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Renal response to mechanical ventilation in patients with chronic hypercapnia
Renal Response to Mechanical Ventilation in Patients with Chronic Hypercapnia
GERARD
M. TURINO,
ROBERTA HENRY
0.
M.D.
M. GOLDRING, HEINEMANN,
M.D M.D.
New York, New York
From the Departments of Medicine, College of Physicians & Surgeons, Columbia University, New York University School of Medicine and The New York Hospital-Cornell Medical Center, New York New York. This study was supported in part by U.S. Public Health Service Grants CA 11096 and HE 13921 (H.O.H.). Requests for reprints should be addressed to Dr. Henry 0. Heinemann, Cornell University Medical College, 1300 York Avenue, New York, New York 10021. Manuscript accepted July 5, 1973.
Alkalosis in hypercapneic patients caused by abrupt respiratorinduced reduction of the partial pressure of carbon dioxide leads to bicarbonate diuresis. Potassium is the predominant cation accompanying bicarbonate loss in the urine. The determining variable for induction of proportional changes in renal bicarbonate and potassium excretion is the partial pressure of carbon dioxide. The reduction of the partial pressure of carbon dioxide modifies bicarbonate regeneration directly by limiting the hydration reaction and facilitates potassium loss indirectly by reducing extracellular, and by inference intracellular, hydrogen ion activity. Respiratory acidosis secondary to carbon dioxide retention in patients with chronic lung disease is corrected by the generation of new bicarbonate and sustained elevation of the threshold for renal bicarbonate reabsorption [l-4]. The generation and excretion of bicarbonate by the kidneys and the elimination of carbqn dioxide by the lungs have different time constants, and situations therefore easily arise in which bicarbonate generated to balance rising carbon dioxide tensions may become superfluous as the hypercapnia is corrected [5,6]. Bicarbonate excess following transient aggravation of carbon dioxide retention is not uncommon in patients with chronic hypercapnia, especially if complicating heart failure requires restricted sodium chloride intake and diuretic therapy. It is thought that such inappropriate bicarbonate retention is in part a consequence of inadequate chloride supply which raises the threshold for bicarbonate reabsorption [7,8]. In addition to chloride there are other variables which modify renal bicarbonate reabsorption such as the volume of the extracellular fluid and, most importantly, the partial pressure of carbon dioxide itself [g-13]. Recently Gennari, Goldstein and Schwartz [14] demonstrated in dogs that adaptive changes in plasma bicarbonate concentration to hypocapnia induced by exposure to a low oxygen environment are linked to over-all cation rather than chloride balance. In this study the interrelations between bicarbonate excretion, partial pressure of carbon dioxide and cation as well as chloride balance were measured in patients with stable chronic hypercapnia without fluid retention in whom the partial pressure of carbon dioxide was reduced by mechanical ventilation. The results demonstrate that renal bicarbonate loss accompanying
February 1974
The American Journal of Medicine
Volume 56
151
RENAL
RESPONSE
TABLE
I
TO VENTILATION
IN HYPERCAPNIA-TURIN0
Lung Volumes and Maximal
__~ Subject
Sex,Age(yr) BSA
R.C. W.K. R.T. J.H.
M,66,2.03 M,43,1.14 F,54,1.61 M,59,1.10
Breathing
IC
ET /iL.
Capacity
ml
% pred.
ml
% pred.
2,550 539 1,451
94 23 72
750 224 680
89 29 105
...
...
...
. ..
NOTE: IC = inspiratory capacity; ERV = expiratory capacity; MBC = maximal breathing capacity.
ml
% pred.
3,350 763 2,011 850
94 23 78 28
reserve
volume;
abrupt reduction of the partial pressure of carbon dioxide in blood is independent of chloride balance and related to potassium and, to a lesser extent, sodium excretion. The significance of these observations will be discussed. GENERAL
PROCEDURES
Four patients with chronic stable lung disease and normal renal function were studied. Their age and relevant clinical data are summarized in Table I. One patient (J.H.) was studied on two occasions 2 years apart. All patients were kept on a metabolic ward where they were given constant diets “low” in sodium chloride (<20 meq/day) alternated with diets “high” in sodium chloride (f100 meq/day). Fluid intake and body weight were recorded daily. The 24-hour urine was collected under mineral oil with toluene as a preservative and stored at 4°C. The urinary excretion of creatinine, sodium, potassium, chloride and total hydrogen ion was determined daily. All excretion rates are expressed in micromoles or milligrams per minute or as concentration ratios with creatinine as the common denominator. Venous blood samples were obtained periodically for the determination of serum sodium, potassium, chloride and total carbon dioxide content. Arterial blood samples were drawn at regular intervals before and during mechanical ventilation for determination of pH, carbon dioxide tension (pCO2) and oxygen tension (pop). EXPERIMENTAL
February 1974
The American Journal of Medicine
VC =
TLC
MBC
ml
% pred.
ml
% pred.
BV/ TLC (%>
2,600 1,365 3,430
130 100 299
5,950 2,119 5,441
113 48 146
44 64 63
,..
...
...
...
...
vital
capacity;
RV =
residual
volume;
(Inters/ % min) pred. 95 34 18 35
89 47 25 45
TLC = total lung
in which potassium chloride supplements (1 meqlkg body weight during treatment in the respirator) were given intravenously. Arterial blood samples were drawn at regular intervals before and during mechanical ventilation. The patients were allowed to void spontaneously. All urine samples were collected under mineral oil. On the day of the experiment a single urine collection was made before starting the respirator (period C). The excretion rate of creatinine and electrolytes during this period was found to be similar to the average excretion rates during two 24 hour periods preceding the day of the experiment. ANALYTICAL
METHODS
The sodium and potassium concentrations in serum and urine were measured by flame photometry; chloride in serum and urine was measured by potentiometric titration [15]; ammonia was measured by means of the diffusion technic of Seligson and Hirahara [16]; creatinine was analyzed by the method of Bonsnes and Taussky [17]. The titratable acid of the urine was obtained by titration to pH 7.4. The carbon dioxide content of the urine was determined by the method of Van Slyke and Neil1 [18]. The partial pressure of oxygen and carbon dioxide in arterial blood was measured by specific electrodes. The pH of arterial blood was measured anaerobically at 37.5”C with a glass electrode. RESULTS
PROTOCOL
Experiments were carried out after 3 to 6 days of constant diet. On the day of the study, the patients were placed in an Emerson body respirator for 3 to 4 hours. A water load (600 to 800 ml) was given orally 1 hour prior to the study. An indwelling arterial needle was placed in the right brachial artery. An intravenous infusion of 5 per cent dextrose in water was started before mechanical ventilation, and an infusion rate of 300 ml/hour was maintained throughout the period of assisted respiration. The rate of mechanical ventilation and the pressure level were adjusted in each patient to achieve pCOz reductions which the patient could tolerate. Each patient was studied at least twice on separate occasions while on a diet high or low in sodium chloride. In addition, studies were carried out
152
RV
vc
ERV
A representative study on one patient (R.C.) is shown in Figure 1. The results obtained in all patients are summarized in Table II and Figures 2 through 9. Relationship Between the Partial Pressure of Carbon Dioxide (CO2) in Arterial Blood, Renal Bicarbonate (HC03-:CR) and Total Hydrogen Ion (H+:CR) Excretion Rates. Reduction of the partial pressure of carbon dioxide leads to bicarbonate loss in the urine (Figure 2). The bicarbonate concentration in the urine and the partial pressure of carbon dioxide in blood are exponentially related whether bicarbonate is represented in concentration units using creatinine as the glomerular
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RESPONSE
IN HYPERCAPNIA-TURIN0
ET AL.
tassium excretion by the kidneys (Figure 2). The pC0~ in arterial blood and the potassium concentration in the urine (K:CR in micromoles per milligram) are exponentially related. This relationship is not modified by potassium chloride supplementation or variations in sodium intake (Figure 6). But the lowest rate of potassium excretion appears to occur while the patients are on a high sodium intake (Figure 2). There is no apparent relationship between the partial pressure of carbon dioxide and the sodium over creatinine concentration ratio while the patients are on a low sodium diet (Figure 7). On a high sodium diet, with or without potassium chloride supplements, the sodium over creatinine concentration ratio is higher for any given pCOs. There is no apparent relationship between pCO2 and the excretion of chloride, and the excretion of this anion remains essentially unchanged except when patients on a high sodium chloride intake
marker (Figure 3) or is expressed as a urine to plasma (U : P) ratio with plasma bicarbonate as the denominator (Figure 4). Differences in sodium chloride intake and infusion of potassium chloride have no apparent effect on the relationship between bicarbonate in urine and the partial pressure of carbon dioxide in blood. Total hydrogen ion excretion expressed in the change in hydrogen over creatinine concentration ratio in micromoles per milligram (AH+/CR) declines during treatment in the respirator because of diminished acid and increased bicarbonate output (Figure 2). The change in total hydrogen ion over creatinine concentration ratio is linearly related to the change in bicarbonate over creatinine ratio (Figure 5). Relationship Between the Partial Pressure of Carbon Dioxide and the Excretion Rates of Potassium, Sodium and Chloride. Lowering of the partial pressure of carbon dioxide leads to increased po-
,+, mM/l_
3.6
I,
05
mM/L
TO VENTILATION
02.mMlL
36
C02,mmHg Ii * 1%
58 7.41 87
3.1 82 33 26 7.71 88
3.0 85 36 43 7.56 77
3.4 84 37 65 7.37 84
4.2 86 34 41 7.53 61
3.9 85 34 52 7.43 82
RESPIRATOR KCI
Figure 7. Two studies in patient R.C. are shown. The two control periods (C) reflect, respectively, the excretion rates in pmoles per minute 24 hours before the day of the experiment and on the day of the experiment just prior to treatment in the respirator. Periods 1-4 during the first study and 1-5 during the second represent collections study urine while the patient was in the respirator; period 5 during the first experiment and period 6 during the second experiment represent samples collected immediately after discontinuing the respirator. The excretion rate of potassium was not measured during the fourth period of the first experiment. Note the changes in pCO2 and pH in blood and total hydrogen, bicarbonate, chloride and potassium excretion in the urine without and with potassium chloride supplement (50 mmol). With potassium chloride, total bicarbonate excretion during treatment in the respirator is more conspicuous despite a lesser change in pCO:!.
