may be related to the degree of decompression insult. Thus, in one case where a severe decompression from saturation was accidentally imposed on an awake animal, not only the tissue to blood nitrogen elimination was compromised but also elimination through the lungs-possibly by the very presence of gas emboli and their sequelae. This was so marked that at one point the arteriovenous nitrogen difference disappeared for several minutes. Thi s is shown in Fig. 8. Some minutes after this point the mixed venous nitrogen tension aga .in began to elevate and to reflect increased nitrogen elimination from the tissue to the blood, and the animal was therapeutically recompressed. In two other experiments shown in Fig. 9, following saturation to 33 fsw, decompression was allowed to proceed in three increments of 11 fsw each (that is, onethird of an atmosphere). The animals were held either 5 or 14 min following each decompression increment. Mixed venous blood sa mples were collected i mmediately prior to and following the staging with the 5-min hold period and during the 15-min hold period. The results of these two different procedures on two different dives revealed that given a certain minimum staging time of 15 min the mixed venous nitrogen content began to rise again following, and probably as a result of, the first decompression stop indicating that initially the tissue to blood nitrogen clearance was reduced. With an even shorter staging time of 5 min,
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DECOMPRESSION-INDUCED
DECREASE
AWAKE
15 kg
ARTERIAL
IN
N,
353
ELIMINATION
DOG
8 VENOUS
BLOOD
NITROGEN
CONTENT
FOLLOWING DECOMPRESSION FROM SATURATION AT 2 ATA 66 FEET OF SEA WATER BENDS(REOUIRING
@J2)
TREATMEN
1 RESULTED
PRESENTED
AT 7 MIN
ul 2o Cc
5
IO
15
20 MINUTES
25
30
35
FIG. 8. Elimination of a-t difference in acute decompression sickness. a = arterial N, content ml/L blood; v = [vN,] ml/L blood. A 20kg dog was saturated at 66 fsw and decompressed in less than 1 min. Large size of the animal and rapid decompression were undoubtedly factors in the decompression sickness (DS) observed. Note the essential disappearance of a-v difference at lo-15 min after surfacing, with a gradual increase in [vN,] beginning at 14 min. DS was so severe at about 30 min that the dog was recompressed and saved.
2.Q9TA +&--
TIME BETW_EEN STOPS
-
5 0
r
I
IO
I
I 20
I
1 30
1
4b
MINUTES FIG. 9. Evidence of “recovery” of tissue to blood nitrogen clearance following less extreme decompressions from saturation. Two experiments are shown where decompression was in increments of 0.33 atm, i.e., 11 fsw. In one (X-X) a 15min hold at each level was maintained and blood samples taken. In the other (O- - -0) only 5 min were allowed and samples were also collected. In 15-min hold [vN,] increases; i.e., tissue to blood N, transport “recovers” late in the staging period at both the 22- and ll-fsw levels, whereas with 5min hold insufficient time is allowed for this “recovery” to occur, and therefore net decompression stress is increased.
recovery was not seen. The secondary rise in [VN,] following decompression has not been observed with the 66- and 99-ft saturations, possibly because the decompression effect is more severe and long lasting, and recovery from it is accordingly not detectable with our methods. DISCUSSION
AND
CONCLUSIONS
The results of this study clearly demonstrate that inadequate decompression decreases the total rate of gas elimination. This finding is consistent with the
observations of Heimbecker et al. (16) and Buckles (6), and indeed might justifiably have been predicted by them if their experiments had involved less extreme pressures. Our results are also consistent with current concepts of the bends (l), and would appear also to demonstrate the ideas of Hempleman (17, 18) and those of Hills (19). The merit of our approach is that the response can be “titrated” to the “minimal decompression” causing it and thus reflect a “critical” decompression. The decrease in gas elimination rate is manifested as an unnaturally low mixed venous inert gas content. Whether this is a result of separated gas (bubbles) causing capillary stasis through interference with hemodynamic control or other factors is not clear from this study;” _ however, I such a view is consistent with all current studies of which we are aware. Certain information about the pathological consequences of inadequate decompression is known; the presence of gas within the small vasculature of soft t’ issue organs and bone has been demonstrated (31). These gas emboli, as well as the tissue damage they have caused, can initiate the hemostatic process (21, 28) and cause hemoconcentration, increased viscosity and reduced flow (5, 6, 11, 24, 32). These changes, however, are observed to follow a more delayed time course than the rapid changes in elimination rate we have described here. They are undoubtedly related to the latter in some manner but the causal nature of the relationship is unknown. It is possible that endothelial damage, due either to moving gas emboli physically contacting the endothelial cell surface or actually forming underneath the endothelium, could initially stimulate vessel stasis which would decrease total tissue blood flow and therefore gas elimination. This endothelial damage would then initiate the longer term hematological sequelae. Damaged endothelial surfaces have been demonstrated by Warren (34) and Stegall et al. (31) following decompression. It is clear from the time course of the mixed venous blood desaturation that the blood, itself a well-stirred short half-time tissue, sustains a high excess content or supersaturation for only a few minutes. Therefore, under the conditions studied, mixed venous blood is not a reliable indicator of the actual rate of gas elimination following decompression, but indicates the effects of decompression itself. It remains to discover the degree of supersaturation sustained by the blood and different tissues under these conditions, since such high residual gas contents could represent both microbubbles and/or higher tensions. Without better understanding than we now have concerning the relative stability of a given degree of supersaturation in a certain tissue type at any particular pressure, it is too early to conclude as some have done (19) that “no-supersaturation” models are to be preferred. It appears likely that certain minimal supersaturations are relatively stable (23). In the meantime, however, the significance of these results to actual decompression protocol depends somewhat on which decompression model one is using. The decompression model which is least accommodating to
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354
D’AOUST,
our results as it is presently used is the “neo-Haldane” multiple parallel exponential compartment model (22) used in the US and many other countries except the UK. There are two important weaknesses of this model. One is that it makes no allowance for the long-suspected functional asymmetry of gas elimination following decompression which we have demonstrated. Second, it uses “minimal” times for initial decompression stops following a considerable depth change; this is contrary to conclusions resulting from our data. An immediate practical conclusion of this study would seem to be that the minimum staging time during decompression should at least be designed to adequately compensate for the slower gas elimination occasioned by the initial “jump” (or step function increase in AP, i.e., tissue inert gas tension - ambient pressure) to a shallower depth regardless of the decompression model used. As noted above, current procedures often use stops as short as l-3 min. The time taken to desaturate the mixed venous blood to the shoulder of the saturation curve (Figs. l-4) is approximately 10 min in the awake dog and can be expected to be somewhat greater in man. It would seem desirable both to reduce the extent of initial “jump” and to make initial decompression stops at least long enough to take advantage of this relatively high initial rate of nitrogen clearance. It must be emphasized, however, that this rationale is in response to our results of decompression from saturation. There can be little doubt that the severity of the effect we described is related to the “dose” of decompression stress sustained- a function of the total amount of
SMITH,
AND
SWANSON
gas dissolved and the relative decompression imposed. We do not yet have a sufficiently quantitative picture of such a parameter, although some recent work (3, 7, 9) suggests that it is experimentally definable. In any case, it is reasonable to suggest that certain minimal decompression insults are without the response we have described. We are now attempting to determine this minimal “dose” of decompression stress causing the asymmetry. In such a case it is also reasonable to suppose that a symmetrical transport model would be acceptable. We point out, however, that elimination from even the 33-fsw depth showed the same asymmetry, although a much greater spread of the data, as the 2and 3-atm experiments. This pressure drop corresponds to the original highly empirical Haldane ratio of approximately 2.0-2.25 which has been adjusted to varying degrees by all workers in this area to suit the model or the half-time in use. Thus, once again it appears necessary to suggest that further reduction in the permissible supersaturation and ascent rate is desirable. We thank Dr. C. J. Martin and Dr. Steve Lewis of the Institute of Respiratory Physiology, VMRC, for their interest and assistance in providing computer time and programs for data analysis, Mr. Roland White for his interest and engineering skill throughout the project, and Mr. Michael Newman, Mr. John Buczek and Mr. Lee Stayton for chamber operation and control. This study was supported by National Institutes of Health Grants HL-12015 and HL-14801 and National Heart and Lung Institute RCDA Award K04-HL-70543. Received
for publication
1 March
1976.
