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Pulmonary function with acute loss of excess lung water by hemodialysis in patients with chronic uremia
CLINICAL
STUDIES
Pulmonary Function with Acute Loss of Excess Lung Water by Hemodialysis in Patients with, Chronic Uremia
A. ZIDULKA, P. J. DESPAS, J. MILIC-EMILI.
M.D.* M.D. M.D.
N. Ft. ANTHONISEN; Montreal.
M.D.
Quebec, Canada
From the Joint Cardiac and Respiratory Divisions, Royal Victoria Hospital, Montreal, Quebec, Canada. This study was supported by a Canadian Tuberculosis and Respiratory Disease Association scholarship and the Medical Research Council of Canada. Requests for reprints should be addressed to Dr. A. Zidulka. Manuscript accepted February 28, 1973. * Present address: Meakins Christie Laboratories, Royal Victoria Hospital, 687 Pine Montreal 112, Quebec, Avenue West, Canada.
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We studied lung function in six patients with advanced renal failure who were on a chronic hemodialysis program. With the patients in the seated position, both before and after hemodialysis, we measured lung volumes, maximal mid-expiratory flow rates (MMFR) and alveolar arterial oxygen differences (A-a DO2). Using xenon 133 (133Xe) we also studied regional Lung function and the volume at which “airway closure” began (“closing capacity”). Before dialysis a restrictive pattern was observed, with normal MMFR and reduced lung volumes. With removal of body fluid the residual volume decreased further with a concomitant increase in vital capacity and in MMFR. Before dialysis the majority of patients had an increased residual volume in basal lung regions which decreased after dialysis. In five of six patients the “closing capacities” decreased with dialysis. These results reflected reversible premature airway closure and gas trapping at the lung bases perhaps due to accumulation of edema around small airways. In addition, most of the patients had decreased ventilation and perfusion at the lung bases which improved with dialysis. Little change occurred, however, in the A-a DO2 with dialysis. In acute pulmonary edema in dogs Staub et al. [l] demonstrated that edema fluid appeared in the loose connective tissue around extra-alveolar vessels and airways before there was any significant change in alveolar wall thickness. Hughes and Rosenzweig [2] showed that in the isolated perfused dog lung the volume of trapped gas increased with increased lung water and was greater in the more dependent parts of the lung in which pulmonary edema was most prominent upon histologic examination. It was postulated that peribronchiolar edema might cause airways to close at abnormally high distending pressures resulting in the trapping of larger volumes of gas. Ruff et al. [3] recently demonstrated that this same phenomenon might be present in patients with hepatic cirrhosis. They concluded that gas trapping in the dependent lung zones could. be an important cause of the impaired gas exchange which is often seen in cirrhotic patients. Our investigation was carried out to test the hypothesis that if increased lung water caused an increased volume, of trapped gas in the lungs, then removal of some of the excess water
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ought to decrease the volume of gas trapping. We selected patients who had chronic renal failure and who were on a hemodialysis program. Both before and after hemodialysis we performed routine pulmonary function tests and studies of gas exchange, and we examined regional pulmonary function and “closing capacities” using xenon 133 ‘(133Xe). MATERIALS
AND
METHODS
The patients studied were in chronic renal failure and were on a chronic hemodialysis program. Some had concomitant clinical heart failure without pleural effusion. All but one (V.A.) had dyspnea before dialysis; in most, dyspnea diminished after dialysis had resulted in a loss of body fluid. Six patients were studied before hemodialysis and again within 1 hour after dialysis. All measurements were made‘ with the patients in the seated position. Because some of the patients were quite dyspneic and debilitated, not all the studies were carried out on the same dialysis day. Routine pulmonary function testing consisted of measuring lung volumes by spirometry and helium dilution [4], and measuring maximum mid-expiratory flow rate (MMFR) by spirometry. Diffusing capacity was measured by the steady state technic [5]. Results of these tests were compared with predicted normal values [6]. The alveolar-arterial oxygen differences (A-a DOp) were measured in the conventional way [7] while the patients were seated and breathing room air. The patients breathed through a mouthpiece connected to a Hans-Rudolph valve. After a period of adjustment expired gas was collected in a meteorologic balloon for 2 min. A simultaneous arterial blood gas sample was also drawn over the 2 min. Because these patients might have needed their superficial arteries for arteriovenous fistulas for hemodialysis, indwelling arterial catheters were not used for sampling arterial blood. Instead, the area around the brachial artery was thoroughly anesthetized before the study and blood was collected from a stab puncture of the artery. Expired gas was analyzed for oxygen and carbon dioxide content by the micro Scholander technic, with duplicate measurements agreeing within 6.04 per cent. Arterial blood samples were analyzed for carbon dioxide tension (PaCOp) and pH by appropriately calibrated electrodes. Using PaC02 and expired gas oxygen and carbon dioxide concentrations, “ideal” alveolar oxygen tension was calculated and compared with measured arterial oxygen tension (PaOz) [7]. The methods used for the study of regional lung function have been described in detail previously [8]. Lung regions were defined by six collimated scintillation counters which were positioned at 5 cm intervals over the back of each hemithorax from apex to base. Regional residual volumes were measured by having the patients inhale ls3Xe in known concentration from residual volume (RV) to total lung capacity (TLC) and hold their breath at TLC while regional count rates were recorded [9]. Regional functional residual capac-
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ities were measured by having the patients inhale ‘133Xe in known concentration from functional residual capacity (FRC) to TLC and hold their breath while regional count rates were recorded [9]. Regional ventilation was assessed by injecting a bolus (1 to 2 mCi in 2 to 4 cc) into the mouthpiece while the subject held his breath at FRC. The subject then inhaled slowly (0.2 to 0.6 liters/set) to TLC and held his breath while regional count rates were recorded [9]. Regional perfusion was assessed by injecting slugs of 133Xe intravenously while subjects held their breath at FRC. When the injected isotope had entered the alveolar gas, the subjects inhaled room air to TLC where count rates were recorded [lo]. Each of these maneuvers was completed twice in each study, and each inhaled volume of labelled and/ or unlabelled gas was measured spirometrically. The regional count rates measured at TLC during each of these maneuvers were converted to regional concentrations by equilibrating the subject with 133Xe in known concentration and again recording regional count rates during a series of breath-holds at TLC [8]. Regional concentrations resulting from tests of ventilation and perfusion distributions were expressed as indices or percentages of the regional concentrations which would have been present if ventilation and perfusion had been even [8]. Regional residual volumes and functional residual capacities were expressed as fractions of regional total lung capacities (RVr:TLCr, FRCr:TLCr) [9]. In addition the lung volume at which “airway closure” begins [ll] was measured (Figure 1). Subjects exhaled to RV and a bolus of 133Xe was injected into the mouthpiece. The bolus was then inhaled at the onset of a slow inspiratory VC maneuver, 133Xe entering areas with open airways at or near RV. Subjects then made slow VC expirations while 133Xe concentration was measured at the mouth and plotted against lung volume on an x-y recorder. Figure 1 shows a sample tracing. After dead space washout (I and II), there was a slowly rising alveolar plateau (I II), but at low lung volumes the slope of the plateau suddenly became steeper with a rapid rise of 133Xe concentration until RV was reached (IV). The volume at which the slope of the plateau changes is the “volume at which airway closure begins” (I I I-IV junction). At this point 133Xe poor units stop contributing to the expirate; presumably the reason such units were 133Xe poor was that their airways had been closed when the bolus was inhaled. The volume between RV and the Ill-IV junction has been called “closing volume.” We measured “closing capacities,” the absolute lung volume at the Ill-IV junction (“closing volume” plus RV). RESULTS
The results of routine pulmonary function both before and after hemodialysis are presented in Table I and Figure 2. Before dialysis there was a restrictive pattern with a reduction in all lung volumes. In only one subject was RV above the pre-
August 1973
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135
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FUNCTION
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AJ
I .