60mM
332 --’
February 1974
The American Journal of Medicine
Volume 56
153
M&6,2.03
M,43,1.14
F,54,1.61
M,59,1.10
M,61,1.10
M,61,1.10
M,66,2.03
M,43,1.14
F,54,1.61
W.K.
R.T.
J.H.
J.H.
J.H.
R.C.
W.K.
R.T.
BSA
Sex,AgeW),
135 57 20 28 39 100 98 60 62 64 96 104 125 45
C
E-l E-2 E-3 E-4 C E-l E-2 E-3 E-4 C E-l E-2 E-3
150 75 60 60 130 80 65 63 90 42 35 85 50 83 62 53 78 117 65 61 163 100 78 136
Time (min)
55.8
38.7
81.4
36.1
36.5
37.7
55.0
38.3
81.9
pH
TA
1.0 1.9 3.3 3.3 3.4 1.5 1.4 5.3 6.2 5.5 2.6 1.8 1.5 6.0
0.8 3.0 5.9 2.5 0.4 4.3 5.1 6.4 2.6 5.5 6.4 3.0 0.6 2.5 3.8 2.8 0.9 2.1 2.9 1.8 0.9 2.2 2.1 0.4
15 18 2 0 2 6 3 4 2 2 2 1 6 6 2 0 8 0 0 0 6 2 0 0
6.0 6.4 6.3 7.9 7.9 6.9 7.0 6.9 6.9 7.2 7.0 7.0 7.4 7.2
14 23 39 0 0 4 2 7 6 4 6 3 0 5
NH,+
Control
34 51 60 54 27 10 8 35 44 42 30 17 13 23
Chloride
35 87 75 32 6 20 25 30 27 34 32 ... 18 14 16 14 19 32 38 23 17 28 21 5
Chloride
B. Low Sodium
6.2 6.6 7.3 7.8 6.9 6.9 7.0 7.1 6.4 6.7 6.7 7.1 6.3 6.8 7.3 7.7 6.6 7.4 7.7 7.9 6.4 7.0 7.5 7.8
A. Low Sodium
_. HOW (ml/ min)
Blood and Serum During
Weight (kg)
in Urine,
C E-l E-2 E-3 C E-l E-2 E-3 C E-l E-2 E-3 C E-l E-2 E-3 C E-l E-2 E-3 C E-l E-2 E-3
Period
Measurements
R.C.
Subject
TABLE II
Hf
48 96 -33 -46 7 -17 4 -1 18 12 5 ... 23 -15 -76 -95 20 -22 -70 -74 18 4 -29 -9
5 8 60 35 3 11 10 10 15 27 29 19 10 20 5 6 15 28 57 57 2 6 8 8
Potassium
Na
3 10 10 264 187 8 6 20 22 32 7 14 26 55
45 64 89 -210 -160 6 4 22 28 14 29 6 -13 -27
3 4 5 61 49 16 7 13 12 14 9 17 17 18
Diet With Potassium
2 9 110 78 1 43 24 35 12 24 29 11 1 35 94 109 7 54 108 97 5 27 50 14
Diet Without
HCOs-
”
Urine (umol/min)
Cl
39 79 100 332 321 45 39 65 50 44 18 21 47 87
Chloride
35 79 190 148 22 64 46 38 18 19 18 10 42 63 95 98 56 75 100 92 31 40 64 18
0.69 0.95 0.88 0.78 0.31 0.77 0.31 0.39 0.55 0.55 0.51 0.44 0.51 0.38 0.38 0.36 0.44 0.21 0.20 0.28 0.25 0.30 0.13 0.15
0.81 1.12 1.30 0.73 1.01 0.57 0.45 0.75 0.56 0.44 0.57 0.49 0.56 0.84
Supplements 1 1 1 3 3 29 15 18 9 6 8 13 16 24
PH
7.37 7.42 j.53 7.43 7.51 7.33 ... 7.40 7.40 7.46 7.38 7.39 7.39 7.40
7.41 7.45 7.71 7.53 7.39 ... .,. 7.47 7.40 ... 7.40 7.43 7.38 7.52 7.58 7.68 7.39 7.54 7.59 7.60 7.34 7.52 7.57 7.61
Supplements
(mg/min)
65 55 41 52 43 56 ... 48 51 43 65 59 58 58
58 55 26 43 53 ... ... 41 58 ... 56 51 62 44 37 27 47 33 30 27 53 33 31 27
(mm Hg)
pCOz
84 ... ... ... 89 ... ... ... ... 85 82 ... ... , .
87 ... ... ... 86 ... *. . 91 89 ... ... 89 91 ... ... 98 95 ... ... 97 94 ... ... 97
(%)
02 Saturation
37 35 33 ... 34 29 ... 29 29 30 38 ... ... ...
36 37 ... 35 32 ... ... 30 35 ... ... 34 36 36 35 34 28 ... ... 27 29 ... ... 28
HCO,-
Hyperventilation
Blood
of Mechanical
Creatinine
Periods
1 1 1 1 8 19 5 3 13 11 6 9 12 9 12 11 22 16 17 1 12 9 13 4
Chloride
K
Periods (C) and Experimental
3.4 3.2 4.2 ... 3.9 4.1 ... 4.0 ... 3.3 3.7 4.6 4.3
.,. .
...
3.6 3.4 ... 3.1 3.9 3.7 ... 3.7 3.6 ... 3.7 3.7 4.4 4.0 4.0 3.8 4.2 4.0 3.5 3.5 4.1 3.9 3.9 3.7
K
132 130 132 ... 130 136 ... 131 ... 137 146 137 136
133 133 ... 133 134 134 ... 137 142 .., 143 138 142 137 139 138 134 132 131 131 131 132 132 134
Na
Serum &mol/liter)
(E)
..
84 84 86 ... 85 90 ... 90 ... 95 93 91 92
85 85 ... 82 93 90 ... 92 95 ... 96 96 101 100 102 102 94 94 96 96 94 93 96 97
Cl
C E-l C E-l E-2 E-3 E-4 C E-l E-2 E-3 E-4 c E-l E-2
M,61,1.10
M,66,2.03
F,54,1.61
M,59,1.10
M,61,1.10
M,43,1.14
M,59,1.10
M,61,1.10
J.H.
R.C.
R.T.
J.H.
J.H.
W.K.
J.H.
J.H.
NOTE: BSA = body surface * Previous day.
E-2
c E-l E-2 E-3 E-4 C E-1 E-2 E-3 E-4 c E-l
C E-l E-2 E-3 C* E-l
M,59,1.10
J.H.
37.0
39.1
38.1
36.5
39.2
54.2
86.7
36.7
37.5 6.7 7.1 7.6 8.2 6.3 7.1
6 6 0 0 9 3
11 21 41 10 9 9
7.1 7.1 7.2 6.1 7.1 7.4
5.3 5.8’ 5.0 0.9 1.8 4.8
1.4 2.4 5.1 4.0 5.7 0.6 1.3 2.7 3.3 6.0 0.7 1.6 1.7
2 3 0 0 3 3
7.1 7.1 7.7 7.4 6.9 7.1
7.6 1.9 7.6 0.5 2.8
5 6 1 2 9 1 0 0
0 6 2 1
7.1 7.2 7.3 7.3 5.9 7.3 7.8 7.9
7.8 6.3 7.0 7.3
74 59 65 101 4 25 43 45 47 5 22 95
12 14 10 12 16 19 19 21 17 26 18 36
4 21 52 47 53 1 9 90
142 132 3 25 27
10
14 19 8 9 9
19 37 32 33 17 7 13
11 14 24 26 7 6
-20 -19 -25 43 -1 -59
-60 -42 -55 -89 15 -3
26 -14 12
59 69 64 78 23 86
153 105 103 146 57 50
31 73 59
23 29 35 13 33 39 68 139 211 199 37 47 96
11
7
14 13 12 10
53 58 40 84 17 5
48 41 35 59 30 69
43 51 96 78 109 39 42 103 146 193 28 38 61
44 50 60 40 53 55 68 112 179 308 46 47 78 --.__
7.40 ... 7.63 7.58 7.36 7.54
0.35 0.38 0.32 0.59 0.15 0.34
0.63 0.53 0.55 0.81 0.35 0.36
0.68 0.78 0.67
0.55 0.34 0.56 0.42 0.57 0.50 0.31 0.34 0.34 0.36 0.24 0.20 0.24
7.39 ... ... ... 7.44 7.36 7.41 7.49 7.45 7.44 7.36 7.52 7.52 ~-
7.39 ... 7.40 7.43 7.38 7.58 7.62
... 7.43 ... 7.44 7.35
7.37 7.57 7.42
Supplements
0.46 0.36 0.29 0.30 0.20 0.29
Supplements
58 53 32 45 63 53
30 23 15 30 38 50
Chloride
36 48 45
24 49 21
Chloride
44 51 77 92 35 58
[(NHI+ + TA) - HCOB-I.
3 -9 -14 -18 25 -1 -77 -128 -113 11 -14 -17
11
Diet With Potassium
1 45 16
21 31 24
Chtoride
16 16 10 -65 16 -8
Diet Without Potassium
2 20
75
1 11 51
acid; H + = total hydrogen
5
6.7
D. High Sodium
4 5 5 22 3 0
6 0 4
6.5 7.5 6.6
0.4 0.9 3.0 9.7
C. High Sodium Chloride
0.5 1.4 2.7 0.7 0.6 1.2
area (m?); TA = titratable
82 139 79 85 45 62 65 55 55 25 109 106 115
140 305 55 22 31 84 70 109 47 32 36 44 51 132 58
44 52 55 149 ... 293
40 53 45 34 37 38 55 34 36 -
.. ... ...
50
50 44 53 27 25
...
52 55 48
...
52
...
58 34 60
35 53 33
59 ... 29
72 ... ... ... 92 94 ... ... ... 95 94 . . 96 -
28
97
31 ... 29
... ... ... . ..
27 29
... ... ...