REFERENCES K. H., D. E. HOLNESS, AND C. A. SCOTT. Measurement of the in vivo uptake and elimination of N, in tissue. In: Proceedings of the 5th Symposium on Underwater Physiology, Freeport, British Bahamas, 1972, edited by C. J. Lambertsen. Bethesda, Md.: Fed. Am. Sot. Exptl. Biol., 1976. BEHNKE, A. R. Some early studies of decompression. In: The Physiology and Medicine of Diving, edited by P. B. Bennett and D. H. Elliott. Baltimore, Md.: Williams & Wilkins, 1969, p. 226251. BEYER, D., B. G. D’AOUST, E. CASILLAS, AND L. S. SMITH. Decompression and isobaric supersaturation in fluid breathing vertebrates: timed response via bioassay, hematology and ultrasonic bubble detections. In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. BOND, G. F., F. L. FISHBACK, M. W. LIPPITT, AND R. D. WOODSON. Multiple inert gas transport patterns. In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. BOVE, A. A., J. M. HALLENBECK, AND D. H. ELLIOTT. Circulatory responses to venous air embolism and decompression sickness. Undersea Biomed. Res. 1: ,207-220, 1974. BUCKLES, R. G. The physics of bubble formation and growth. Aerospace Med. 39: 1062-1068, 1968. D’AOUST, B. G., AND L. S. SMITH. Bends in fish. Comp. Biochem. Physiol. 49A: 311-321, 1974. D’AOUST, B. G., AND H. T. SWANSON. Bubble-free decompression of blood samples. J. Appl. Physiol. 37: 589-591, 1974. D’AOUST, B. G., R. WHITE, AND H. SEIBOLD. Direct measurement of total dissolved gas partial pressure. Undersea Biomed. Res. 2: 141-149, 1975. DIETER, K. H. On a mathematical theory of decompression. IEEE Trans. Biomed. Eng. BME14: 124-146, 1967. END, E. The use of new equipment and helium gas in a world
1. ACKLES,
2.
3.
4.
5.
6. 7. 8. 9.
10. 11.
record dive. J. Znd. Hyg. Toxicol. 20: 511-520, 1938. 12. EVANS, A., E. E. P. BARNHARD, AND D. N. WALDER. Detection of gas bubbles in man at decompression. Aerospace Med. 43: 10951096, 1972. 13. GROOM, A. C., AND L. E. FARHI. Cutaneous diffusion of atmospheric N, during N, washout in the dog. J. Appl. Physiol. 22: 740-748, 1967. 14. GROOM, A. C., R. MORIN, AND L. E. FARHI. Determination of dissolved N, in blood and investigation of N, washout from the body. J. Appl. Physiol. 23: 706-712, 1967. 15. GROOM, A. C., S. H. SONG, Y. OHTA, AND L. E. FARHI. Effect of anesthesia on the rate of N, washout from body stores. J. Appl. Physiol. 37: 219-223, 1974. 16. HEIMBECKER, R. O., G. LEMIRE, C. H. CHEN, J. KOVER, D. LEASK, AND W. R. DRUCKER. Role of gas embolism in decompression sicknessa new look at “the bends.” Surgery 64: 264-272, 1968. 17. HEMPLEMAN, H. V. British decompression theory and practice. In: The Physiology and Medicine of Diving, edited by P. B. Bennett and D. H. Elliott. Baltimore, Md.: Williams 8~ Wilkins’, 1969, p. 291-318. 18. HEMPLEMAN, H. V. The unequal rates of uptake and elimination of tissue nitrogen gas in diving. Proc. RNPRC Report 62/1019, 1960. 19. HILLS, B. A. Thermodynamic decompression: an approach based upon the concept of phase equilibration in tissue. In: The Physiology and Medicine of Diving, edited by P. B. Bennett and D. H. Elliott. Baltimore, Md.: Williams & Wilkins, 1969, p. 319-356. 20. LEMESSURIER, D. H. Supersaturation and “preformed nuclei” in the etiology of decompression sickness. In: Proceedings of the 2nd International Meeting on Aerospace Medicine, Melbourne, 1972. 21. PHILP, R. B. Historical evolution of the blood-bubble interaction hvpothesis in the pathogenesis of decompression sickness. In:
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DECOMPRESSION-INDUCED
22.
23. 24.
25. 26.
27.
28.
29.