O-
DL
+5
MR
6.1
I LL
1 CiOSlNG i
~-CAPACITY
7
Figure 1. Relationship between coun’ts per second’in expired air and expired volume following an inspiratory VC maneuver during which a bolus of 133Xe was inhaled at RV. The plateau (phase 111) shows a small gradual rise with well marked cardiogenic oscillations followed by a steeper rise with reduced oscillations (phase IV). The arrow represents the junction between phase 111and IV. CV = closing volume.
120 t
r]
Pre - dialysis
m
Post-dlalysls
I
0
20
I
40
60
I
80 0
REGIONAL
20
W/TLC
4
40
60
60
(%I
Figure 3. Relationship between distance down the lung from apex to base and regional residual volumes expressed as a per cent of the regional TLC. The solid lines are the results before dialysis; the dashed lines are the results after dialysis. The per cent change in weight with dialysis is indicated for each oatient.
IOO60-
p .+ e a S
604020O-
TLC
FRC
“5
ns
vc p-2
IO
RV
MMFR
Dco
PC.10
PC.05
“S
Figure 2. Mean results fl standard error of the mean of six patients of the routine pulmonary function tests expressed as a percentage of predicted. The significance of changes before and after dialysis (by paired t test) are shown on the bottom line. ns = nonsignificant.
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of Medicine
Volume
‘Closing
Capacity’
F’re-dialysis
(liters)
Figure 4. Comparison of “closing capacity” and after hemodialysis for each subject.
55
before
6.1
Yes
M.R.,19
Before dialysis After dialysis Predicted (4.80)
3.71 3.91
(6.38)
4.56 4.72
4.9
No
A.J.,23
Before dialysis After dialysis Predicted
3.42 2.81 (4.51)
3.8
Yes
J.S.,23
Before dialysis After dialysis Predicted
3.48 3.86 (4.12)
Yes
D.L.,28
Before dialysis After dialysis Predicted
4.5
No
V.A.,37
Before dialysis After dialysis Predicted
6.23 5.55 (6.71) 6.09 6.01 (7.10)
5.1
No
R.D.,24
Before dialysis After dialysis Predicted 9.6
(%)
TLC (liters)
1.99 2.06 (2.54)
1.89 2.38 (3.50)
1.61 1.41 (2.42)
1.52 1.98 (2.18)
3.07 3.49 (3.95)
2.74 2.18 (3.63)
FRC (liters)
2.38 2.72 (3.49)
3.31 3.83 (4.63)
2.69 2.47 (3.16)
2.53 2.86 (2.93)
4.24 4.43 (4.95)
4.14 4.59 (4.98)
vc (liters)
1.33 1.19 ‘(1.31)
1.25 0.89 (1.75)
0.73 0.34 (1.35)
0.95 1.00 (1.20)
1.85 1.58 (2.15)
2.09
in Body Weight with Dialysis and Pulmonary
A Weight
Per Cent Change
Smoker
Patient and
Age, Smoking History,
Age ur)
TABLE I
9.4 10.0 (19.0)
10.6 14.3 (19.4)
5.05 6.21 (4.19) 2.37 2.45 (3.76)
...
(,“,I”,)
2.02 1.67
...
1.79 1.37
1.08 0.64
6.7
...
-0.03 +0.39 ...
+0.10 +1.01 ...
+0.53 +0.77 ...
+0.06 +0.49 ...
1.46 1.49 8.8 ,I::,
+0.52 +1.12 ...
...
... 2.55 2.37 ...
-0.42 +0.01
3.26 2.17
Closing Capacity (liters)
11.6 (1:::)
13.8 11.8 (21.1)
DLCO
FRC Minus Closing Capacity (liters)
83 72
...
(E)
71 76
...
33.5 36.0
44.5 39.5
... 36.5 97
...
32.5 34.0
41.0 38.0 ...
...
21
(Z)
29
(E)
...
...
(llj5
_
95 94
98 103 ...
35.5
78
PaCOz (mm Hg)
PaOz (mm Hg)
10
10 (1;)
23
(mm Hg)
A-a DOa
Before and After Hemodialysis
2.99 3.40 (3.27)
3.08 3.30 (3.27)
5.83 6.15 (4.04)
4.65 4.98 (4.49)
sac)
MMFR (liters/
Function of Patients
PULMONARY
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UREMIA-ZIDULKA
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dieted normal range before dialysis. The MMFR was depressed in only one subject (M.R.), in three others it was in the normal range and in two it was definitely increased. Dialysis resulted in no significant change in TLC or FRC. After dialysis there was, however, an increase in VC and MMF with a decrease in RV. The diffusing capacities were significantly decreased before dialysis as was the hematocrit. There was no significant change in either of these values with dialysis. Figure 3 shows the RV,:TLC, for the six subjects. Because the results in both the right and left lungs were similar, for ease of presentation these results have been averaged for each horizontal level at a given distance from the lung apices. In normal erect subjects when RV,.:TLC,. is plotted against vertical distance a “hockey stick” results: RV,:TLC, diminishes over the top 10 to 15 cm of the lung and gives a constant, low value over the bottom 10 to 15 cm. The distribution of RVr for normal seated subjects is shown in Figure 3 [9]. Before dialysis in three of the subjects RV,:TLC, increased as the lung base was approached; in one (A.J.) basal RVr:TLC,. were the same throughout, and in two (V.A. and D.L.) there was roughly a linear decrease from apex to base. After dialysis, basal RV,:TLC, decreased in five subjects whereas apical RV,:TLC, changed in a more variable manner. In only one subject (V.A.) did basal RV,:TLC, increase slightly as a result of dialysis. This latter subject differed clinically from the others in that he was the only one who was not dyspneic before dialysis. The “closing capacity” of each subject both before and after dialysis is compared in Table I and Figure 4. With dialysis there was a significant decrease in “closing capacity” (p CO.05 by paired t test). By subtracting the “closing capacity” from the FRC, it was possible to estimate whether or not the dependent airways were open or closed during normal tidal volume breathing [12]. These values were plotted with respect to age (Figure 5) on a graph of depicting data on normal seated subjects obtained from McCarthy et al.[13]. Before dialysis in three subjects this difference was approximately zero and in one subject significantly negative; implying that the dependent airways were “closed” at FRC. In two subjects the FRC minus “closing capacity” volume was within the normal range, and significantly greater than zero, implying that the dependent airways were open at FRC. With dialysis this difference (p (0.01 by paired t test) was significantly increased in all subjects, implying a greater tendency for the dependent airways to be open at FRC.