30
31
... ... . <. ...
35 30
... . *. ...
...
31 30.5 38
36 . . 30 32 29 28
87 88 90 . *. .. ... 89 91 ... ... . . ... 94 ..
89 ... . . 95 94 96
140 136 ... 139 132 144 138 136 135 137 137 136 136
134 135 147 ... 143 ... 144 138 ... ... .. ... 136 134 134
137 ... 134 136 133 127
3.6 3.9 . . 3.8 3.5 4.5 4.6 4.9 4.7 4.6 3.9 4.2 4.3
4.2 ... ... ... ... 4.3 3.6 3.7
3.6
...
3.8
...
3.6 3.6 4.0
4.3 ... 4.8 4.1 4.2 4.4
0’ <
2 r 5 2 z I 4
100 98
103 102 103 100 100 98 102 98 98 100
z
g
3
97 97
...
z n 2 B
. 95 ..
z
...
103 ... ...
98 95 98 ... 97 ... 97
97 ... 96 95 94 95
RENAL RESPONSE
TO VENTILATION
IN HYPERCAPNIA-TURIN0
AH+
I
AK
A HCO;
B
II
ET AL
Low NoC ‘IH ligh NoCI[( LOWNoC
lb
,KC I
-
L!ICI
I
.ow No C I I-ligh No C
ligh NoC
IIH
_ow No Cllh ligh Na C I 1aw NoC lighNoC,I t KC I t KC +KCl +KCI
I
1 0
-!
-L
+
f
-
-
-
-
-
Figure 2. Average changes and the range of change from control of the excretion rate with respect to creatinine (CR) of total hydrogen (AH+/CR), bicarbonate (AHC03/CR), potassium (AK/CR), sodium (ANafCR) and chloride (AC//C/?) fn subjects with hypercapnia undergoing mechanical ventilation. The patients’ diet was alternated (high and low sodium chloride intake) and was given either with or without potassium chloride supplements (see text).
f l
+
HCO;
‘8
1S 0
0 0
0
0
A
A
0.5 I
400
0
600
A
HCOS pM/mg CR
Figure 3. Relationship between the partial pressure of carbon dioxide in arterial blood (pCO2 in mm Hg) and the concentration of bicarbonate in urine expressed as the bicarbonate over creatinine concentration ratio (HCOs-/CR in pmollmg). The relationship is described by the equation y = 51.6 e-0.0015x. The correlation coefficient is r = 0.701. In this and subsequent figures open circles = low sodium chloride diet; closed circles = low sodium chloride diet plus potassium chloride supplements; open triangles = high sodium chloride diet; closed triangles = high sodium chloride diet -t potassium chloride supplements.
156
February 1674
The American Journal of Medicine
0
A
J
1
200
0
“B
/
O.e
0
0.
0
0
0
0 0
0
(
I
10
20 A pC0,
.
I
I
30
40
J
mmHg
Figure 4. Relationship between changes in the partial pressure of carbon dioxide in arterial blood (ApCOz in mm Hg) and the ratio of urine over plasma The relabicarbonate concentration (U/P HC03-). tionship is described by the equation y = 0.1586 e”.06gx. The correlation coefficient r = 0.607
Volume 56
RENAL
RESPONSE
TO VENTILATION
IN HYPERCAPNIA-TURIN0
ET AL.
bb 0
6o “sa0%
O 8oorc oAAQAo
50-
AH+
A0 A
b
CR
.
PC02
8
pM/mg
oA A
mm Hg
0
0,’
40-
A
0 .
. 0 .
0
A
lA
%
300
0
0
A
0
0
a0
20
/
, 200
I
I
I
+200
t400
K CR
I
+600
AHCO; CRPM/V
Figure 5. Relationship between changes in total hydrogen ((TA + NH4+) - HC03-) and bicarbonafe (HC03-) excretion in the urine expressed as concentration ratios using urine creatinine as the common denominator. The highly significant correlation between these two variables (r = 0.95) indicates that rising bicarbonate concentration is the principal determinant for reduction in total hydrogen output in the setting of these experiments. The data also show good recovery of bicarbonate reflecting adequate sampling technic.
receive potassium chloride supplements (Figure 2). Relationship Between Potassium, Sodium, Chloride and Bicarbonate Output. There is a statistically significant relationship between the bicarbonate over creatinine and the potassium over creatinine concentration ratios in the urine which is independent of sodium intake or potassium supplementation (Figure 8). A comparable reiationship cannot be established for bicarbonate and sodium except when the sodium intake is high and potassium chloride supplements are given (Figure 8). Relationship Between Hydrogen Ion Activity in Blood and Urine and the Excretion of Potassium, Sodium and Chloride. There is no apparent correlation between hydrogen ion activity in urine, expressed as concentration units in nanomoles per liter, and potassium, sodium or chloride excretion. There is also no relationship between hydrogen ion activity in blood and sodium or chioride excretion. However, there is a statistically significant inverse correlation between hydrogen ion activity in blood and the potassium over creatinine ratios in the urine irrespective of variations in sodium intake (Figure 9).
I
I
400
600
pM/mg
Figure 6. Relationship between the partial pressure of carbon dioxide in blood (pCO2 in mm Hg) and the concentration of potassium in urine expressed as the potassium over creatinine concentration ratio (K/CR in pmol/mg). The relationship is described by the equation y = 54.74 e-o.oo14x. The correlation coefficient is r = -0.656.
60
“ab.
A A3
.O PC02
,‘o
mmHg
A
.
A
AA A
A
0
AA
08
40
‘A
.
0 0,
.
0
.
0
0
b O
.
. .A
00
20i
A
0 A
,
,
200
,
400 g
600
pM/mg
Figure 7. Relationship between the partial pressure of carbon dioxide in blood (pCO2 in mm Hg) and the concentration of sodium in the urine expressed as the sodium over creatinine concentration ratio (NaICR in pmoljmg). Note that the Na/CR ratio rises with lowering of the pCO2 only when sodium intake is high.
COMMENTS These observations demonstrate in man that reduction of the partial pressure of carbon dioxide, achieved here by means of treatment in a respirator, promotes renal bicarbonate loss and at the same time causes increased excretion of potassium and to a lesser extent sodium ions without affecting chloride output (Figure 2). The implication
February 1974
The American Journal of Medicine
Volume 56
157
RENAL
RESPONSE
TO VENTILATION
IN HYPERCAPNIA-TURIN0
ET AL.
HCO; CR Wmg
.
I
400
200 &
600
200
400 E
@/mg
I
600
pM/mg
Figure 8. Relationship between HC03P/CR and K/CR or Na/CR, respectively. Note the linear relationship between HCO3-/CR and Na/CR is not as good except for observations during high sodium intake with potassium chloride supplementation (r = 0.59; p
of these observations will be discussed in the following paragraphs. Partial Pressure of Carbon Dioxide and the Excretion of Bicarbonate. The organism has to depend largely on renal bicarbonate excretion for the maintenance of the extracellular hydrogen ion activity following abrupt reduction of the partial pres-
,
I
1
200
I
400
!
J
600
&FM/w
Figure 9. Relationship between hydrogen ion activity in blood expressed in nanomoles per liter (nmlliter) and potassium over creatinine concentration ratio (pmol/mg) in urine. The data points shown represent experimental periods in which potassium chloride supplements were not given. There is a statistically significant correlation between these variables (r = -0.60; p
February 1974
The American Journal of Medicine
sure of carbon dioxide. The bicarbonate loss in altered renal bicarbonate the urine, reflecting is exponentially related to the reabsorption, change in partial pressure of carbon dioxide in blood. In this exponential relationship the increments in the excretion rate of bicarbonate are limited as the elevated partial pressure of carbon dioxide is reduced toward normal to become more marked as the pCO2 is lowered below the normal range (Figure 3). The ultimate concentration of bicarbonate in the urine is not determined by the absolute pCO2 in arterial blood but rather by the change in pCO2 since a single exponential relationship can be identified between the change in partial pressure of carbon dioxide (ApCO2) and the U:P ratio for bicarbonate (Figure 4). The pathway by which filtered bicarbonate is normally reabsorbed involves, according to current concepts of renal physiology, primarily new generation within tubular cells which is linked to tubular secretion of hydrogen ions, although it cannot be excluded that part of the bicarbonate is transferred as an intact ion [19-221. The driving force for the generation of new bicarbonate, i.e., hydrogen ion secretion, is the partial pressure of carbon dioxide with carbonic anhydrase acting to facilitate the hydration reaction. The pCO;! in turn, is ultimately determined by carbon dioxide production in tissues and alveolar ventilation. The relationship between bicarbonate excretion and the partial pressure of carbon dioxide observed in these hypercapneic patients indicates that alter-
Volume 56
RENAL
ation of pCO2-dependent bicarbonate reabsorption is best demonstrated if changes in pC0~ are large. There are other, less well defined, variables which can affect over-all bicarbonate reabsorption as well. For example, the threshold for renal bicarbonate reabsorption is modified by changes in extracellular fluid volume [l O-l 31. The patients observed in this study were given 5 per cent dextrose in water intravenously to maintain urine flow. The positive water balance did not exceed 300 ml at any given moment, and diuresis often preceded any changes in bicarbonate excretion. Although the retained volume of fluid remained small, it may nevertheless have modified the rate of bicarbonate excretion since Slatopolsky et al. [12] observed changes in bicarbonate reabsorption in man receiving as little as 2.5 ml/min of 5 per cent dextrose in water intravenously. That volume expansion might have contributed to reduce renal bicarbonate reabsorptive capacity is supported by the fact that the highest rate of renal bicarbonate excretion was observed late during the experimental period when positive fluid balance was presumably maximal. Other variables which might have contributed to the observed bicarbonate diuresis are the increased urine flow per se, which was also maximal late during the experimental period, and respirator-induced hemodynamic changes which could have augmented venous return, cardiac output and, by inference, renal blood flow. No consistent relationship between urine flow and bicarbonate excretion could be identified, and cardiac output or renal blood flow was not measured in this study. However, the rate of creatinine excretion, reflecting glomerular filtration, did not change in any consistent manner, nor was there a relationship between changes in creatinine excretion and bicarbonate concentration in the urine. It would appear, therefore, that in these studies changes in renal bicarbonate reabsorption were predominantly pCO2-dependent. The nature of other variables which may have contributed to the changes in bicarbonate excretion was not identified. Interrelation Between Bicarbonate, Sodium and Potassium Excretion. For the excretion of filtered bicarbonate which is not dissipated by interaction with secreted hydrogen ions, cations have to be retained in the tubular fluid to maintain electroneutrality. The principal cation available for excretion with bicarbonate is not sodium but potassium (Figures 2 and 6). The highly significant correlation observed between bicarbonate and potassium excretion, irrespective of the provision of supplemental potassium as the chloride salt or sodium
RESPONSE
TO VENTILATION
IN HYPERCAPNIA-TURIN0
ET AL.