DECREASE
IN
N,
ELIMINATION
Proceedings of a Symposium on Blood-Bubble Interaction in Decompression Sickness, DCIEM, Downsview, Ontario, 1973, edited by K. N. Ackles. SCHREINER, H. R., AND P. L. KELLY. A pragmatic view of decompression. In: Underwater Physiology, edited by C. J. Lambertsen. New York: Academic, 1971, p. 205-219. SKRIPOV, V. P. Metastable Liquids. New York: Wiley, 1974, p. 18-54. SMITH, K. H., ET AL. Possible effects of bubble-induced coagulation following decompression. In: Proceedings of a Symposium on Blood-Bubble Interaction in Decompression Sickness, DCIEM, Downsview, Ontario, 1973, edited by K. N. Ackles. SMITH, K. H., AND D. C. JOHANSON. Technical Report, ONR Contract NO0014 69 C 0402, Proj. NR 101-750, 1970. SMITH, K. H., AND M. P. SPENCER. Doppler indices of decompression sickness: their evaluation and use. Aerospace Med. 41: 13961400, 1970. SMITH, K. H., AND L. STAYTON. Safe decompression procedures must they be bubble free? In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. SMITH, K. H., AND P. J. STEGALL. The etiology and pathogenesis of decompression sickness: evaluation of decompression profiles in animals and man. In: Proceedings of the 5th Symposium on Underwater Physiology, Freeport, British Bahamas, 1972, edited by C. J. Lambertsen. Bethesda, Md.: Fed. Am. Sot. Exptl. Biol., 1976. SPENCER, M. P., AND H. F. CLARK. Precordial monitoring of
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31
32
33.
34.
35.
36.
pulmonary gas embolism and decompression bubbles. Aerospace Med. 43: 762-767, 1972. SPENCER, M. P., AND D. C. JOHANSON. Decompression limits for compressed air determined by ultrasonically detected blood bubbles. In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. STEGALL, P. J., K. H. SMITH, AND T. HUANG. Pathogenesis of osteonecrosis as the result of inadequate decompression. In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. SWINDLE, P. F. Occlusion of blood vessels by agglutinated red cells, mainly as seen in tadpoles and very young kangaroos. Am. J. Physiol. 120: 59-74, 1937. VANN, R. D., AND H. G. CLARK. Bubble growth and mechanical properties of tissue in decompression. Undersea Biomed. Res. 2: 185-194, 1975. WARREN, B. A. The ultrastructure of the blood-bubble interface and related alterations in the blood and vessel walls in air embolism. In: Proceedings of a Symposium on Blood-Bubble Interaction in Decompression Sickness, DCIEM, Downsview, Ontario, 1973, edited by K. N. Ackles. WORKMAN, R. D. Calculation of Decompression Schedules for Nitrogen-Oxygen and Helium-Oxygen Dives. Washington, DC.: US Navy Experimental Diving Unit, 1965. (Res. Rept. 6-65) YOUNG, A. C., C. J. MARTIN, AND S. TSUMODA. Lung volumes in diffuse obstructive pulmonary syndromes. J. Clin. Invest. 53: 1178-1184, 1974.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
Vol.
41,
OF
APPLIED
PHYSIOLOGY
No. 3, September
1976.
Printed
in U.S.A.
Decompressian-induced decrease elimination rate in awake dogs B. G. D’AOUST, K. H. SMITH, Virginia Mason Research Center,
in nitrogen
AND H. T. SWANSON Seattle, Washington 98101
D’AOUST, B. G., K. H. SMITH, AND H. T. SWANSON. Decompression-induced decrease in nitrogen elimination rate in awake dogs. J. Appl. Physiol. 41(3): 348-355. 1976. -Formulation of safe decompression procedures still requires unproven assumptions regarding both gas equilibration rates and the associated ascent criteria. Although the assumption of symmetry of uptake and elimination rates has been suspect for several years, few data are available. Measurements of actual mixed venous blood nitrogen content [TN21 during compression and following decompression in chronically catheterized awake dogs have clearly demonstrated that desaturation is markedly slower than saturation, and that this effect can be imposed by decompression. The disappearance of arteriovenous nitrogen concentration differences during desaturation following a decompression that produced decompression sickness indicates that cardiopulmonary and cardiovascular changes induced by mechanisms associated with decompression per se can potentiate its deleterious effects. Current US practices do not provide for such asymmetry, while those used in the UK have incorporated this in their models for the last decade. gas uptake and elimination; decompression sickness; bends; ascent criteria; diving; supersaturation; asymmetry; inert gas
TIME SPENT UNDER PRESSURE must be repaid. Although
saturation diving presents the more extreme decompression problem, it is often less dangerous in practice because by maintaining crews under pressure for many days adequate decompression is more cost effective. On the other hand, with short nonsaturation deep dives, for which there is an increasing need in undersea exploration, there remains a challenge to physiologists to provide both safe and efficient decompression procedures. Viewed physiologically, there are two basic problems: prediction of saturation and desaturation rates, and prediction or calculation of critical conditions for bubble production or phase separation. Solution of both problems rests on measurements as yet inaccessible to us. Reliable measurements of tissue inert gas tension under hyperbaric conditions are only just beginning to be measured in animals and man (1, 4) since up until recently measurements of dissolved gas tension in vivo have been impossible. Thus only a gross picture is available of the combinations of time, depth, supersaturation, and hydrostatic pressure that allow gas phase initiation and bubble growth (10, 23, 33). Since 1968, however, it has been repeatedly demon-
strated (12, 25-27, 29, 30) that symptom-free dives can still produce vascular and avascular bubbles. This places in doubt not only the assumptions regarding the degree of supersaturation tolerated, but also the assumption of symmetry of gas uptake and elimination. In fact, recent studies report direct observation of phenomena which argue against the symmetry assumption. Heimbecker et al. (16) saw capillary stasis following decompression in the hamster cheek pouch and in dog mesentery, both tissues being completely saturated with gas. Buckles (6) observed the same result in the hamster cheek pouch upon decompression from a time/ depth profile that did not induce observable bubbles. More recently Bove et al. (5) have observed the same phenomena in the epidural vertebral venous system, but with the presence of bubble emboli. While it appears that the assumption that tissues can sustain a certain but still unknown degree of supersaturation is justified, it is unlikely that a well-stirred or mechanically active tissue such as blood or muscle under exercise would tolerate as great a supersaturation for as long a time as “unstirred” tissue. More information is required regarding the time period over which a given degree of supersaturation may be tolerated without the appearance of a gas phase. There is more than enough evidence then that decompression per se is not without its physiological effects. It is therefore of interest to directly determine the mixed venous blood content of inert gas during desaturation following decompression. If bubble formation or vascular changes or both occur during decompression, gas elimination must follow a different curve (19, 20). Since decompression immediately precedes desaturation in the diving situation, it is desirable to check its effect on gas elimination. Most measurements of the rates of desaturation of man have revealed “compartments” having half-times ranging from 3 to 310 min (2); such studies have been carried out at ambient pressure of 1 atm or in altitude chambers. This has been considered supporting evidence for the use in diving table calculations of a multiple parallel compartment model. Further, studies of animals under pressure have usually used anesthesia. To our knowledge, no data concerning the time course of change of mixed venous blood inert gas content or tension in awake animals under pressure or following decompression have been reported; however, recent work by Groom et al. (15) at atmospheric pressure has indicated that the unanesthetized dog eliminates half its