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1973
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of Medicine
Volume
- Pm-
dlalysls
0
Post-dlalysls
z 6 1,5f -r ‘, IO :: I_? ----____ -0.5 5 --i-_ _z E
t o---i2 LI - 0.5’
f
Mean _---____ I
---___
-_ --_
-=-_
li 20
40
30
_2SD 50
AGE Iyears)
Figure 5. Relationship between FRC minus closing capacity and age before (x) and after (0) hemodialysis for each subject.
Ventilation at the lung bases was decreased in four of six subjects (Figure 6), and it was these subjects who demonstrated “closing capacities” equal to or greater than FRC. These subjects probably had closure of basal airways at FRC; boat this lung volume luses of 133Xe administered tended to be distributed to the lung apices. With dialysis “closing capacity” decreased, FRC did not change, and ls3Xe administered at FRC tended to be distributed more to the lung bases. These Or RD
g
0
r Js
r v*
L
0
I 1600
I
1
40
1
I
1
80
I
I
I
120 160
REGIONALVENTILATIONt%) between distance down the Figure 6. Relationship lung and the regional ventilation. The results represented by solid lines are before dialysis; the dashed lines are after dialysis.
55
PULMONARY
0
r
RD
r
FUNCTION
IN CHRONIC
UREMIA-ZIDULKA
ET AL.
zero ornegative. In the two subjects with a normal A-a D02, one (D.L.) had the FRC minus “closing capacity” only minimally above zero. With dialysis, despite significant improvement in the FRC minus “closing capacity” volume in all subjects, the A-a DO2 did not ch,ange significantly in two subjects (R.D. and A.J.) and increased in one subject (M.R.). Thus, there was little correlation of the A-a DO2 with the “opening” or “closing” of dependent airways.
JS
COMMENTS
6
Or
I.
0
DL
-
40
8.
60
*
m
1
II
I
*
120 160 0 40 REGIONAL PERFUSION
II
11
80 (%I
I,
120
160
Figure 7. Relation&hip between distance down the lung and the regional perfusion. The ‘results represented by solid lines are before dialysis; the dashed lines are after dialysis.
data are also compatible with basal airway closure being reversed by dialysis, and therefore likely due to edema fluid in or around these airways. Before dialysis the distribution of perfusion (Figure 7) was similar to the distribution of ventilation, i.e. in five of six subjects perfusion at the lung bases was reduced from normal. With dialysis the improvement in basal lung perfusion was similar to the basal lung ventilation in all but one subject (M.R.). In this patient, basal lung ventilation improved, however, basal lung perfusion remained decreased. Of interest is that after dialysis the A-a DO2 increased from 21 to 33 mm Hg, perhaps as a result of ventilation to perfusion mismatching. Whether the dependent airways are during normal tidal volume “open” or “closed” breathing has been shown to be related to gas exchange by Craig et al. [12], i.e., the more the “closing capacity” exceeded the FRC, the greater was the A-a Don. For technical reasons the A-a DO2 was not obtained on one subject (J.S.) before dialysis. Before dialysis, three of five subjects had an elevated A-a DO2 (Table I), and in these the FRC minus “closing capacity” was close to
We have been unable to find previous data regarding pulmonary function in patients with uremia. Before dialysis, on routine pulmonary function testing, a restrictive pattern emerged. The TLC, FRC, VC and RV were all significantly reduced below predicted values whereas the MMFR was normal. This was not changed with removal of excess body fluid; TLC and FRC remained constant, RV decreased further, and VC and MMFR increased. Five of our six patients were dyspneic and their condition worsened with excess fluid. As patients in chronic renal failure are subject to hypertension and heart failure, it is possible that these results simply represented heart failure. However, decrease in all lung volumes with preservation of expiratory flow rates is not typical of heart failure and suggests lung fibrosis [14]. Heard [15] and Perry [16] have described parenchymal fibrosis and fibrin masses in the air spaces of chronic uremic patients, supporting the foregoing hypothesis. The reduction in diffusing capacity both before and after dialysis is compatible with pulmonary fjbrosis, but it is difficult to interpret due to coexistent anemia in these subjects with chronic uremia [17]. We interpret the pulmonary effects of hemodialysis as being due to removal of lung water and believe that our results support the hypothesis that a major effect of lung edema on pulmonary function is due to accumulation of fluid in or around the airways, chiefly in dependent lung regions. Such fluid accumulation would narrow, airways and make them susceptible to closure at higher lung volumes. The increase in MMFR after dialysis implied a decrease in airway resistance. This is supported by the findings of Hogg et al. [18] who found that peripheral airway resistance increased with the development of interstitial pulmonary edema. Over-all RV and “closing capacity” declined after dialysis whereas TLC remained constant, suggesting that the RV before dialysis had been in part determined by airway “closure.” Our studies of regional lung function supported
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this argument. The change in basal RV,:TLC, induced by dialysis suggested that the removal of fluid decreased gas trapping in dependent lung zones. In normal subjects, Sutherland et al. [9] found that as one scanned the lung from apex to base regional RV:TLC decreased and at the lung bases attained a constant value. Before dialysis all our subjects demonstrated the initial decrease in the regional RV:TLC in going from apex to base (Figure 3), but in the lower 10 cm of the lung this ratio increased in four of six subjects. This increase was pronounced in only one subject. Dialysis, however, produced a decrease in the basal RV,:TLCr in five of six patients. This consistent change iinplied that the initial increases in basal RV,:TLC, were due to excess fluid. In only two subjects (J.S. and V.A.) did ventilation increase from apex to base before dialysis; these were the two subjects in whom FRC was unequivocally greater than “closing capacity.” The other four subjects, whose FRC minus closing “capacity volumes” were equal to or less than zero, demonstrated decreased ventilation at the lung bases before dialysis. This decreased basal ventilation was best explained then, by the presence of basal airway “closure” at FRC. With dialysis all but one subject (A.J.) demonstrated increased ventilation to basal regions as the FRC minus “closing capacity” volume increased. In one subject (R.D.) ventilation of the lung bases after dialysis remained low; in this subject even after dialysis FRC and “closing capacity” were substantially the same. Hughes et al. [19] with rapid freezing of excised dog lungs demonstrated that at low lung volumes airway closure occurred in the terminal bronchioles. Burger and Macklem [3] provided evidence for true closure of airways in normal human subjects occurring at low lung volumes. Staub et al. [l] demonstrated that in the development of pulmonary edema in dogs, fluid accumulated first around the basal conducting airways and vessels that are extra-alveolar. This was also demonstrated by O’Connor et al. [20] in induced pulmonary edema in intact dogs. In excised dog lungs, lliff [21] found that by increasing alveolar pressure greater than vascular pressure it was possible to shut down the capillary bed. It was then possible to study the permeability of extraalveolar arteries and veins independently from the capillaries. With a 4 to 6 per cent weight gain of the excised dog lungs, interstitial fluid cuffing consistently occurred around arteries, veins and airways. Similar results were also found by Goldenberg et al. [22]. Recently Iliff et al. [23] found in the isolated dog lung that the develop-