chloride in the diet, would suggest that bicarbonate in tubular fluid is a major determinant for induction of potassium diuresis. However, according to concepts presented by Maren [22], Berliner [23], Malnic et al. [24] and Giebisch et al. [25], the rate of potassium secretion in the distal tubule is not determined by bicarbonate in tubular fluid but by other variables which include (1) the intracellular potassium concentration, (2) the electrical potential difference across the luminal cell membrane, (3) the passive potassium permeability across tubular cells, and (4) the capacity of an active potassium reabsorptive mechanism within tubular cells. The variables, which may have contributed to potassium loss in the experiments presented here, are the reduction of extracellular hydrogen ion activity which favors the entry of potassium ions into cells and reduction of the intracellular hydrogen ion activity secondary to ventilation-induced lowering of the pCO2. Hydrogen ion dependent entry of potassium ions into an intracellular exchangeable potassium pool of tubular cells and modification of the transepithelial potential gradient in distal tubulesperhaps secondary to the combined effects of increased intratubular bicarbonate concentration and lowering of the intracellular hydrogen ion activity-could have facilitated potassium loss. To what extent changes in intracellular pH are responsible for the observed potassium diuresis cannot be assessed, but one might speculate that the correlation between the partial pressure of carbon dioxide and the potassium over creatinine concentration ratio (Figure 6), which is almost identical to the relationship between the partial pressure of carbon dioxide and the bicarbonate over creatinine concentration ratio (Figures 3 and 8), is evidence for a specific relationship between the partial pressure of carbon dioxide and the potassium over creatinine concentration ratio most likely via the secondary changes in hydrogen ion activity within tubular cells. In blood, changes in the partial pressure of carbon dioxide and lowering of the hydrogen ion activity are linearly related. The changes in hydrogen ion activity in blood in turn parallel the reduction in the serum potassium concentration. Furthermore, a significant correlation exists between the hydrogen ion activity in blood and potassium excretion in the urine (Figure 9). This can be interpreted to indicate that potassium excretion is directly modified by hydrogen ion activity in blood in the setting of ventilation-induced changes in PH. It is known that lowering of the pH in blood not only promotes the entry of potassium into tubular cells [25] but also causes proportional changes in in-
February 1974
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159
RENAL RESPONSE
TO VENTILATION
IN HYPERCAPNIA-TURIN0
ET AL.
tracellular hydrogen ion activity [26]. One could argue, therefore, that the observed relationship between changes in hydrogen ion activity in blood and the urine potassium over creatinine concentration ratio reflect pH-dependent entry into and subsequent extrusion of potassium from tubular cells. The hydrogen ion activity in the final urine has no consistent relationship to the potassium over creatinine concentration ratio. Indeed, at urine pH above 7.7 when hydrogen ion concentration declines below 20 nm/liter potassium excretion continues to rise. Since the pH in the final urine only approximates intratubular hydrogen ion activity [21], no conclusions can be drawn from these measurements. Furthermore, micropuncture studies in hyperventilating rats failed to establish firm correlations between pH and potassium concentration in tubular fluid [21,25]. These observations therefore only permit the tentative conclusion that potassium loss in the urine during hyperventilation is determined by the induced changes in the partial pressure of carbon dioxide. These changes in partial pressure of carbon dioxide not only affect intratubular bicarbonate concentration but potassium loss as well, presumably by reducing extracellular and, by inference, intracellular hydrogen ion activity. Interrelation Between Bicarbonate and Sodium Excretion. On a low sodium intake the predominant cation associated with the bicarbonate diuresis is potassium, and sodium excretion changes little (Figure 2). Provision of potassium chloride supplements further limits sodium loss suggesting that with restricted intake sodium reaching the potassium secretory site within the tubular system is more effectively reabsorbed if excess potassium is available for excretion. On a high sodium chloride intake more sodium and less potassium appear in the urine in associa-
tion with the bicarbonate diuresis (Figure 2). Addition of potassium chloride supplements will augment the concentrations of sodium and potassium in the final urine and also lead to a chloride diures/s (Figure 2). The appearance of more sodium during bicarbonate diuresis on a high sodium intake with potassium supplements suggests that bicarbonate freed proximally will carry sodium along for ultimate excretion in the urine if less sodium is reabsorbed at a site within the tubular system where potassium is secreted. CONCLUSION The observation that alkalosis induced by abrupt reduction of the partial pressure of carbon dioxide is associated with proportional renal loss of bicarbonate and potassium suggests that the determining variable for induction of these changes is the partial pressure of carbon dioxide. The reduced pCO;! modifies bicarbonate regeneration directly by limiting the hydration reaction and affects potassium excretion indirectly by reducing extracellular, and by inference, intracellular hydrogen ion activity. The organism therefore depends ultimately on modifications in pCOs, i.e., alveolar ventilation, for correction of bicarbonate excess. Sodium accompanies bicarbonate excretion only when the sodium intake is high. There is no apparent relationship between bicarbonate and chloride excretion within the setting of this experimental protocol. The clinical implication of these observations is that induced abrupt reductions in the partial pressure of carbon dioxide are associated with renal potassium loss which, depending on the circumstances, may lead to potassium depletion. ACKNOWLEDGMENT We acknowledge Miss L. Harwood.
the valuable
secretarial
help of
REFERENCES 1.
2.
3.
4.
160
Engel K, Dell RB, Rahill J. Denning CR, Winters RW: Quantitative Displacement of acid-base equilibrium in chronic respiratory acidosis. J Appl Physiol 24: 288, 1968. Polak A, Haynie GD, Hays RM, Schwartz WB: Effects of chronic hypercapnia on electrolyte and acid-base equilibrium. I. Adaptation. J Clin Invest 40: 1223, 1961. Levitin HW, Branscome W, Epstein FH: The pathogenesis of hypochloremia in respiratory acidosis. J Clin Invest 37: 1667, 1958. Warren Y, Luke RG, Kashgarian M, Levitin H: Micropuncture studies of chloride and bicarbonate reabsorption in the proximal renal tubule of the rat in respiratory acidosis and in chloride depletion. Clin Sci 38: 375, 1970.
February 1974
The American Journal of Medicine
5.
8.
7.
8.
9.
Volume 56
Schwartz WB, Hays RM, Polak A, Haynie GD: Effects of chronic hypercapnia on electrolyte and acid-base equilibrium. II. Recovery with special reference to the influence of chloride intake. J Clin Invest 40: 1238, 1961. Aber GM, Bishop JM: Serial changes in renal function, arterial gas tensions and the acid-base state in patients with chronic bronchitis and oedema. Clin Sci 28: 511, 1965. Kassirer JP, Berkman PM, Lawrenz DR. Schwartz WB: The critical role of chloride in the correction of hypokalemic alkalosis in man. Am J Med 38: 172, 1965. Goldring RM, Turin0 GM, Heinemann HO: Respiratoryrenal adjustments in chronic hypercapnia in man. Am J Med 51: 772, 1971. Brazeau P, Gilman A: Effect of plasma CO2 tension on
RENAL
10.
11.
12.
13.
14.
15.
16.
17.
renal tubular reabsorption of bicarbonate. Am J Physiol 175: 33, 1953. Cohen JJ, Ellis JH: Correction of metabolic alkalosis by the kidney after isometric expansion of extracellular fluid. J Clin Invest 47: 1181, 1968. Purkerson ML, Lubowitz RW, Bricker NS: On the influence of extracellular fluid volume expansion on bicarbonate reabsorption in the rat. J Clin Invest 48: 1754,1969. Slatopolsky E, Hoffsten P, Purkerson M, Bricker NS: On the influence of extracellular fluid volume expansion and of uremia on bicarbonate reabsorption in man. J Clin Invest 49: 988, 1970. Kurtzman NA: Regulation of renal bicarbonate reabsorption by extracellular volume. J Clin Invest 49: 586,197O. Gennari FJ, Goldstein MB, Schwartz WB: The nature of the renal adaptation to chronic hypocapnia. J Clin Invest 51: 1722,1972. Cotlove E, Trantham HV, Bowman RL: An instrument and method for automatic, rapid, accurate and sensitive titration of chloride in biologic samples. J Lab Clin Med 51: 461, 1958. Seligson D, Hirahara K: The measurement of ammonia in whole blood, erythrocytes and plasma. J Lab Clin Med 49: 962,1957. Bonsnes RW. Taussky HH: On the calorimetric deter-
February
RESPONSE TO VENTILATION
18.
19
20. 21.
22. 23. 24.
25.
26.
1974
IN HYPERCAPNIA-TURIN0
ET AL.
mination of creatinine by the Jaffe reaction. J Biol Chem 158: 581, 1945. Van Slyke DD, Neil1 JM: The determination of gases in blood and other solutions by vacuum extraction and manometric measurement. J Biol Chem 61: 523, 1924. Rector FC Jr, Carter NW, Seldin DW: The mechanism of bicarbonate reabsorption in the proximal and distal tubules of the kidney. J Clin Invest 44: 278., 1965. Seldin DW, Rector FC Jr: The generation and maintenance of metabolic alkalosis. Kid Int 1: 306, 1972. Malnic G, de Mello Aries M, Giebisch G: Micropuncture study of renal tubular hydrogen ion transport in the rat. Am J Physiol 222: 147. 1972. Maren TH: Carbonic anhydrase: chemistry, physiology and inhibition. Physiol Rev 47: 595, 1967. Berliner RW: Renal mechanisms for potassium excretion. Harvey Lect 55: 141, 1961. Malnic G, de Mello Aries M, Giebisch G: Potassium transport across renal distal tubules during acid-base disturbances. Am J Physiol 221: 1192, 1971. Giebisch G, Boulpaep EL, Whittembury G: Electrolyte transport in kidney tubule cells. Trans Roy Sot London 8262: 175, 1971. Struyvenberg A, Morrison RB, Relman AS: Acid-base behavior of separated canine renal tubule cells. Am J Physiol 214: 1155. 1968.