348
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DECOMPRESSION-INDUCED
DECREASE
IN
N,
349
ELIMINATION
total N, store in one quarter the time of the anesthetized dog To a first approximation, mixed venous blood inert gas content reflects the average state of saturation of the body’s tissues during saturation and desaturation, neglecting spatial and temporal changes in perfusion. Thus, changes in desaturation rate should first be reflected in mixed venous blood nitrogen content. Such analyses form the basis of this study. METHODS
Mongrel dogs, 15 kg, have been catheterized under anesthesia through the pulmonary artery by SwanGanz catheter. After at least a 24-h recovery period, they were serially &mpled while awake during either saturation to or desaturation from an additional pressure of 1, 2, or 3 atm (33, 66, or 99 ft of seawater [fsw]). Gas analyses were carried out by means of vacuum extraction with a volumetric Van Slyke and transfer of the sample into a gas chromatograph according to the method of Groom et al. (14). In our hands this method gave a sensitivity of kO.05 ~1 nitrogen (sTPn)/ml blood. To accomplish accurate analyses of mixed venous blood samples collected under pressure, a technique was needed to decompress the blood without bubble formation, which seriously decreases accuracy. By dilution of the blood sample with a quantity of gas-free saline previously loaded in the sample syringe, it has been possible to decompress blood samples from any pressure desired by simply adding enough gas-free saline to the blood samples to absorb the excess gas at depth without it becoming supersaturated (8). This technique was used successfully in all analyses of mixed venous and arterial blood, and provided a standard deviation of analyses of no more than 0.5 ,ul nitrogen/ml blood. Because the “no-decompression” profile at the 66- and 99-fsw depths allowed only a small amount of bottom time, few saturation data points were obtained. A longer desaturation sampling of mixed venous blood was carried out on the surface following the decompression. The experimental protocol was as follows: the awake animal was restrained in a standing position, the degree of restraint being the minimum required for strainrelieving the pulmonary artery catheter, but never seriously uncomfortable for the dog. When the animal had adjusted to this situation at surface pressure, the hatch was secured and pressurization begun at 60 ft/min to the test depth. Immediately on reaching the test depth, serial samples of blood were collected rapidly at first at geometrically increasing time intervals until the nodecompression limits (US Navy Tables l-11, 1970, 33) were almost reached for personnel in the chamber. At this point, if more samples were desired, another individual was “locked down” through the entry lock while the first “locked out.” Sampling in this manner during the saturation phase of the experiment was continued for up to 2 h in the 2-atm exposure and up to 1 h in the 4atm exposure. Most emphasis was placed on sampling thoroughly during the first 60 min following the compression and decompression, so as to accurately de-
pict the rapidly changing form of the venous blood nitrogen content curve. The animal was then left unrestrained in the chamber overnight at pressure and room temperature with adequate water. Decompression was carried out the next day with the same arrangement for restraining the animal and a similar sampling protocol. In both cases, compression at the rate of 60 ft/min and decompression at the rate of 25 ft/min, the pressure change was assumed to be essentially a step function, although it must be emphasized that such approximation can only be valid with respect to relatively longer time periods than required for compression and decompression. For studies of isobaric desaturation (Fig. 2), a tracheostomy was performed under general anesthesia 1 wk prior to the experiment and healing was complete. The same restraint was used as in the pressure studies, and the animals were standing (taking their own weight) inside the frame. The arrangement was satisfactory for both the experimental subject and the experimenter. Following collection, samples were stored for analysis under water so as to minimize contamination and analyzed by the above methods within 24 h. The results of all analyses of mixed venous blood nitrogen content [VNJ or arterial nitrogen content [aN,] were expressed as ~1 nitrogen/ml of blood. RESULTS
The average mixed venous nitrogen content found per atm of air was 9.86 ,ul N,/ml of blood which is computed from all initial precompression samples during the study. Consequently, this figure was used to compute the equilibrium values to which whole-body saturation or desaturation was approaching as a result of the pressure change imposed. The figure agrees well with that determined by Groom et al. (14) of 9.5 ,&ml. There are slight but significant differences in [iiNS] and [aN,] due to solubility differences; however, for the purposes of this study these differences were neglected. Figure 1 indicates a comparison of uptake and elimination in an awake dog when the pressure change was 2 atm (i.e., 66 fsw). Exponential constants are extracted from the saturation curve (solid line) by the graphical backward extrapolation method (14). The “slow” compartment of our saturation curve is similar to the slow components of the elimination curve reported by Groom et al. (14) (dotted line) which has been included for comparison. The “fast” component of our saturation curve, however, is much faster than the fast component of their elimination curve. This is an expected difference in gas kinetics between anesthetized and unanesthetized animals and supports our rationale that only awake animals should be used for such studies. It has recently been thoroughly documented by Groom et al. (15). A further implication from Fig. 1 is that uptake and elimination were indeed asymmetric, although our data shown in this curve for elimination is not suitable for graphical analyses. Further work used a least-squares analysis for extraction of constants. The projected values of initial and final [CN,3, based
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350
D’AOUST,
SMITH,
AND
SWANSON
100
EXPONENTIAL TO
AND
PLOT
OF SATURATION
DESATURATlON
horn
gt gl
FROM
66
f.sw.
I
ATA
AT
SURFACE
(1967)-anesthetized
Y = 782&
16.0;‘=
t+
582°0’30t
--‘) oL---‘_
---_
0
0
0 -a--
--
0
P---s-
O--O
dew
tumtion
Y = 75.0.e I j
lb i
20I
30
0101 -4,It 40
60 MINUTES
+ .25 e
6b
50I
701
FIG. 1. Semilogarithmic plot of saturation to and desaturation from 66 fsw of air. Arteriovenous difference is plotted as percent of total expected change in mixed venous nitrogen content [vN,] against time in min. Compression and decompression times are short in comparison to saturation and desaturation times and are considered as step function changes in PN~. Open circles (0) reflect desaturation; ( X) indicates saturation rate from which the lower expression for Y was arrived at graphically. Components a and b refer to the saturation curve (x) shown by the solid line. Data of Groom et al. (14) (0) are compared to the saturation curve. Differences in our data and their “fast” compartment are probably due to anesthesia (see Groom et al. (15)).