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The American Journal of Medicine
ment of interstitial edema diverted both ventilation and blood flow away from the basal region to the middle and apical lobes, and perivascular and peribronchial edema was more marked in the dependent lung regions. Ruff et al. [3] found increased gas trapping in the lower lung zones of hepatic cirrhotic patients with reduced ventilation to this region. It was suggested that the premature airway closure was due to mechanical compression of small airways by dilated blood vessels and/or interstitial pulmonary edema. It is of interest that the basal increase in RVr:TLC,. in the study with cirrhotic subjects was much greater than the increase we found in RV,:TLC, in the present study. None of the cirrhotic subjects had evidence of fluid overload, i.e., they had neither cardiorespiratory disease nor ascites. Their serum albumin was below normal but not in the range expected to cause interstitial pulmonary edema. Therefore there would appear to be a discrepancy between our results and those of Ruff et al. [3]: our patients probably had greater intrapulmonary fluid accumulation than theirs but less striking airway closure. A possible explanation for this might be that our patients also had evidence of restrictive lung disease. Although we did not measure static pressure volume curves in our patients, the combination of low lung volumes and normal flow rates suggests that these curves were shifted to the right, i.e., that elastic recoil was increased. It has been shown that “airway closure” increases as elastic recoil decreases [24], and it would therefore be reasonable to postulate that increases in elastic recoil decrease the tendency for “airway closure” to occur. Thus, the restrictive abnormality seen in these patients, which was presumably due to lung fibrosis, may have protected them from the extensive “airway closure” noted in cirrhotic subjects. Before dialysis, there was a decrease in basal lung perfusion in five of six patients (Figure 8). This distribution of decreased basal lung perfusion has been observed previously in patients with mitral stenosis [25,26]. The decrease in basal perfusion with pulmonary venous hypertension has been attributed to perivascular edema in the dependent lung regions, with the accumulated fluid causing a high resistance to blood flow [27]. With removal of body fluid the basal lung perfusion increased in five of six subjects, consistent with reductions of perivascular fluid. Before dialysis there was a poor correlation between the A-a DOn and whether or not the volume of the “closing capacity” was greater than the FRC. After dialysis the “closing capacity” volume increased relative to the FRC volume in all
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subjects but, contrary to the results of Craig et al. [12], the A-a DO2 did not decrease but increased in three patients and did not change in two. The reasons for this remain speculative. Possibly accounting for the large initial A-a DO2 was the severe anemia as a result of chronic uremia. Anemia by itself can result in an elevated A-a DO2 [28-301. Housley [30] attributed the increased A-a DO2 with anemia to both an increase in the anatomic shunt and ventilation to perfusion abnormalities. Further, these patients had a diffuse lung abnormality of a restrictive nature, which may increase the A-a DO2 in the absence of airway closure either by causing mismatch of
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ventilation to perfusion ratios or by inducing alveolar capillary block [31]. If maldistributions of ventilation to perfusion ratios occurred within, as opposed to between, lung regions, then the present regional measurements would not detect them [32]. Because of their anemia the decreased Dco observed in our patients could not be attributed either to ventilation to perfusion abnormality or alveolar capillary block. ACKNOWLEDGMENT
We are thankful to Dr. A. Gonda and Dr. R. D. Guttman, Renal Service, Royal Victoria Hospital, for their cooperation with this study.
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Burrows B. Niden AH: Effects of anemia on CO diffusion in the perfused dog lung. Fed Proc 21: 443, 1982. Hogg JC, Agarawal JB, Gardiner AJS, Palmer WH, Macklem PT: Distribution of airway resistance with developing pulmonary edema in dogs. J Appl Physiol 32: 20, 1972. Hughes JM, Rosenzweig DY, Kivitz PB: Site of airway closure in excised dog lungs: histologic demonstration. J Appl Physiol 29: 340, 1970. O’Connor NE, Sheh JM, Rartlett RH, Bass H: Gas exchange and pressures in pulmonary edema. Rev Surg 28: 145, 1971. lliff LD: Extra-alveolar vessels and oedema development in excised dog lungs. Circ Res 28: 524, 1971. Goldenberg VE, Smith HC, Cheney FW, Butler T: Pathogenesis of edema in excised lungs. Fed Proc 28: 282, 1969. lliff LD, Greene RE, Hughes JMB: Effect of interstitial edema on distribution of ventilation and perfusion in isolated lung. J Appi Physio133: 462, 1972. Anthonisen NR, Danson J, Robertson PC, Ross WRD: Airway closure as a function of age. Resp Physiol 8: 58,1969/?0. Dollery CT, West JB: Regional uptake of radioactive oxygen, carbon monoxide and carbon dioxide in the lungs of patients with mitral stenosis. Circ Res 8: 765.1980. Dawson A, Kaneko K, McGregor M: Regional lung function in patients with mitral stenosis studied with xenon-133 during air and oxygen breathing. J Clin Invest 44: 999, 1965. West JB. Dollery CT, Naimark A: Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol 19: 713, 1964. Ryan JM, Hickam JB: The alveolar-arterial oxygen pressure gradient in anemia. J Clin Invest 31: 188, 1952. Sproule BJ, Mitchell JH, Miller WF: Cardiopulmonary physiological responses to heavy exercise in patients with anemia. J Clin Invest 39: 378, 1960. Housley E: Respiratory gas exchange in chronic anaemia. Clin Sci 32: 19. 1967. Arndt H, King TK, Briscoe WA: Diffusing capacities and ventilation: perfusion ratios in patients with the clinical syndrome of alveolar capillary block. J C/in Invest 49: 408, 1970. Anthonisen NR, Bass H, Oriol A, Place G. Bates DV: Regional lung function in patients with chronic bronchitis. Clin Sci 35: 495, 1968.