The American
Journal of Medicine
Volume 56
161
GERARD
M. TURINO,
ROBERTA HENRY
0.
M.D.
M. GOLDRING, HEINEMANN,
M.D M.D.
New York, New York
From the Departments of Medicine, College of Physicians & Surgeons, Columbia University, New York University School of Medicine and The New York Hospital-Cornell Medical Center, New York New York. This study was supported in part by U.S. Public Health Service Grants CA 11096 and HE 13921 (H.O.H.). Requests for reprints should be addressed to Dr. Henry 0. Heinemann, Cornell University Medical College, 1300 York Avenue, New York, New York 10021. Manuscript accepted July 5, 1973.
Alkalosis in hypercapneic patients caused by abrupt respiratorinduced reduction of the partial pressure of carbon dioxide leads to bicarbonate diuresis. Potassium is the predominant cation accompanying bicarbonate loss in the urine. The determining variable for induction of proportional changes in renal bicarbonate and potassium excretion is the partial pressure of carbon dioxide. The reduction of the partial pressure of carbon dioxide modifies bicarbonate regeneration directly by limiting the hydration reaction and facilitates potassium loss indirectly by reducing extracellular, and by inference intracellular, hydrogen ion activity. Respiratory acidosis secondary to carbon dioxide retention in patients with chronic lung disease is corrected by the generation of new bicarbonate and sustained elevation of the threshold for renal bicarbonate reabsorption [l-4]. The generation and excretion of bicarbonate by the kidneys and the elimination of carbqn dioxide by the lungs have different time constants, and situations therefore easily arise in which bicarbonate generated to balance rising carbon dioxide tensions may become superfluous as the hypercapnia is corrected [5,6]. Bicarbonate excess following transient aggravation of carbon dioxide retention is not uncommon in patients with chronic hypercapnia, especially if complicating heart failure requires restricted sodium chloride intake and diuretic therapy. It is thought that such inappropriate bicarbonate retention is in part a consequence of inadequate chloride supply which raises the threshold for bicarbonate reabsorption [7,8]. In addition to chloride there are other variables which modify renal bicarbonate reabsorption such as the volume of the extracellular fluid and, most importantly, the partial pressure of carbon dioxide itself [g-13]. Recently Gennari, Goldstein and Schwartz [14] demonstrated in dogs that adaptive changes in plasma bicarbonate concentration to hypocapnia induced by exposure to a low oxygen environment are linked to over-all cation rather than chloride balance. In this study the interrelations between bicarbonate excretion, partial pressure of carbon dioxide and cation as well as chloride balance were measured in patients with stable chronic hypercapnia without fluid retention in whom the partial pressure of carbon dioxide was reduced by mechanical ventilation. The results demonstrate that renal bicarbonate loss accompanying
February 1974
The American Journal of Medicine
Volume 56
151
RENAL
RESPONSE
TABLE
I
TO VENTILATION
IN HYPERCAPNIA-TURIN0
Lung Volumes and Maximal
__~ Subject
Sex,Age(yr) BSA
R.C. W.K. R.T. J.H.
M,66,2.03 M,43,1.14 F,54,1.61 M,59,1.10
Breathing
IC
ET /iL.
Capacity
ml
% pred.
ml
% pred.
2,550 539 1,451
94 23 72
750 224 680
89 29 105
...
...
...
. ..
NOTE: IC = inspiratory capacity; ERV = expiratory capacity; MBC = maximal breathing capacity.
ml
% pred.
3,350 763 2,011 850
94 23 78 28
reserve
volume;
abrupt reduction of the partial pressure of carbon dioxide in blood is independent of chloride balance and related to potassium and, to a lesser extent, sodium excretion. The significance of these observations will be discussed. GENERAL
PROCEDURES
Four patients with chronic stable lung disease and normal renal function were studied. Their age and relevant clinical data are summarized in Table I. One patient (J.H.) was studied on two occasions 2 years apart. All patients were kept on a metabolic ward where they were given constant diets “low” in sodium chloride (<20 meq/day) alternated with diets “high” in sodium chloride (f100 meq/day). Fluid intake and body weight were recorded daily. The 24-hour urine was collected under mineral oil with toluene as a preservative and stored at 4°C. The urinary excretion of creatinine, sodium, potassium, chloride and total hydrogen ion was determined daily. All excretion rates are expressed in micromoles or milligrams per minute or as concentration ratios with creatinine as the common denominator. Venous blood samples were obtained periodically for the determination of serum sodium, potassium, chloride and total carbon dioxide content. Arterial blood samples were drawn at regular intervals before and during mechanical ventilation for determination of pH, carbon dioxide tension (pCO2) and oxygen tension (pop). EXPERIMENTAL
February 1974
The American Journal of Medicine
VC =
TLC
MBC
ml
% pred.
ml
% pred.
BV/ TLC (%>
2,600 1,365 3,430
130 100 299
5,950 2,119 5,441
113 48 146
44 64 63
,..
...
...
...
...
vital
capacity;
RV =
residual
volume;
(Inters/ % min) pred. 95 34 18 35
89 47 25 45
TLC = total lung
in which potassium chloride supplements (1 meqlkg body weight during treatment in the respirator) were given intravenously. Arterial blood samples were drawn at regular intervals before and during mechanical ventilation. The patients were allowed to void spontaneously. All urine samples were collected under mineral oil. On the day of the experiment a single urine collection was made before starting the respirator (period C). The excretion rate of creatinine and electrolytes during this period was found to be similar to the average excretion rates during two 24 hour periods preceding the day of the experiment. ANALYTICAL
METHODS
The sodium and potassium concentrations in serum and urine were measured by flame photometry; chloride in serum and urine was measured by potentiometric titration [15]; ammonia was measured by means of the diffusion technic of Seligson and Hirahara [16]; creatinine was analyzed by the method of Bonsnes and Taussky [17]. The titratable acid of the urine was obtained by titration to pH 7.4. The carbon dioxide content of the urine was determined by the method of Van Slyke and Neil1 [18]. The partial pressure of oxygen and carbon dioxide in arterial blood was measured by specific electrodes. The pH of arterial blood was measured anaerobically at 37.5”C with a glass electrode. RESULTS
PROTOCOL
Experiments were carried out after 3 to 6 days of constant diet. On the day of the study, the patients were placed in an Emerson body respirator for 3 to 4 hours. A water load (600 to 800 ml) was given orally 1 hour prior to the study. An indwelling arterial needle was placed in the right brachial artery. An intravenous infusion of 5 per cent dextrose in water was started before mechanical ventilation, and an infusion rate of 300 ml/hour was maintained throughout the period of assisted respiration. The rate of mechanical ventilation and the pressure level were adjusted in each patient to achieve pCOz reductions which the patient could tolerate. Each patient was studied at least twice on separate occasions while on a diet high or low in sodium chloride. In addition, studies were carried out
152
RV
vc
ERV
A representative study on one patient (R.C.) is shown in Figure 1. The results obtained in all patients are summarized in Table II and Figures 2 through 9. Relationship Between the Partial Pressure of Carbon Dioxide (CO2) in Arterial Blood, Renal Bicarbonate (HC03-:CR) and Total Hydrogen Ion (H+:CR) Excretion Rates. Reduction of the partial pressure of carbon dioxide leads to bicarbonate loss in the urine (Figure 2). The bicarbonate concentration in the urine and the partial pressure of carbon dioxide in blood are exponentially related whether bicarbonate is represented in concentration units using creatinine as the glomerular
Volume 56
RENAL
RESPONSE
IN HYPERCAPNIA-TURIN0
ET AL.
tassium excretion by the kidneys (Figure 2). The pC0~ in arterial blood and the potassium concentration in the urine (K:CR in micromoles per milligram) are exponentially related. This relationship is not modified by potassium chloride supplementation or variations in sodium intake (Figure 6). But the lowest rate of potassium excretion appears to occur while the patients are on a high sodium intake (Figure 2). There is no apparent relationship between the partial pressure of carbon dioxide and the sodium over creatinine concentration ratio while the patients are on a low sodium diet (Figure 7). On a high sodium diet, with or without potassium chloride supplements, the sodium over creatinine concentration ratio is higher for any given pCOs. There is no apparent relationship between pCO2 and the excretion of chloride, and the excretion of this anion remains essentially unchanged except when patients on a high sodium chloride intake
marker (Figure 3) or is expressed as a urine to plasma (U : P) ratio with plasma bicarbonate as the denominator (Figure 4). Differences in sodium chloride intake and infusion of potassium chloride have no apparent effect on the relationship between bicarbonate in urine and the partial pressure of carbon dioxide in blood. Total hydrogen ion excretion expressed in the change in hydrogen over creatinine concentration ratio in micromoles per milligram (AH+/CR) declines during treatment in the respirator because of diminished acid and increased bicarbonate output (Figure 2). The change in total hydrogen ion over creatinine concentration ratio is linearly related to the change in bicarbonate over creatinine ratio (Figure 5). Relationship Between the Partial Pressure of Carbon Dioxide and the Excretion Rates of Potassium, Sodium and Chloride. Lowering of the partial pressure of carbon dioxide leads to increased po-
,+, mM/l_
3.6
I,
05
mM/L
TO VENTILATION
02.mMlL
36
C02,mmHg Ii * 1%
58 7.41 87
3.1 82 33 26 7.71 88
3.0 85 36 43 7.56 77
3.4 84 37 65 7.37 84
4.2 86 34 41 7.53 61
3.9 85 34 52 7.43 82
RESPIRATOR KCI
Figure 7. Two studies in patient R.C. are shown. The two control periods (C) reflect, respectively, the excretion rates in pmoles per minute 24 hours before the day of the experiment and on the day of the experiment just prior to treatment in the respirator. Periods 1-4 during the first study and 1-5 during the second represent collections study urine while the patient was in the respirator; period 5 during the first experiment and period 6 during the second experiment represent samples collected immediately after discontinuing the respirator. The excretion rate of potassium was not measured during the fourth period of the first experiment. Note the changes in pCO2 and pH in blood and total hydrogen, bicarbonate, chloride and potassium excretion in the urine without and with potassium chloride supplement (50 mmol). With potassium chloride, total bicarbonate excretion during treatment in the respirator is more conspicuous despite a lesser change in pCO:!.