1. Exponential Surface
i deviation, % S* deviation, %
fsw
99 fsw
0.358
9.35
0.331 -0.1
Desaturation 0.682 0.0291 0.866 0.114 -1.03
0.52 0.12 0.73 0.26 -0.24
0.26 0.014 0.92 0.08 -0.07
0.341
15.3
4.2
0.65
0.011 0.669
B,
66
6.9
13.2
0.412
B2
fsw
0.21 -0.84
i deviation, % S* deviation, %
k2
33
0.446 0.004 0.733 0.266 - 0.04
h k2 B, B2
h
constants and coefficients* Saturation 0.344 0.0040 0.782 0.218 -0.26
0.003t 0.79
fit of all data to double exponential t Limitations of the data prelower than 0.003. Therefore this than an estimate of a low value.
on the known average venous blood N, solubility (above), were then used for curve fitting the data to a simple two-compartment exponential model given by Y = Ble-“lt + B2e-kd where Y equals the total fraction of saturation, B, and & are the coefficients characterizing the two compartments (blood flow in a perfusion limited model), and k 1and k, are the respective time constants. All results, with the exception of those shown in Fig. 1, were analyzed by a least-squares fit to this doubleexponential equation, modeling a two-compartment system. Essentially the same computer program used by Young et al. (36) was used for this analysis.
----_
--
I
1
90
120
FIG. 2. Isobaric desaturation of N, in a 12-kg tracheostomized awake dog as indicated by [iiN,] sampled from the pulmonary artery. A step function change in alveolar PN~ (neglecting lung washout) was accomplished by suddenly valving pure 0, into the trachea through an endotracheal tube. Results of two experiments are pooled. Curve and data points are also plotted (dotted line) in Figs. 3-5 for comparison. Ordinate: [VN,]; abscissa: time in min.
Constants extracted from the least-squares doubleexponential program (Table 1) were used to draw curves to the same fractional scale by a computer-plotter summarizing the data and reflecting only the apparent rate of saturation and desaturation of the tissues, as reflected by the nitrogen inert gas content of mixed venous blood. These curves are drawn in Figs. 2-5 which include the data points to which they are fitted. Figure 6 is a composite without the data points of the curves extracted from Figs. 2-5. Figures 2-5 are all drawn to the same fractional scale to facilitate comparison. Figure 2 represents an isobaric desaturation, i.e., no total pressure change, whereas Figs. 3-5 represent l-, 2-, and 3-atm pressure changes, respectively. Two prominent features of these data are illustrated in these figures. One is a greater degree of variability of [VNJ during initial saturation of the animal at any particular pressure, whether at 33, 66, or 99 fsw (2, 3, or 4 ATA). This probably reflects dynamic fluctuations in
.
* Extracted from least-squares equation: Y = Ble+’ + B,e-‘+‘. vented calculation of constants value cannot be considered more
I
-0090 t
minutes
TABLE
30I
0
--we l
.
.
(N2)
.
2 ATA
751 0
FIG. 3. additional 8) following saturation Wang X-Y constants
I I5
I 30
I 45
I 60 MINUTES
33 FS.W.
I 75
1 90
I I05
1 120
Saturation (0) to and desaturation ( X) from 33 fsw (one atmosphere of compressed air) in awake 15kg dogs (N = compression and decompression at time 0. Isobaric de(0) is plotted for comparison. All curves were plotted by a plotter using the formula Y = B,eekl’ + Bp-“” and from Table 1.
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DECOMPRESSION-INDUCED
DECREASE
IN
N,
351
ELIMINATION
v (N2)
20
OESATURATION
(ISOBARK)
7 0 5J---,
I I5
30
r 45
I
I
I
I
60
75
90
105
3o
MINUTES
5. Same kind from a total pressure ance of the desaturation
45
60
75
90
105
I20
MINUTES
FIG. 4. Same kind of experiment as shown in Fig. 3 but to and from a total pressure change of 2 atm (N = 3). Note the much lower variance of the pooled data in the desaturation curve, suggesting a less dynamically varying state of the cardiovascular system.
FIG.
30
126
MINUTES
lN2)
15
of experiment as shown in Fig. 4 but to and change of 3 atm. Note the same narrow varicurve as compared to saturation N = 4.
total systemic blood flow and distribution, cardiac output, and tissue perfusion. In contrast, during desaturation the data show considerably less spread (except for decompression from the 33-ft exposures). The other and most significant feature of the results is an apparently more rapid decrease in [VN,] toward the final value of 9.86 ~1 NJml of blood following decompression than an increase toward the anticipated value of (P (in ATA) x 9.86 ml N, per ml of blood) following compression. This is evident in Figs. 2-4. Comparison of these elimination curves to the uptake curves suggests a) that the [VN,] is not a reliable index of either the rate or the state of body saturation following decompression; b) that providing cardiac output is not drastically changed throughout the 2-h sampling period following decompression, the elimination rate of N, from the body must be much reduced from the rate of uptake in the experimental situations studied. This result would be expected if the response observed by Heimbecker et al. (16) and Buckles (6) is happening in the capillary beds of these animals. Further, this assumption demands the corollary that considerable N,
FIG. 6. Composite plot to the same fractional scale as Figs. 2-5 showing basic similarity in uptake and elimination curve, regardless of the pressure change. Isobaric desaturation is also included. Note its greater similarity to the saturation curve than to the elimination curve. Also compare the constants in Table 1.