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STUDIES
Pulmonary Function with Acute Loss of Excess Lung Water by Hemodialysis in Patients with, Chronic Uremia
A. ZIDULKA, P. J. DESPAS, J. MILIC-EMILI.
M.D.* M.D. M.D.
N. Ft. ANTHONISEN; Montreal.
M.D.
Quebec, Canada
From the Joint Cardiac and Respiratory Divisions, Royal Victoria Hospital, Montreal, Quebec, Canada. This study was supported by a Canadian Tuberculosis and Respiratory Disease Association scholarship and the Medical Research Council of Canada. Requests for reprints should be addressed to Dr. A. Zidulka. Manuscript accepted February 28, 1973. * Present address: Meakins Christie Laboratories, Royal Victoria Hospital, 687 Pine Montreal 112, Quebec, Avenue West, Canada.
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We studied lung function in six patients with advanced renal failure who were on a chronic hemodialysis program. With the patients in the seated position, both before and after hemodialysis, we measured lung volumes, maximal mid-expiratory flow rates (MMFR) and alveolar arterial oxygen differences (A-a DO2). Using xenon 133 (133Xe) we also studied regional Lung function and the volume at which “airway closure” began (“closing capacity”). Before dialysis a restrictive pattern was observed, with normal MMFR and reduced lung volumes. With removal of body fluid the residual volume decreased further with a concomitant increase in vital capacity and in MMFR. Before dialysis the majority of patients had an increased residual volume in basal lung regions which decreased after dialysis. In five of six patients the “closing capacities” decreased with dialysis. These results reflected reversible premature airway closure and gas trapping at the lung bases perhaps due to accumulation of edema around small airways. In addition, most of the patients had decreased ventilation and perfusion at the lung bases which improved with dialysis. Little change occurred, however, in the A-a DO2 with dialysis. In acute pulmonary edema in dogs Staub et al. [l] demonstrated that edema fluid appeared in the loose connective tissue around extra-alveolar vessels and airways before there was any significant change in alveolar wall thickness. Hughes and Rosenzweig [2] showed that in the isolated perfused dog lung the volume of trapped gas increased with increased lung water and was greater in the more dependent parts of the lung in which pulmonary edema was most prominent upon histologic examination. It was postulated that peribronchiolar edema might cause airways to close at abnormally high distending pressures resulting in the trapping of larger volumes of gas. Ruff et al. [3] recently demonstrated that this same phenomenon might be present in patients with hepatic cirrhosis. They concluded that gas trapping in the dependent lung zones could. be an important cause of the impaired gas exchange which is often seen in cirrhotic patients. Our investigation was carried out to test the hypothesis that if increased lung water caused an increased volume, of trapped gas in the lungs, then removal of some of the excess water
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ought to decrease the volume of gas trapping. We selected patients who had chronic renal failure and who were on a hemodialysis program. Both before and after hemodialysis we performed routine pulmonary function tests and studies of gas exchange, and we examined regional pulmonary function and “closing capacities” using xenon 133 ‘(133Xe). MATERIALS
AND
METHODS
The patients studied were in chronic renal failure and were on a chronic hemodialysis program. Some had concomitant clinical heart failure without pleural effusion. All but one (V.A.) had dyspnea before dialysis; in most, dyspnea diminished after dialysis had resulted in a loss of body fluid. Six patients were studied before hemodialysis and again within 1 hour after dialysis. All measurements were made‘ with the patients in the seated position. Because some of the patients were quite dyspneic and debilitated, not all the studies were carried out on the same dialysis day. Routine pulmonary function testing consisted of measuring lung volumes by spirometry and helium dilution [4], and measuring maximum mid-expiratory flow rate (MMFR) by spirometry. Diffusing capacity was measured by the steady state technic [5]. Results of these tests were compared with predicted normal values [6]. The alveolar-arterial oxygen differences (A-a DOp) were measured in the conventional way [7] while the patients were seated and breathing room air. The patients breathed through a mouthpiece connected to a Hans-Rudolph valve. After a period of adjustment expired gas was collected in a meteorologic balloon for 2 min. A simultaneous arterial blood gas sample was also drawn over the 2 min. Because these patients might have needed their superficial arteries for arteriovenous fistulas for hemodialysis, indwelling arterial catheters were not used for sampling arterial blood. Instead, the area around the brachial artery was thoroughly anesthetized before the study and blood was collected from a stab puncture of the artery. Expired gas was analyzed for oxygen and carbon dioxide content by the micro Scholander technic, with duplicate measurements agreeing within 6.04 per cent. Arterial blood samples were analyzed for carbon dioxide tension (PaCOp) and pH by appropriately calibrated electrodes. Using PaC02 and expired gas oxygen and carbon dioxide concentrations, “ideal” alveolar oxygen tension was calculated and compared with measured arterial oxygen tension (PaOz) [7]. The methods used for the study of regional lung function have been described in detail previously [8]. Lung regions were defined by six collimated scintillation counters which were positioned at 5 cm intervals over the back of each hemithorax from apex to base. Regional residual volumes were measured by having the patients inhale ls3Xe in known concentration from residual volume (RV) to total lung capacity (TLC) and hold their breath at TLC while regional count rates were recorded [9]. Regional functional residual capac-
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ities were measured by having the patients inhale ‘133Xe in known concentration from functional residual capacity (FRC) to TLC and hold their breath while regional count rates were recorded [9]. Regional ventilation was assessed by injecting a bolus (1 to 2 mCi in 2 to 4 cc) into the mouthpiece while the subject held his breath at FRC. The subject then inhaled slowly (0.2 to 0.6 liters/set) to TLC and held his breath while regional count rates were recorded [9]. Regional perfusion was assessed by injecting slugs of 133Xe intravenously while subjects held their breath at FRC. When the injected isotope had entered the alveolar gas, the subjects inhaled room air to TLC where count rates were recorded [lo]. Each of these maneuvers was completed twice in each study, and each inhaled volume of labelled and/ or unlabelled gas was measured spirometrically. The regional count rates measured at TLC during each of these maneuvers were converted to regional concentrations by equilibrating the subject with 133Xe in known concentration and again recording regional count rates during a series of breath-holds at TLC [8]. Regional concentrations resulting from tests of ventilation and perfusion distributions were expressed as indices or percentages of the regional concentrations which would have been present if ventilation and perfusion had been even [8]. Regional residual volumes and functional residual capacities were expressed as fractions of regional total lung capacities (RVr:TLCr, FRCr:TLCr) [9]. In addition the lung volume at which “airway closure” begins [ll] was measured (Figure 1). Subjects exhaled to RV and a bolus of 133Xe was injected into the mouthpiece. The bolus was then inhaled at the onset of a slow inspiratory VC maneuver, 133Xe entering areas with open airways at or near RV. Subjects then made slow VC expirations while 133Xe concentration was measured at the mouth and plotted against lung volume on an x-y recorder. Figure 1 shows a sample tracing. After dead space washout (I and II), there was a slowly rising alveolar plateau (I II), but at low lung volumes the slope of the plateau suddenly became steeper with a rapid rise of 133Xe concentration until RV was reached (IV). The volume at which the slope of the plateau changes is the “volume at which airway closure begins” (I I I-IV junction). At this point 133Xe poor units stop contributing to the expirate; presumably the reason such units were 133Xe poor was that their airways had been closed when the bolus was inhaled. The volume between RV and the Ill-IV junction has been called “closing volume.” We measured “closing capacities,” the absolute lung volume at the Ill-IV junction (“closing volume” plus RV). RESULTS
The results of routine pulmonary function both before and after hemodialysis are presented in Table I and Figure 2. Before dialysis there was a restrictive pattern with a reduction in all lung volumes. In only one subject was RV above the pre-
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AJ
I .