60mM
332 --’
February 1974
The American Journal of Medicine
Volume 56
153
M&6,2.03
M,43,1.14
F,54,1.61
M,59,1.10
M,61,1.10
M,61,1.10
M,66,2.03
M,43,1.14
F,54,1.61
W.K.
R.T.
J.H.
J.H.
J.H.
R.C.
W.K.
R.T.
BSA
Sex,AgeW),
135 57 20 28 39 100 98 60 62 64 96 104 125 45
C
E-l E-2 E-3 E-4 C E-l E-2 E-3 E-4 C E-l E-2 E-3
150 75 60 60 130 80 65 63 90 42 35 85 50 83 62 53 78 117 65 61 163 100 78 136
Time (min)
55.8
38.7
81.4
36.1
36.5
37.7
55.0
38.3
81.9
pH
TA
1.0 1.9 3.3 3.3 3.4 1.5 1.4 5.3 6.2 5.5 2.6 1.8 1.5 6.0
0.8 3.0 5.9 2.5 0.4 4.3 5.1 6.4 2.6 5.5 6.4 3.0 0.6 2.5 3.8 2.8 0.9 2.1 2.9 1.8 0.9 2.2 2.1 0.4
15 18 2 0 2 6 3 4 2 2 2 1 6 6 2 0 8 0 0 0 6 2 0 0
6.0 6.4 6.3 7.9 7.9 6.9 7.0 6.9 6.9 7.2 7.0 7.0 7.4 7.2
14 23 39 0 0 4 2 7 6 4 6 3 0 5
NH,+
Control
34 51 60 54 27 10 8 35 44 42 30 17 13 23
Chloride
35 87 75 32 6 20 25 30 27 34 32 ... 18 14 16 14 19 32 38 23 17 28 21 5
Chloride
B. Low Sodium
6.2 6.6 7.3 7.8 6.9 6.9 7.0 7.1 6.4 6.7 6.7 7.1 6.3 6.8 7.3 7.7 6.6 7.4 7.7 7.9 6.4 7.0 7.5 7.8
A. Low Sodium
_. HOW (ml/ min)
Blood and Serum During
Weight (kg)
in Urine,
C E-l E-2 E-3 C E-l E-2 E-3 C E-l E-2 E-3 C E-l E-2 E-3 C E-l E-2 E-3 C E-l E-2 E-3
Period
Measurements
R.C.
Subject
TABLE II
Hf
48 96 -33 -46 7 -17 4 -1 18 12 5 ... 23 -15 -76 -95 20 -22 -70 -74 18 4 -29 -9
5 8 60 35 3 11 10 10 15 27 29 19 10 20 5 6 15 28 57 57 2 6 8 8
Potassium
Na
3 10 10 264 187 8 6 20 22 32 7 14 26 55
45 64 89 -210 -160 6 4 22 28 14 29 6 -13 -27
3 4 5 61 49 16 7 13 12 14 9 17 17 18
Diet With Potassium
2 9 110 78 1 43 24 35 12 24 29 11 1 35 94 109 7 54 108 97 5 27 50 14
Diet Without
HCOs-
”
Urine (umol/min)
Cl
39 79 100 332 321 45 39 65 50 44 18 21 47 87
Chloride
35 79 190 148 22 64 46 38 18 19 18 10 42 63 95 98 56 75 100 92 31 40 64 18
0.69 0.95 0.88 0.78 0.31 0.77 0.31 0.39 0.55 0.55 0.51 0.44 0.51 0.38 0.38 0.36 0.44 0.21 0.20 0.28 0.25 0.30 0.13 0.15
0.81 1.12 1.30 0.73 1.01 0.57 0.45 0.75 0.56 0.44 0.57 0.49 0.56 0.84
Supplements 1 1 1 3 3 29 15 18 9 6 8 13 16 24
PH
7.37 7.42 j.53 7.43 7.51 7.33 ... 7.40 7.40 7.46 7.38 7.39 7.39 7.40
7.41 7.45 7.71 7.53 7.39 ... .,. 7.47 7.40 ... 7.40 7.43 7.38 7.52 7.58 7.68 7.39 7.54 7.59 7.60 7.34 7.52 7.57 7.61
Supplements
(mg/min)
65 55 41 52 43 56 ... 48 51 43 65 59 58 58
58 55 26 43 53 ... ... 41 58 ... 56 51 62 44 37 27 47 33 30 27 53 33 31 27
(mm Hg)
pCOz
84 ... ... ... 89 ... ... ... ... 85 82 ... ... , .
87 ... ... ... 86 ... *. . 91 89 ... ... 89 91 ... ... 98 95 ... ... 97 94 ... ... 97
(%)
02 Saturation
37 35 33 ... 34 29 ... 29 29 30 38 ... ... ...
36 37 ... 35 32 ... ... 30 35 ... ... 34 36 36 35 34 28 ... ... 27 29 ... ... 28
HCO,-
Hyperventilation
Blood
of Mechanical
Creatinine
Periods
1 1 1 1 8 19 5 3 13 11 6 9 12 9 12 11 22 16 17 1 12 9 13 4
Chloride
K
Periods (C) and Experimental
3.4 3.2 4.2 ... 3.9 4.1 ... 4.0 ... 3.3 3.7 4.6 4.3
.,. .
...
3.6 3.4 ... 3.1 3.9 3.7 ... 3.7 3.6 ... 3.7 3.7 4.4 4.0 4.0 3.8 4.2 4.0 3.5 3.5 4.1 3.9 3.9 3.7
K
132 130 132 ... 130 136 ... 131 ... 137 146 137 136
133 133 ... 133 134 134 ... 137 142 .., 143 138 142 137 139 138 134 132 131 131 131 132 132 134
Na
Serum &mol/liter)
(E)
..
84 84 86 ... 85 90 ... 90 ... 95 93 91 92
85 85 ... 82 93 90 ... 92 95 ... 96 96 101 100 102 102 94 94 96 96 94 93 96 97
Cl
C E-l C E-l E-2 E-3 E-4 C E-l E-2 E-3 E-4 c E-l E-2
M,61,1.10
M,66,2.03
F,54,1.61
M,59,1.10
M,61,1.10
M,43,1.14
M,59,1.10
M,61,1.10
J.H.
R.C.
R.T.
J.H.
J.H.
W.K.
J.H.
J.H.
NOTE: BSA = body surface * Previous day.
E-2
c E-l E-2 E-3 E-4 C E-1 E-2 E-3 E-4 c E-l
C E-l E-2 E-3 C* E-l
M,59,1.10
J.H.
37.0
39.1
38.1
36.5
39.2
54.2
86.7
36.7
37.5 6.7 7.1 7.6 8.2 6.3 7.1
6 6 0 0 9 3
11 21 41 10 9 9
7.1 7.1 7.2 6.1 7.1 7.4
5.3 5.8’ 5.0 0.9 1.8 4.8
1.4 2.4 5.1 4.0 5.7 0.6 1.3 2.7 3.3 6.0 0.7 1.6 1.7
2 3 0 0 3 3
7.1 7.1 7.7 7.4 6.9 7.1
7.6 1.9 7.6 0.5 2.8
5 6 1 2 9 1 0 0
0 6 2 1
7.1 7.2 7.3 7.3 5.9 7.3 7.8 7.9
7.8 6.3 7.0 7.3
74 59 65 101 4 25 43 45 47 5 22 95
12 14 10 12 16 19 19 21 17 26 18 36
4 21 52 47 53 1 9 90
142 132 3 25 27
10
14 19 8 9 9
19 37 32 33 17 7 13
11 14 24 26 7 6
-20 -19 -25 43 -1 -59
-60 -42 -55 -89 15 -3
26 -14 12
59 69 64 78 23 86
153 105 103 146 57 50
31 73 59
23 29 35 13 33 39 68 139 211 199 37 47 96
11
7
14 13 12 10
53 58 40 84 17 5
48 41 35 59 30 69
43 51 96 78 109 39 42 103 146 193 28 38 61
44 50 60 40 53 55 68 112 179 308 46 47 78 --.__
7.40 ... 7.63 7.58 7.36 7.54
0.35 0.38 0.32 0.59 0.15 0.34
0.63 0.53 0.55 0.81 0.35 0.36
0.68 0.78 0.67
0.55 0.34 0.56 0.42 0.57 0.50 0.31 0.34 0.34 0.36 0.24 0.20 0.24
7.39 ... ... ... 7.44 7.36 7.41 7.49 7.45 7.44 7.36 7.52 7.52 ~-
7.39 ... 7.40 7.43 7.38 7.58 7.62
... 7.43 ... 7.44 7.35
7.37 7.57 7.42
Supplements
0.46 0.36 0.29 0.30 0.20 0.29
Supplements
58 53 32 45 63 53
30 23 15 30 38 50
Chloride
36 48 45
24 49 21
Chloride
44 51 77 92 35 58
[(NHI+ + TA) - HCOB-I.
3 -9 -14 -18 25 -1 -77 -128 -113 11 -14 -17
11
Diet With Potassium
1 45 16
21 31 24
Chtoride
16 16 10 -65 16 -8
Diet Without Potassium
2 20
75
1 11 51
acid; H + = total hydrogen
5
6.7
D. High Sodium
4 5 5 22 3 0
6 0 4
6.5 7.5 6.6
0.4 0.9 3.0 9.7
C. High Sodium Chloride
0.5 1.4 2.7 0.7 0.6 1.2
area (m?); TA = titratable
82 139 79 85 45 62 65 55 55 25 109 106 115
140 305 55 22 31 84 70 109 47 32 36 44 51 132 58
44 52 55 149 ... 293
40 53 45 34 37 38 55 34 36 -
.. ... ...