actually remains in the animal when the [VN,] is almost at ambient equilibrium. Although slight differences are clear in the curves of desaturation from 1, 2, and 3 ATA in Fig. 6, the data spread shown in Figs. 3-5 makes it clear that much more data would be required for significant comparison. We must assume, then, that during desaturation following decompression, the efficiency of transport of inert gases from the tissues to the venous blood has been decreased, and that much less nitrogen is being transferred from tissues to blood at any time after decompression than was transferred from the blood to tissues in the same period of time during saturation. This can be seen in the family of curves plotted in Fig. 6 which summarizes the essential asymmetry of saturation and desaturation following decompression. This difference is more clearly shown by comparison to the “isobaric desaturation” curve which shows the results of two experiments in which a tracheostomized, awake animal was suddenly allowed to breathe pure 02, a 0.7%atm sudden decrease in nitrogen tension effected without a hydrostatic pressure decrease. The latter curve is more nearly symmetrical with the hyperbaric saturation curves to 1, 2, and 3 additional atm of pressure as would be expected. The skin effect demonstrated by Groom et al. (13, 15) can contribute only a small amount to this curve which reflects chiefly the faster components. This indicates that it is decompression per se which by some as yet unknown mechanism imposes the asymmetry. The opposite control experiment, namely isobaric saturation, has not been carried out here because it obviously requires the experimentally difficult initial N, washout. Its absence is unimportant relative to the implications of the results, that uptake and elimination are not symmetrical under diving conditions. The fact that the desaturation curves plotted for the 66- and 99.ft dives exhibit considerably less variability as compared to their saturation counterparts is consistent with the conclusion that certain factors associated with decompression (possibly bubble formation, capillary stasis, or both) have severely limited the rate of transfer of tissue inert gas to the venous blood, interfer-
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352
D’AOUST,
ing with the dynamic control of tissue perfusion, thereby producing the apparently rapid desaturation of venous blood and yet at the same time leaving much inert gas still in the animal. It can be calculated on the basis of the total Nz store of the animal, the concentration of nitrogen in the venous blood and tissues and the coefficients and exponential constants computed in Table 1, that it would be impossible for the dog to completely desaturate by the time mixed venous blood nitrogen levels have decreased nearly to the value expected at one atmosphere. The amount of N, remaining and the degree of asymmetry imposed can be crudely estimated from this data and published values of the nitrogen store of dogs. Based on kinetic analysis of the body N,-washout curve in anesthetized dogs, Groom et al. (14) estimated an average N, concentration in the dog to be 22.5 ml kg-i atm+, although their values ranged between 17.9 and 34.7 ml=kg+ l atm? Their analysis used a-v differences throughout and assumed a [VN,] value of 9.5 pi/ml blood and a cardiac output (Q) of 115 ml mirP kg? Their value for cardiac output appears low, as compared with other measurements by us not in this study, whereas our values for [vN,], 9.86 ml STPD. ml blood-l atm-*, are similar to theirs. Except for the data shown in Fig. 1, our analysis uses only [TN,3 values and assumes that the v-a difference (during desaturation) is approximated by [vN,3 -9.86 ml l-l l atm-l and by PATA x 9.86 ml l-l atm-I[VNJ during saturation. Due to the unknown degree of physiological shunt, dead space errors, and difference in cardiac output in our own dogs versus those of Groom et al. (14), the results are not strictly comparable. However, the self-consistency of our results and the added interpretive advantage of work on awake animals justifies the following simple comparisons. Figure 7 illustrates an estimate of the “average supersaturation” sustained by our animals as a result of decompression (upper curves) compared to that expected if N, was eliminated according to the curve for “isobaric desaturation” shown in Fig. 5. The supersaturation was calculated on the basis of total nitrogen store, and N, removed at a given time, using the average value of 22.5 mlkg-* l atm+. It is clear that these supersaturation levels would not be sustained for very long; bubbles or a tissue gas phase would surely form in a short time. They represent the degree of decompression stress to which the animals have been subjected. On the other hand, the lower levels show less difference in supersaturation in spite of a threefold pressure difference. During saturation the [TN,] is subject to all the vascular inhomogeneities and nonlinearities which may occur as a result of shifts in cardiac output, vasodilation, capillary flow, and blood composition. One would normally expect similar fluctuations of venous blood inert gas content during desaturation since it is similarly affected by these same spatial and time-varying rates of blood-tissue inert gas transfer. The fact that this is not observed suggests that such effects are “masked” by the effects of the decompression itself. The results of other experiments carried out at 33 and 66 ft suggest that the degree of reduction of tissue to l
AND
SWANSON
MINUTES
l
l
l
SMITH,
l
7. A comparison of the residual “average” supersaturation levels remaining-in dogs decompressed from saturation at one, two and three atmospheres, assuming a) the elimination of N, proceeds according to the curve of “isobaric” desaturation, and b) that elimination oFN, has been limited according to the decompression desaturation curve. Supersaturations are computed as a) lower curves, remaining relative state of saturation as shown by the desaturation curve divided by ambient pressure; b) total N, store of the animal minus that amount of N, removed at time (t) divided by N, store at 1 atm. Both of these estimates are “average” total body values and therefore only comparable with M values in use for tissues with similar half-times. Note that residual supersaturations from l-, 2-, and 3-atm pressure change would be much less and also would differ less than those actually imposed by decompression (top three = a) “average” tissue saturation X curves). Supersaturation ratio pressure in atm + 1 atm (lower curves “isobaric desaturation”); b) total N, store per atm x pressure in atm minus (amount of N, removed as indicated by lowest curve in figure at time t) divided by N, store per atm. FIG.
blood inert gas transport during decompression may be related to the degree of decompression insult. Thus, in one case where a severe decompression from saturation was accidentally imposed on an awake animal, not only the tissue to blood nitrogen elimination was compromised but also elimination through the lungs-possibly by the very presence of gas emboli and their sequelae. This was so marked that at one point the arteriovenous nitrogen difference disappeared for several minutes. Thi s is shown in Fig. 8. Some minutes after this point the mixed venous nitrogen tension aga .in began to elevate and to reflect increased nitrogen elimination from the tissue to the blood, and the animal was therapeutically recompressed. In two other experiments shown in Fig. 9, following saturation to 33 fsw, decompression was allowed to proceed in three increments of 11 fsw each (that is, onethird of an atmosphere). The animals were held either 5 or 14 min following each decompression increment. Mixed venous blood sa mples were collected i mmediately prior to and following the staging with the 5-min hold period and during the 15-min hold period. The results of these two different procedures on two different dives revealed that given a certain minimum staging time of 15 min the mixed venous nitrogen content began to rise again following, and probably as a result of, the first decompression stop indicating that initially the tissue to blood nitrogen clearance was reduced. With an even shorter staging time of 5 min,
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DECOMPRESSION-INDUCED
DECREASE
AWAKE
15 kg
ARTERIAL
IN
N,
353
ELIMINATION
DOG
8 VENOUS
BLOOD
NITROGEN
CONTENT
FOLLOWING DECOMPRESSION FROM SATURATION AT 2 ATA 66 FEET OF SEA WATER BENDS(REOUIRING
@J2)
TREATMEN
1 RESULTED
PRESENTED
AT 7 MIN
ul 2o Cc
5
IO
15
20 MINUTES
25
30
35
FIG. 8. Elimination of a-t difference in acute decompression sickness. a = arterial N, content ml/L blood; v = [vN,] ml/L blood. A 20kg dog was saturated at 66 fsw and decompressed in less than 1 min. Large size of the animal and rapid decompression were undoubtedly factors in the decompression sickness (DS) observed. Note the essential disappearance of a-v difference at lo-15 min after surfacing, with a gradual increase in [vN,] beginning at 14 min. DS was so severe at about 30 min that the dog was recompressed and saved.