O-
DL
+5
MR
6.1
I LL
1 CiOSlNG i
~-CAPACITY
7
Figure 1. Relationship between coun’ts per second’in expired air and expired volume following an inspiratory VC maneuver during which a bolus of 133Xe was inhaled at RV. The plateau (phase 111) shows a small gradual rise with well marked cardiogenic oscillations followed by a steeper rise with reduced oscillations (phase IV). The arrow represents the junction between phase 111and IV. CV = closing volume.
120 t
r]
Pre - dialysis
m
Post-dlalysls
I
0
20
I
40
60
I
80 0
REGIONAL
20
W/TLC
4
40
60
60
(%I
Figure 3. Relationship between distance down the lung from apex to base and regional residual volumes expressed as a per cent of the regional TLC. The solid lines are the results before dialysis; the dashed lines are the results after dialysis. The per cent change in weight with dialysis is indicated for each oatient.
IOO60-
p .+ e a S
604020O-
TLC
FRC
“5
ns
vc p-2
IO
RV
MMFR
Dco
PC.10
PC.05
“S
Figure 2. Mean results fl standard error of the mean of six patients of the routine pulmonary function tests expressed as a percentage of predicted. The significance of changes before and after dialysis (by paired t test) are shown on the bottom line. ns = nonsignificant.
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Volume
‘Closing
Capacity’
F’re-dialysis
(liters)
Figure 4. Comparison of “closing capacity” and after hemodialysis for each subject.
55
before
6.1
Yes
M.R.,19
Before dialysis After dialysis Predicted (4.80)
3.71 3.91
(6.38)
4.56 4.72
4.9
No
A.J.,23
Before dialysis After dialysis Predicted
3.42 2.81 (4.51)
3.8
Yes
J.S.,23
Before dialysis After dialysis Predicted
3.48 3.86 (4.12)
Yes
D.L.,28
Before dialysis After dialysis Predicted
4.5
No
V.A.,37
Before dialysis After dialysis Predicted
6.23 5.55 (6.71) 6.09 6.01 (7.10)
5.1
No
R.D.,24
Before dialysis After dialysis Predicted 9.6
(%)
TLC (liters)
1.99 2.06 (2.54)
1.89 2.38 (3.50)
1.61 1.41 (2.42)
1.52 1.98 (2.18)
3.07 3.49 (3.95)
2.74 2.18 (3.63)
FRC (liters)
2.38 2.72 (3.49)
3.31 3.83 (4.63)
2.69 2.47 (3.16)
2.53 2.86 (2.93)
4.24 4.43 (4.95)
4.14 4.59 (4.98)
vc (liters)
1.33 1.19 ‘(1.31)
1.25 0.89 (1.75)
0.73 0.34 (1.35)
0.95 1.00 (1.20)
1.85 1.58 (2.15)
2.09
in Body Weight with Dialysis and Pulmonary
A Weight
Per Cent Change
Smoker
Patient and
Age, Smoking History,
Age ur)
TABLE I
9.4 10.0 (19.0)
10.6 14.3 (19.4)
5.05 6.21 (4.19) 2.37 2.45 (3.76)
...
(,“,I”,)
2.02 1.67
...
1.79 1.37
1.08 0.64
6.7
...
-0.03 +0.39 ...
+0.10 +1.01 ...
+0.53 +0.77 ...
+0.06 +0.49 ...
1.46 1.49 8.8 ,I::,
+0.52 +1.12 ...
...
... 2.55 2.37 ...
-0.42 +0.01
3.26 2.17
Closing Capacity (liters)
11.6 (1:::)
13.8 11.8 (21.1)
DLCO
FRC Minus Closing Capacity (liters)
83 72
...
(E)
71 76
...
33.5 36.0
44.5 39.5
... 36.5 97
...
32.5 34.0
41.0 38.0 ...
...
21
(Z)
29
(E)
...
...
(llj5
_
95 94
98 103 ...
35.5
78
PaCOz (mm Hg)
PaOz (mm Hg)
10
10 (1;)
23
(mm Hg)
A-a DOa
Before and After Hemodialysis
2.99 3.40 (3.27)
3.08 3.30 (3.27)
5.83 6.15 (4.04)
4.65 4.98 (4.49)
sac)
MMFR (liters/
Function of Patients
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dieted normal range before dialysis. The MMFR was depressed in only one subject (M.R.), in three others it was in the normal range and in two it was definitely increased. Dialysis resulted in no significant change in TLC or FRC. After dialysis there was, however, an increase in VC and MMF with a decrease in RV. The diffusing capacities were significantly decreased before dialysis as was the hematocrit. There was no significant change in either of these values with dialysis. Figure 3 shows the RV,:TLC, for the six subjects. Because the results in both the right and left lungs were similar, for ease of presentation these results have been averaged for each horizontal level at a given distance from the lung apices. In normal erect subjects when RV,.:TLC,. is plotted against vertical distance a “hockey stick” results: RV,:TLC, diminishes over the top 10 to 15 cm of the lung and gives a constant, low value over the bottom 10 to 15 cm. The distribution of RVr for normal seated subjects is shown in Figure 3 [9]. Before dialysis in three of the subjects RV,:TLC, increased as the lung base was approached; in one (A.J.) basal RVr:TLC,. were the same throughout, and in two (V.A. and D.L.) there was roughly a linear decrease from apex to base. After dialysis, basal RV,:TLC, decreased in five subjects whereas apical RV,:TLC, changed in a more variable manner. In only one subject (V.A.) did basal RV,:TLC, increase slightly as a result of dialysis. This latter subject differed clinically from the others in that he was the only one who was not dyspneic before dialysis. The “closing capacity” of each subject both before and after dialysis is compared in Table I and Figure 4. With dialysis there was a significant decrease in “closing capacity” (p CO.05 by paired t test). By subtracting the “closing capacity” from the FRC, it was possible to estimate whether or not the dependent airways were open or closed during normal tidal volume breathing [12]. These values were plotted with respect to age (Figure 5) on a graph of depicting data on normal seated subjects obtained from McCarthy et al.[13]. Before dialysis in three subjects this difference was approximately zero and in one subject significantly negative; implying that the dependent airways were “closed” at FRC. In two subjects the FRC minus “closing capacity” volume was within the normal range, and significantly greater than zero, implying that the dependent airways were open at FRC. With dialysis this difference (p (0.01 by paired t test) was significantly increased in all subjects, implying a greater tendency for the dependent airways to be open at FRC.