50
50 44 53 27 25
...
52 55 48
...
52
...
58 34 60
35 53 33
59 ... 29
72 ... ... ... 92 94 ... ... ... 95 94 . . 96 -
28
97
31 ... 29
... ... ... . ..
27 29
... ... ...
30
31
... ... . <. ...
35 30
... . *. ...
...
31 30.5 38
36 . . 30 32 29 28
87 88 90 . *. .. ... 89 91 ... ... . . ... 94 ..
89 ... . . 95 94 96
140 136 ... 139 132 144 138 136 135 137 137 136 136
134 135 147 ... 143 ... 144 138 ... ... .. ... 136 134 134
137 ... 134 136 133 127
3.6 3.9 . . 3.8 3.5 4.5 4.6 4.9 4.7 4.6 3.9 4.2 4.3
4.2 ... ... ... ... 4.3 3.6 3.7
3.6
...
3.8
...
3.6 3.6 4.0
4.3 ... 4.8 4.1 4.2 4.4
0’ <
2 r 5 2 z I 4
100 98
103 102 103 100 100 98 102 98 98 100
z
g
3
97 97
...
z n 2 B
. 95 ..
z
...
103 ... ...
98 95 98 ... 97 ... 97
97 ... 96 95 94 95
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AH+
I
AK
A HCO;
B
II
ET AL
Low NoC ‘IH ligh NoCI[( LOWNoC
lb
,KC I
-
L!ICI
I
.ow No C I I-ligh No C
ligh NoC
IIH
_ow No Cllh ligh Na C I 1aw NoC lighNoC,I t KC I t KC +KCl +KCI
I
1 0
-!
-L
+
f
-
-
-
-
-
Figure 2. Average changes and the range of change from control of the excretion rate with respect to creatinine (CR) of total hydrogen (AH+/CR), bicarbonate (AHC03/CR), potassium (AK/CR), sodium (ANafCR) and chloride (AC//C/?) fn subjects with hypercapnia undergoing mechanical ventilation. The patients’ diet was alternated (high and low sodium chloride intake) and was given either with or without potassium chloride supplements (see text).
f l
+
HCO;
‘8
1S 0
0 0
0
0
A
A
0.5 I
400
0
600
A
HCOS pM/mg CR
Figure 3. Relationship between the partial pressure of carbon dioxide in arterial blood (pCO2 in mm Hg) and the concentration of bicarbonate in urine expressed as the bicarbonate over creatinine concentration ratio (HCOs-/CR in pmollmg). The relationship is described by the equation y = 51.6 e-0.0015x. The correlation coefficient is r = 0.701. In this and subsequent figures open circles = low sodium chloride diet; closed circles = low sodium chloride diet plus potassium chloride supplements; open triangles = high sodium chloride diet; closed triangles = high sodium chloride diet -t potassium chloride supplements.
156
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0
A
J
1
200
0
“B
/
O.e
0
0.
0
0
0
0 0
0
(
I
10
20 A pC0,
.
I
I
30
40
J
mmHg
Figure 4. Relationship between changes in the partial pressure of carbon dioxide in arterial blood (ApCOz in mm Hg) and the ratio of urine over plasma The relabicarbonate concentration (U/P HC03-). tionship is described by the equation y = 0.1586 e”.06gx. The correlation coefficient r = 0.607
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bb 0
6o “sa0%
O 8oorc oAAQAo
50-
AH+
A0 A
b
CR
.
PC02
8
pM/mg
oA A
mm Hg
0
0,’
40-
A
0 .
. 0 .
0
A
lA
%
300
0
0
A
0
0
a0
20
/
, 200
I
I
I
+200
t400
K CR
I
+600
AHCO; CRPM/V
Figure 5. Relationship between changes in total hydrogen ((TA + NH4+) - HC03-) and bicarbonafe (HC03-) excretion in the urine expressed as concentration ratios using urine creatinine as the common denominator. The highly significant correlation between these two variables (r = 0.95) indicates that rising bicarbonate concentration is the principal determinant for reduction in total hydrogen output in the setting of these experiments. The data also show good recovery of bicarbonate reflecting adequate sampling technic.
receive potassium chloride supplements (Figure 2). Relationship Between Potassium, Sodium, Chloride and Bicarbonate Output. There is a statistically significant relationship between the bicarbonate over creatinine and the potassium over creatinine concentration ratios in the urine which is independent of sodium intake or potassium supplementation (Figure 8). A comparable reiationship cannot be established for bicarbonate and sodium except when the sodium intake is high and potassium chloride supplements are given (Figure 8). Relationship Between Hydrogen Ion Activity in Blood and Urine and the Excretion of Potassium, Sodium and Chloride. There is no apparent correlation between hydrogen ion activity in urine, expressed as concentration units in nanomoles per liter, and potassium, sodium or chloride excretion. There is also no relationship between hydrogen ion activity in blood and sodium or chioride excretion. However, there is a statistically significant inverse correlation between hydrogen ion activity in blood and the potassium over creatinine ratios in the urine irrespective of variations in sodium intake (Figure 9).
I
I
400
600
pM/mg
Figure 6. Relationship between the partial pressure of carbon dioxide in blood (pCO2 in mm Hg) and the concentration of potassium in urine expressed as the potassium over creatinine concentration ratio (K/CR in pmol/mg). The relationship is described by the equation y = 54.74 e-o.oo14x. The correlation coefficient is r = -0.656.
60
“ab.
A A3
.O PC02
,‘o
mmHg
A
.
A
AA A
A
0
AA
08
40
‘A
.
0 0,
.
0
.
0
0
b O
.
. .A
00
20i
A
0 A
,
,
200
,
400 g
600
pM/mg
Figure 7. Relationship between the partial pressure of carbon dioxide in blood (pCO2 in mm Hg) and the concentration of sodium in the urine expressed as the sodium over creatinine concentration ratio (NaICR in pmoljmg). Note that the Na/CR ratio rises with lowering of the pCO2 only when sodium intake is high.
COMMENTS These observations demonstrate in man that reduction of the partial pressure of carbon dioxide, achieved here by means of treatment in a respirator, promotes renal bicarbonate loss and at the same time causes increased excretion of potassium and to a lesser extent sodium ions without affecting chloride output (Figure 2). The implication
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HCO; CR Wmg
.
I
400
200 &
600
200
400 E
@/mg
I
600
pM/mg
Figure 8. Relationship between HC03P/CR and K/CR or Na/CR, respectively. Note the linear relationship between HCO3-/CR and Na/CR is not as good except for observations during high sodium intake with potassium chloride supplementation (r = 0.59; p
of these observations will be discussed in the following paragraphs. Partial Pressure of Carbon Dioxide and the Excretion of Bicarbonate. The organism has to depend largely on renal bicarbonate excretion for the maintenance of the extracellular hydrogen ion activity following abrupt reduction of the partial pres-
,
I
1
200
I
400
!
J
600
&FM/w
Figure 9. Relationship between hydrogen ion activity in blood expressed in nanomoles per liter (nmlliter) and potassium over creatinine concentration ratio (pmol/mg) in urine. The data points shown represent experimental periods in which potassium chloride supplements were not given. There is a statistically significant correlation between these variables (r = -0.60; p
February 1974
The American Journal of Medicine
sure of carbon dioxide. The bicarbonate loss in altered renal bicarbonate the urine, reflecting is exponentially related to the reabsorption, change in partial pressure of carbon dioxide in blood. In this exponential relationship the increments in the excretion rate of bicarbonate are limited as the elevated partial pressure of carbon dioxide is reduced toward normal to become more marked as the pCO2 is lowered below the normal range (Figure 3). The ultimate concentration of bicarbonate in the urine is not determined by the absolute pCO2 in arterial blood but rather by the change in pCO2 since a single exponential relationship can be identified between the change in partial pressure of carbon dioxide (ApCO2) and the U:P ratio for bicarbonate (Figure 4). The pathway by which filtered bicarbonate is normally reabsorbed involves, according to current concepts of renal physiology, primarily new generation within tubular cells which is linked to tubular secretion of hydrogen ions, although it cannot be excluded that part of the bicarbonate is transferred as an intact ion [19-221. The driving force for the generation of new bicarbonate, i.e., hydrogen ion secretion, is the partial pressure of carbon dioxide with carbonic anhydrase acting to facilitate the hydration reaction. The pCO;! in turn, is ultimately determined by carbon dioxide production in tissues and alveolar ventilation. The relationship between bicarbonate excretion and the partial pressure of carbon dioxide observed in these hypercapneic patients indicates that alter-
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ation of pCO2-dependent bicarbonate reabsorption is best demonstrated if changes in pC0~ are large. There are other, less well defined, variables which can affect over-all bicarbonate reabsorption as well. For example, the threshold for renal bicarbonate reabsorption is modified by changes in extracellular fluid volume [l O-l 31. The patients observed in this study were given 5 per cent dextrose in water intravenously to maintain urine flow. The positive water balance did not exceed 300 ml at any given moment, and diuresis often preceded any changes in bicarbonate excretion. Although the retained volume of fluid remained small, it may nevertheless have modified the rate of bicarbonate excretion since Slatopolsky et al. [12] observed changes in bicarbonate reabsorption in man receiving as little as 2.5 ml/min of 5 per cent dextrose in water intravenously. That volume expansion might have contributed to reduce renal bicarbonate reabsorptive capacity is supported by the fact that the highest rate of renal bicarbonate excretion was observed late during the experimental period when positive fluid balance was presumably maximal. Other variables which might have contributed to the observed bicarbonate diuresis are the increased urine flow per se, which was also maximal late during the experimental period, and respirator-induced hemodynamic changes which could have augmented venous return, cardiac output and, by inference, renal blood flow. No consistent relationship between urine flow and bicarbonate excretion could be identified, and cardiac output or renal blood flow was not measured in this study. However, the rate of creatinine excretion, reflecting glomerular filtration, did not change in any consistent manner, nor was there a relationship between changes in creatinine excretion and bicarbonate concentration in the urine. It would appear, therefore, that in these studies changes in renal bicarbonate reabsorption were predominantly pCO2-dependent. The nature of other variables which may have contributed to the changes in bicarbonate excretion was not identified. Interrelation Between Bicarbonate, Sodium and Potassium Excretion. For the excretion of filtered bicarbonate which is not dissipated by interaction with secreted hydrogen ions, cations have to be retained in the tubular fluid to maintain electroneutrality. The principal cation available for excretion with bicarbonate is not sodium but potassium (Figures 2 and 6). The highly significant correlation observed between bicarbonate and potassium excretion, irrespective of the provision of supplemental potassium as the chloride salt or sodium