2.Q9TA +&--
TIME BETW_EEN STOPS
-
5 0
r
I
IO
I
I 20
I
1 30
1
4b
MINUTES FIG. 9. Evidence of “recovery” of tissue to blood nitrogen clearance following less extreme decompressions from saturation. Two experiments are shown where decompression was in increments of 0.33 atm, i.e., 11 fsw. In one (X-X) a 15min hold at each level was maintained and blood samples taken. In the other (O- - -0) only 5 min were allowed and samples were also collected. In 15-min hold [vN,] increases; i.e., tissue to blood N, transport “recovers” late in the staging period at both the 22- and ll-fsw levels, whereas with 5min hold insufficient time is allowed for this “recovery” to occur, and therefore net decompression stress is increased.
recovery was not seen. The secondary rise in [VN,] following decompression has not been observed with the 66- and 99-ft saturations, possibly because the decompression effect is more severe and long lasting, and recovery from it is accordingly not detectable with our methods. DISCUSSION
AND
CONCLUSIONS
The results of this study clearly demonstrate that inadequate decompression decreases the total rate of gas elimination. This finding is consistent with the
observations of Heimbecker et al. (16) and Buckles (6), and indeed might justifiably have been predicted by them if their experiments had involved less extreme pressures. Our results are also consistent with current concepts of the bends (l), and would appear also to demonstrate the ideas of Hempleman (17, 18) and those of Hills (19). The merit of our approach is that the response can be “titrated” to the “minimal decompression” causing it and thus reflect a “critical” decompression. The decrease in gas elimination rate is manifested as an unnaturally low mixed venous inert gas content. Whether this is a result of separated gas (bubbles) causing capillary stasis through interference with hemodynamic control or other factors is not clear from this study;” _ however, I such a view is consistent with all current studies of which we are aware. Certain information about the pathological consequences of inadequate decompression is known; the presence of gas within the small vasculature of soft t’ issue organs and bone has been demonstrated (31). These gas emboli, as well as the tissue damage they have caused, can initiate the hemostatic process (21, 28) and cause hemoconcentration, increased viscosity and reduced flow (5, 6, 11, 24, 32). These changes, however, are observed to follow a more delayed time course than the rapid changes in elimination rate we have described here. They are undoubtedly related to the latter in some manner but the causal nature of the relationship is unknown. It is possible that endothelial damage, due either to moving gas emboli physically contacting the endothelial cell surface or actually forming underneath the endothelium, could initially stimulate vessel stasis which would decrease total tissue blood flow and therefore gas elimination. This endothelial damage would then initiate the longer term hematological sequelae. Damaged endothelial surfaces have been demonstrated by Warren (34) and Stegall et al. (31) following decompression. It is clear from the time course of the mixed venous blood desaturation that the blood, itself a well-stirred short half-time tissue, sustains a high excess content or supersaturation for only a few minutes. Therefore, under the conditions studied, mixed venous blood is not a reliable indicator of the actual rate of gas elimination following decompression, but indicates the effects of decompression itself. It remains to discover the degree of supersaturation sustained by the blood and different tissues under these conditions, since such high residual gas contents could represent both microbubbles and/or higher tensions. Without better understanding than we now have concerning the relative stability of a given degree of supersaturation in a certain tissue type at any particular pressure, it is too early to conclude as some have done (19) that “no-supersaturation” models are to be preferred. It appears likely that certain minimal supersaturations are relatively stable (23). In the meantime, however, the significance of these results to actual decompression protocol depends somewhat on which decompression model one is using. The decompression model which is least accommodating to
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354
D’AOUST,
our results as it is presently used is the “neo-Haldane” multiple parallel exponential compartment model (22) used in the US and many other countries except the UK. There are two important weaknesses of this model. One is that it makes no allowance for the long-suspected functional asymmetry of gas elimination following decompression which we have demonstrated. Second, it uses “minimal” times for initial decompression stops following a considerable depth change; this is contrary to conclusions resulting from our data. An immediate practical conclusion of this study would seem to be that the minimum staging time during decompression should at least be designed to adequately compensate for the slower gas elimination occasioned by the initial “jump” (or step function increase in AP, i.e., tissue inert gas tension - ambient pressure) to a shallower depth regardless of the decompression model used. As noted above, current procedures often use stops as short as l-3 min. The time taken to desaturate the mixed venous blood to the shoulder of the saturation curve (Figs. l-4) is approximately 10 min in the awake dog and can be expected to be somewhat greater in man. It would seem desirable both to reduce the extent of initial “jump” and to make initial decompression stops at least long enough to take advantage of this relatively high initial rate of nitrogen clearance. It must be emphasized, however, that this rationale is in response to our results of decompression from saturation. There can be little doubt that the severity of the effect we described is related to the “dose” of decompression stress sustained- a function of the total amount of
SMITH,
AND
SWANSON
gas dissolved and the relative decompression imposed. We do not yet have a sufficiently quantitative picture of such a parameter, although some recent work (3, 7, 9) suggests that it is experimentally definable. In any case, it is reasonable to suggest that certain minimal decompression insults are without the response we have described. We are now attempting to determine this minimal “dose” of decompression stress causing the asymmetry. In such a case it is also reasonable to suppose that a symmetrical transport model would be acceptable. We point out, however, that elimination from even the 33-fsw depth showed the same asymmetry, although a much greater spread of the data, as the 2and 3-atm experiments. This pressure drop corresponds to the original highly empirical Haldane ratio of approximately 2.0-2.25 which has been adjusted to varying degrees by all workers in this area to suit the model or the half-time in use. Thus, once again it appears necessary to suggest that further reduction in the permissible supersaturation and ascent rate is desirable. We thank Dr. C. J. Martin and Dr. Steve Lewis of the Institute of Respiratory Physiology, VMRC, for their interest and assistance in providing computer time and programs for data analysis, Mr. Roland White for his interest and engineering skill throughout the project, and Mr. Michael Newman, Mr. John Buczek and Mr. Lee Stayton for chamber operation and control. This study was supported by National Institutes of Health Grants HL-12015 and HL-14801 and National Heart and Lung Institute RCDA Award K04-HL-70543. Received
for publication
1 March
1976.