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Volume
- Pm-
dlalysls
0
Post-dlalysls
z 6 1,5f -r ‘, IO :: I_? ----____ -0.5 5 --i-_ _z E
t o---i2 LI - 0.5’
f
Mean _---____ I
---___
-_ --_
-=-_
li 20
40
30
_2SD 50
AGE Iyears)
Figure 5. Relationship between FRC minus closing capacity and age before (x) and after (0) hemodialysis for each subject.
Ventilation at the lung bases was decreased in four of six subjects (Figure 6), and it was these subjects who demonstrated “closing capacities” equal to or greater than FRC. These subjects probably had closure of basal airways at FRC; boat this lung volume luses of 133Xe administered tended to be distributed to the lung apices. With dialysis “closing capacity” decreased, FRC did not change, and ls3Xe administered at FRC tended to be distributed more to the lung bases. These Or RD
g
0
r Js
r v*
L
0
I 1600
I
1
40
1
I
1
80
I
I
I
120 160
REGIONALVENTILATIONt%) between distance down the Figure 6. Relationship lung and the regional ventilation. The results represented by solid lines are before dialysis; the dashed lines are after dialysis.
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0
r
RD
r
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zero ornegative. In the two subjects with a normal A-a D02, one (D.L.) had the FRC minus “closing capacity” only minimally above zero. With dialysis, despite significant improvement in the FRC minus “closing capacity” volume in all subjects, the A-a DO2 did not ch,ange significantly in two subjects (R.D. and A.J.) and increased in one subject (M.R.). Thus, there was little correlation of the A-a DO2 with the “opening” or “closing” of dependent airways.
JS
COMMENTS
6
Or
I.
0
DL
-
40
8.
60
*
m
1
II
I
*
120 160 0 40 REGIONAL PERFUSION
II
11
80 (%I
I,
120
160
Figure 7. Relation&hip between distance down the lung and the regional perfusion. The ‘results represented by solid lines are before dialysis; the dashed lines are after dialysis.
data are also compatible with basal airway closure being reversed by dialysis, and therefore likely due to edema fluid in or around these airways. Before dialysis the distribution of perfusion (Figure 7) was similar to the distribution of ventilation, i.e. in five of six subjects perfusion at the lung bases was reduced from normal. With dialysis the improvement in basal lung perfusion was similar to the basal lung ventilation in all but one subject (M.R.). In this patient, basal lung ventilation improved, however, basal lung perfusion remained decreased. Of interest is that after dialysis the A-a DO2 increased from 21 to 33 mm Hg, perhaps as a result of ventilation to perfusion mismatching. Whether the dependent airways are during normal tidal volume “open” or “closed” breathing has been shown to be related to gas exchange by Craig et al. [12], i.e., the more the “closing capacity” exceeded the FRC, the greater was the A-a Don. For technical reasons the A-a DO2 was not obtained on one subject (J.S.) before dialysis. Before dialysis, three of five subjects had an elevated A-a DO2 (Table I), and in these the FRC minus “closing capacity” was close to
We have been unable to find previous data regarding pulmonary function in patients with uremia. Before dialysis, on routine pulmonary function testing, a restrictive pattern emerged. The TLC, FRC, VC and RV were all significantly reduced below predicted values whereas the MMFR was normal. This was not changed with removal of excess body fluid; TLC and FRC remained constant, RV decreased further, and VC and MMFR increased. Five of our six patients were dyspneic and their condition worsened with excess fluid. As patients in chronic renal failure are subject to hypertension and heart failure, it is possible that these results simply represented heart failure. However, decrease in all lung volumes with preservation of expiratory flow rates is not typical of heart failure and suggests lung fibrosis [14]. Heard [15] and Perry [16] have described parenchymal fibrosis and fibrin masses in the air spaces of chronic uremic patients, supporting the foregoing hypothesis. The reduction in diffusing capacity both before and after dialysis is compatible with pulmonary fjbrosis, but it is difficult to interpret due to coexistent anemia in these subjects with chronic uremia [17]. We interpret the pulmonary effects of hemodialysis as being due to removal of lung water and believe that our results support the hypothesis that a major effect of lung edema on pulmonary function is due to accumulation of fluid in or around the airways, chiefly in dependent lung regions. Such fluid accumulation would narrow, airways and make them susceptible to closure at higher lung volumes. The increase in MMFR after dialysis implied a decrease in airway resistance. This is supported by the findings of Hogg et al. [18] who found that peripheral airway resistance increased with the development of interstitial pulmonary edema. Over-all RV and “closing capacity” declined after dialysis whereas TLC remained constant, suggesting that the RV before dialysis had been in part determined by airway “closure.” Our studies of regional lung function supported
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this argument. The change in basal RV,:TLC, induced by dialysis suggested that the removal of fluid decreased gas trapping in dependent lung zones. In normal subjects, Sutherland et al. [9] found that as one scanned the lung from apex to base regional RV:TLC decreased and at the lung bases attained a constant value. Before dialysis all our subjects demonstrated the initial decrease in the regional RV:TLC in going from apex to base (Figure 3), but in the lower 10 cm of the lung this ratio increased in four of six subjects. This increase was pronounced in only one subject. Dialysis, however, produced a decrease in the basal RV,:TLCr in five of six patients. This consistent change iinplied that the initial increases in basal RV,:TLC, were due to excess fluid. In only two subjects (J.S. and V.A.) did ventilation increase from apex to base before dialysis; these were the two subjects in whom FRC was unequivocally greater than “closing capacity.” The other four subjects, whose FRC minus closing “capacity volumes” were equal to or less than zero, demonstrated decreased ventilation at the lung bases before dialysis. This decreased basal ventilation was best explained then, by the presence of basal airway “closure” at FRC. With dialysis all but one subject (A.J.) demonstrated increased ventilation to basal regions as the FRC minus “closing capacity” volume increased. In one subject (R.D.) ventilation of the lung bases after dialysis remained low; in this subject even after dialysis FRC and “closing capacity” were substantially the same. Hughes et al. [19] with rapid freezing of excised dog lungs demonstrated that at low lung volumes airway closure occurred in the terminal bronchioles. Burger and Macklem [3] provided evidence for true closure of airways in normal human subjects occurring at low lung volumes. Staub et al. [l] demonstrated that in the development of pulmonary edema in dogs, fluid accumulated first around the basal conducting airways and vessels that are extra-alveolar. This was also demonstrated by O’Connor et al. [20] in induced pulmonary edema in intact dogs. In excised dog lungs, lliff [21] found that by increasing alveolar pressure greater than vascular pressure it was possible to shut down the capillary bed. It was then possible to study the permeability of extraalveolar arteries and veins independently from the capillaries. With a 4 to 6 per cent weight gain of the excised dog lungs, interstitial fluid cuffing consistently occurred around arteries, veins and airways. Similar results were also found by Goldenberg et al. [22]. Recently Iliff et al. [23] found in the isolated dog lung that the develop-