REFERENCES K. H., D. E. HOLNESS, AND C. A. SCOTT. Measurement of the in vivo uptake and elimination of N, in tissue. In: Proceedings of the 5th Symposium on Underwater Physiology, Freeport, British Bahamas, 1972, edited by C. J. Lambertsen. Bethesda, Md.: Fed. Am. Sot. Exptl. Biol., 1976. BEHNKE, A. R. Some early studies of decompression. In: The Physiology and Medicine of Diving, edited by P. B. Bennett and D. H. Elliott. Baltimore, Md.: Williams & Wilkins, 1969, p. 226251. BEYER, D., B. G. D’AOUST, E. CASILLAS, AND L. S. SMITH. Decompression and isobaric supersaturation in fluid breathing vertebrates: timed response via bioassay, hematology and ultrasonic bubble detections. In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. BOND, G. F., F. L. FISHBACK, M. W. LIPPITT, AND R. D. WOODSON. Multiple inert gas transport patterns. In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. BOVE, A. A., J. M. HALLENBECK, AND D. H. ELLIOTT. Circulatory responses to venous air embolism and decompression sickness. Undersea Biomed. Res. 1: ,207-220, 1974. BUCKLES, R. G. The physics of bubble formation and growth. Aerospace Med. 39: 1062-1068, 1968. D’AOUST, B. G., AND L. S. SMITH. Bends in fish. Comp. Biochem. Physiol. 49A: 311-321, 1974. D’AOUST, B. G., AND H. T. SWANSON. Bubble-free decompression of blood samples. J. Appl. Physiol. 37: 589-591, 1974. D’AOUST, B. G., R. WHITE, AND H. SEIBOLD. Direct measurement of total dissolved gas partial pressure. Undersea Biomed. Res. 2: 141-149, 1975. DIETER, K. H. On a mathematical theory of decompression. IEEE Trans. Biomed. Eng. BME14: 124-146, 1967. END, E. The use of new equipment and helium gas in a world
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record dive. J. Znd. Hyg. Toxicol. 20: 511-520, 1938. 12. EVANS, A., E. E. P. BARNHARD, AND D. N. WALDER. Detection of gas bubbles in man at decompression. Aerospace Med. 43: 10951096, 1972. 13. GROOM, A. C., AND L. E. FARHI. Cutaneous diffusion of atmospheric N, during N, washout in the dog. J. Appl. Physiol. 22: 740-748, 1967. 14. GROOM, A. C., R. MORIN, AND L. E. FARHI. Determination of dissolved N, in blood and investigation of N, washout from the body. J. Appl. Physiol. 23: 706-712, 1967. 15. GROOM, A. C., S. H. SONG, Y. OHTA, AND L. E. FARHI. Effect of anesthesia on the rate of N, washout from body stores. J. Appl. Physiol. 37: 219-223, 1974. 16. HEIMBECKER, R. O., G. LEMIRE, C. H. CHEN, J. KOVER, D. LEASK, AND W. R. DRUCKER. Role of gas embolism in decompression sicknessa new look at “the bends.” Surgery 64: 264-272, 1968. 17. HEMPLEMAN, H. V. British decompression theory and practice. In: The Physiology and Medicine of Diving, edited by P. B. Bennett and D. H. Elliott. Baltimore, Md.: Williams 8~ Wilkins’, 1969, p. 291-318. 18. HEMPLEMAN, H. V. The unequal rates of uptake and elimination of tissue nitrogen gas in diving. Proc. RNPRC Report 62/1019, 1960. 19. HILLS, B. A. Thermodynamic decompression: an approach based upon the concept of phase equilibration in tissue. In: The Physiology and Medicine of Diving, edited by P. B. Bennett and D. H. Elliott. Baltimore, Md.: Williams & Wilkins, 1969, p. 319-356. 20. LEMESSURIER, D. H. Supersaturation and “preformed nuclei” in the etiology of decompression sickness. In: Proceedings of the 2nd International Meeting on Aerospace Medicine, Melbourne, 1972. 21. PHILP, R. B. Historical evolution of the blood-bubble interaction hvpothesis in the pathogenesis of decompression sickness. In:
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ELIMINATION
Proceedings of a Symposium on Blood-Bubble Interaction in Decompression Sickness, DCIEM, Downsview, Ontario, 1973, edited by K. N. Ackles. SCHREINER, H. R., AND P. L. KELLY. A pragmatic view of decompression. In: Underwater Physiology, edited by C. J. Lambertsen. New York: Academic, 1971, p. 205-219. SKRIPOV, V. P. Metastable Liquids. New York: Wiley, 1974, p. 18-54. SMITH, K. H., ET AL. Possible effects of bubble-induced coagulation following decompression. In: Proceedings of a Symposium on Blood-Bubble Interaction in Decompression Sickness, DCIEM, Downsview, Ontario, 1973, edited by K. N. Ackles. SMITH, K. H., AND D. C. JOHANSON. Technical Report, ONR Contract NO0014 69 C 0402, Proj. NR 101-750, 1970. SMITH, K. H., AND M. P. SPENCER. Doppler indices of decompression sickness: their evaluation and use. Aerospace Med. 41: 13961400, 1970. SMITH, K. H., AND L. STAYTON. Safe decompression procedures must they be bubble free? In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. SMITH, K. H., AND P. J. STEGALL. The etiology and pathogenesis of decompression sickness: evaluation of decompression profiles in animals and man. In: Proceedings of the 5th Symposium on Underwater Physiology, Freeport, British Bahamas, 1972, edited by C. J. Lambertsen. Bethesda, Md.: Fed. Am. Sot. Exptl. Biol., 1976. SPENCER, M. P., AND H. F. CLARK. Precordial monitoring of
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pulmonary gas embolism and decompression bubbles. Aerospace Med. 43: 762-767, 1972. SPENCER, M. P., AND D. C. JOHANSON. Decompression limits for compressed air determined by ultrasonically detected blood bubbles. In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. STEGALL, P. J., K. H. SMITH, AND T. HUANG. Pathogenesis of osteonecrosis as the result of inadequate decompression. In: Proceedings of the 6th Symposium on Underwater Physiology, San Diego, 1975, edited by C. J. Lambertsen. In press. SWINDLE, P. F. Occlusion of blood vessels by agglutinated red cells, mainly as seen in tadpoles and very young kangaroos. Am. J. Physiol. 120: 59-74, 1937. VANN, R. D., AND H. G. CLARK. Bubble growth and mechanical properties of tissue in decompression. Undersea Biomed. Res. 2: 185-194, 1975. WARREN, B. A. The ultrastructure of the blood-bubble interface and related alterations in the blood and vessel walls in air embolism. In: Proceedings of a Symposium on Blood-Bubble Interaction in Decompression Sickness, DCIEM, Downsview, Ontario, 1973, edited by K. N. Ackles. WORKMAN, R. D. Calculation of Decompression Schedules for Nitrogen-Oxygen and Helium-Oxygen Dives. Washington, DC.: US Navy Experimental Diving Unit, 1965. (Res. Rept. 6-65) YOUNG, A. C., C. J. MARTIN, AND S. TSUMODA. Lung volumes in diffuse obstructive pulmonary syndromes. J. Clin. Invest. 53: 1178-1184, 1974.
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