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ment of interstitial edema diverted both ventilation and blood flow away from the basal region to the middle and apical lobes, and perivascular and peribronchial edema was more marked in the dependent lung regions. Ruff et al. [3] found increased gas trapping in the lower lung zones of hepatic cirrhotic patients with reduced ventilation to this region. It was suggested that the premature airway closure was due to mechanical compression of small airways by dilated blood vessels and/or interstitial pulmonary edema. It is of interest that the basal increase in RVr:TLC,. in the study with cirrhotic subjects was much greater than the increase we found in RV,:TLC, in the present study. None of the cirrhotic subjects had evidence of fluid overload, i.e., they had neither cardiorespiratory disease nor ascites. Their serum albumin was below normal but not in the range expected to cause interstitial pulmonary edema. Therefore there would appear to be a discrepancy between our results and those of Ruff et al. [3]: our patients probably had greater intrapulmonary fluid accumulation than theirs but less striking airway closure. A possible explanation for this might be that our patients also had evidence of restrictive lung disease. Although we did not measure static pressure volume curves in our patients, the combination of low lung volumes and normal flow rates suggests that these curves were shifted to the right, i.e., that elastic recoil was increased. It has been shown that “airway closure” increases as elastic recoil decreases [24], and it would therefore be reasonable to postulate that increases in elastic recoil decrease the tendency for “airway closure” to occur. Thus, the restrictive abnormality seen in these patients, which was presumably due to lung fibrosis, may have protected them from the extensive “airway closure” noted in cirrhotic subjects. Before dialysis, there was a decrease in basal lung perfusion in five of six patients (Figure 8). This distribution of decreased basal lung perfusion has been observed previously in patients with mitral stenosis [25,26]. The decrease in basal perfusion with pulmonary venous hypertension has been attributed to perivascular edema in the dependent lung regions, with the accumulated fluid causing a high resistance to blood flow [27]. With removal of body fluid the basal lung perfusion increased in five of six subjects, consistent with reductions of perivascular fluid. Before dialysis there was a poor correlation between the A-a DOn and whether or not the volume of the “closing capacity” was greater than the FRC. After dialysis the “closing capacity” volume increased relative to the FRC volume in all
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subjects but, contrary to the results of Craig et al. [12], the A-a DO2 did not decrease but increased in three patients and did not change in two. The reasons for this remain speculative. Possibly accounting for the large initial A-a DO2 was the severe anemia as a result of chronic uremia. Anemia by itself can result in an elevated A-a DO2 [28-301. Housley [30] attributed the increased A-a DO2 with anemia to both an increase in the anatomic shunt and ventilation to perfusion abnormalities. Further, these patients had a diffuse lung abnormality of a restrictive nature, which may increase the A-a DO2 in the absence of airway closure either by causing mismatch of
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ventilation to perfusion ratios or by inducing alveolar capillary block [31]. If maldistributions of ventilation to perfusion ratios occurred within, as opposed to between, lung regions, then the present regional measurements would not detect them [32]. Because of their anemia the decreased Dco observed in our patients could not be attributed either to ventilation to perfusion abnormality or alveolar capillary block. ACKNOWLEDGMENT
We are thankful to Dr. A. Gonda and Dr. R. D. Guttman, Renal Service, Royal Victoria Hospital, for their cooperation with this study.
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Burrows B. Niden AH: Effects of anemia on CO diffusion in the perfused dog lung. Fed Proc 21: 443, 1982. Hogg JC, Agarawal JB, Gardiner AJS, Palmer WH, Macklem PT: Distribution of airway resistance with developing pulmonary edema in dogs. J Appl Physiol 32: 20, 1972. Hughes JM, Rosenzweig DY, Kivitz PB: Site of airway closure in excised dog lungs: histologic demonstration. J Appl Physiol 29: 340, 1970. O’Connor NE, Sheh JM, Rartlett RH, Bass H: Gas exchange and pressures in pulmonary edema. Rev Surg 28: 145, 1971. lliff LD: Extra-alveolar vessels and oedema development in excised dog lungs. Circ Res 28: 524, 1971. Goldenberg VE, Smith HC, Cheney FW, Butler T: Pathogenesis of edema in excised lungs. Fed Proc 28: 282, 1969. lliff LD, Greene RE, Hughes JMB: Effect of interstitial edema on distribution of ventilation and perfusion in isolated lung. J Appi Physio133: 462, 1972. Anthonisen NR, Danson J, Robertson PC, Ross WRD: Airway closure as a function of age. Resp Physiol 8: 58,1969/?0. Dollery CT, West JB: Regional uptake of radioactive oxygen, carbon monoxide and carbon dioxide in the lungs of patients with mitral stenosis. Circ Res 8: 765.1980. Dawson A, Kaneko K, McGregor M: Regional lung function in patients with mitral stenosis studied with xenon-133 during air and oxygen breathing. J Clin Invest 44: 999, 1965. West JB. Dollery CT, Naimark A: Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol 19: 713, 1964. Ryan JM, Hickam JB: The alveolar-arterial oxygen pressure gradient in anemia. J Clin Invest 31: 188, 1952. Sproule BJ, Mitchell JH, Miller WF: Cardiopulmonary physiological responses to heavy exercise in patients with anemia. J Clin Invest 39: 378, 1960. Housley E: Respiratory gas exchange in chronic anaemia. Clin Sci 32: 19. 1967. Arndt H, King TK, Briscoe WA: Diffusing capacities and ventilation: perfusion ratios in patients with the clinical syndrome of alveolar capillary block. J C/in Invest 49: 408, 1970. Anthonisen NR, Bass H, Oriol A, Place G. Bates DV: Regional lung function in patients with chronic bronchitis. Clin Sci 35: 495, 1968.
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