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chloride in the diet, would suggest that bicarbonate in tubular fluid is a major determinant for induction of potassium diuresis. However, according to concepts presented by Maren [22], Berliner [23], Malnic et al. [24] and Giebisch et al. [25], the rate of potassium secretion in the distal tubule is not determined by bicarbonate in tubular fluid but by other variables which include (1) the intracellular potassium concentration, (2) the electrical potential difference across the luminal cell membrane, (3) the passive potassium permeability across tubular cells, and (4) the capacity of an active potassium reabsorptive mechanism within tubular cells. The variables, which may have contributed to potassium loss in the experiments presented here, are the reduction of extracellular hydrogen ion activity which favors the entry of potassium ions into cells and reduction of the intracellular hydrogen ion activity secondary to ventilation-induced lowering of the pCO2. Hydrogen ion dependent entry of potassium ions into an intracellular exchangeable potassium pool of tubular cells and modification of the transepithelial potential gradient in distal tubulesperhaps secondary to the combined effects of increased intratubular bicarbonate concentration and lowering of the intracellular hydrogen ion activity-could have facilitated potassium loss. To what extent changes in intracellular pH are responsible for the observed potassium diuresis cannot be assessed, but one might speculate that the correlation between the partial pressure of carbon dioxide and the potassium over creatinine concentration ratio (Figure 6), which is almost identical to the relationship between the partial pressure of carbon dioxide and the bicarbonate over creatinine concentration ratio (Figures 3 and 8), is evidence for a specific relationship between the partial pressure of carbon dioxide and the potassium over creatinine concentration ratio most likely via the secondary changes in hydrogen ion activity within tubular cells. In blood, changes in the partial pressure of carbon dioxide and lowering of the hydrogen ion activity are linearly related. The changes in hydrogen ion activity in blood in turn parallel the reduction in the serum potassium concentration. Furthermore, a significant correlation exists between the hydrogen ion activity in blood and potassium excretion in the urine (Figure 9). This can be interpreted to indicate that potassium excretion is directly modified by hydrogen ion activity in blood in the setting of ventilation-induced changes in PH. It is known that lowering of the pH in blood not only promotes the entry of potassium into tubular cells [25] but also causes proportional changes in in-
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tracellular hydrogen ion activity [26]. One could argue, therefore, that the observed relationship between changes in hydrogen ion activity in blood and the urine potassium over creatinine concentration ratio reflect pH-dependent entry into and subsequent extrusion of potassium from tubular cells. The hydrogen ion activity in the final urine has no consistent relationship to the potassium over creatinine concentration ratio. Indeed, at urine pH above 7.7 when hydrogen ion concentration declines below 20 nm/liter potassium excretion continues to rise. Since the pH in the final urine only approximates intratubular hydrogen ion activity [21], no conclusions can be drawn from these measurements. Furthermore, micropuncture studies in hyperventilating rats failed to establish firm correlations between pH and potassium concentration in tubular fluid [21,25]. These observations therefore only permit the tentative conclusion that potassium loss in the urine during hyperventilation is determined by the induced changes in the partial pressure of carbon dioxide. These changes in partial pressure of carbon dioxide not only affect intratubular bicarbonate concentration but potassium loss as well, presumably by reducing extracellular and, by inference, intracellular hydrogen ion activity. Interrelation Between Bicarbonate and Sodium Excretion. On a low sodium intake the predominant cation associated with the bicarbonate diuresis is potassium, and sodium excretion changes little (Figure 2). Provision of potassium chloride supplements further limits sodium loss suggesting that with restricted intake sodium reaching the potassium secretory site within the tubular system is more effectively reabsorbed if excess potassium is available for excretion. On a high sodium chloride intake more sodium and less potassium appear in the urine in associa-
tion with the bicarbonate diuresis (Figure 2). Addition of potassium chloride supplements will augment the concentrations of sodium and potassium in the final urine and also lead to a chloride diures/s (Figure 2). The appearance of more sodium during bicarbonate diuresis on a high sodium intake with potassium supplements suggests that bicarbonate freed proximally will carry sodium along for ultimate excretion in the urine if less sodium is reabsorbed at a site within the tubular system where potassium is secreted. CONCLUSION The observation that alkalosis induced by abrupt reduction of the partial pressure of carbon dioxide is associated with proportional renal loss of bicarbonate and potassium suggests that the determining variable for induction of these changes is the partial pressure of carbon dioxide. The reduced pCO;! modifies bicarbonate regeneration directly by limiting the hydration reaction and affects potassium excretion indirectly by reducing extracellular, and by inference, intracellular hydrogen ion activity. The organism therefore depends ultimately on modifications in pCOs, i.e., alveolar ventilation, for correction of bicarbonate excess. Sodium accompanies bicarbonate excretion only when the sodium intake is high. There is no apparent relationship between bicarbonate and chloride excretion within the setting of this experimental protocol. The clinical implication of these observations is that induced abrupt reductions in the partial pressure of carbon dioxide are associated with renal potassium loss which, depending on the circumstances, may lead to potassium depletion. ACKNOWLEDGMENT We acknowledge Miss L. Harwood.
the valuable
secretarial
help of
REFERENCES 1.
2.
3.
4.
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Engel K, Dell RB, Rahill J. Denning CR, Winters RW: Quantitative Displacement of acid-base equilibrium in chronic respiratory acidosis. J Appl Physiol 24: 288, 1968. Polak A, Haynie GD, Hays RM, Schwartz WB: Effects of chronic hypercapnia on electrolyte and acid-base equilibrium. I. Adaptation. J Clin Invest 40: 1223, 1961. Levitin HW, Branscome W, Epstein FH: The pathogenesis of hypochloremia in respiratory acidosis. J Clin Invest 37: 1667, 1958. Warren Y, Luke RG, Kashgarian M, Levitin H: Micropuncture studies of chloride and bicarbonate reabsorption in the proximal renal tubule of the rat in respiratory acidosis and in chloride depletion. Clin Sci 38: 375, 1970.
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Schwartz WB, Hays RM, Polak A, Haynie GD: Effects of chronic hypercapnia on electrolyte and acid-base equilibrium. II. Recovery with special reference to the influence of chloride intake. J Clin Invest 40: 1238, 1961. Aber GM, Bishop JM: Serial changes in renal function, arterial gas tensions and the acid-base state in patients with chronic bronchitis and oedema. Clin Sci 28: 511, 1965. Kassirer JP, Berkman PM, Lawrenz DR. Schwartz WB: The critical role of chloride in the correction of hypokalemic alkalosis in man. Am J Med 38: 172, 1965. Goldring RM, Turin0 GM, Heinemann HO: Respiratoryrenal adjustments in chronic hypercapnia in man. Am J Med 51: 772, 1971. Brazeau P, Gilman A: Effect of plasma CO2 tension on
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renal tubular reabsorption of bicarbonate. Am J Physiol 175: 33, 1953. Cohen JJ, Ellis JH: Correction of metabolic alkalosis by the kidney after isometric expansion of extracellular fluid. J Clin Invest 47: 1181, 1968. Purkerson ML, Lubowitz RW, Bricker NS: On the influence of extracellular fluid volume expansion on bicarbonate reabsorption in the rat. J Clin Invest 48: 1754,1969. Slatopolsky E, Hoffsten P, Purkerson M, Bricker NS: On the influence of extracellular fluid volume expansion and of uremia on bicarbonate reabsorption in man. J Clin Invest 49: 988, 1970. Kurtzman NA: Regulation of renal bicarbonate reabsorption by extracellular volume. J Clin Invest 49: 586,197O. Gennari FJ, Goldstein MB, Schwartz WB: The nature of the renal adaptation to chronic hypocapnia. J Clin Invest 51: 1722,1972. Cotlove E, Trantham HV, Bowman RL: An instrument and method for automatic, rapid, accurate and sensitive titration of chloride in biologic samples. J Lab Clin Med 51: 461, 1958. Seligson D, Hirahara K: The measurement of ammonia in whole blood, erythrocytes and plasma. J Lab Clin Med 49: 962,1957. Bonsnes RW. Taussky HH: On the calorimetric deter-
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20. 21.
22. 23. 24.
25.
26.
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mination of creatinine by the Jaffe reaction. J Biol Chem 158: 581, 1945. Van Slyke DD, Neil1 JM: The determination of gases in blood and other solutions by vacuum extraction and manometric measurement. J Biol Chem 61: 523, 1924. Rector FC Jr, Carter NW, Seldin DW: The mechanism of bicarbonate reabsorption in the proximal and distal tubules of the kidney. J Clin Invest 44: 278., 1965. Seldin DW, Rector FC Jr: The generation and maintenance of metabolic alkalosis. Kid Int 1: 306, 1972. Malnic G, de Mello Aries M, Giebisch G: Micropuncture study of renal tubular hydrogen ion transport in the rat. Am J Physiol 222: 147. 1972. Maren TH: Carbonic anhydrase: chemistry, physiology and inhibition. Physiol Rev 47: 595, 1967. Berliner RW: Renal mechanisms for potassium excretion. Harvey Lect 55: 141, 1961. Malnic G, de Mello Aries M, Giebisch G: Potassium transport across renal distal tubules during acid-base disturbances. Am J Physiol 221: 1192, 1971. Giebisch G, Boulpaep EL, Whittembury G: Electrolyte transport in kidney tubule cells. Trans Roy Sot London 8262: 175, 1971. Struyvenberg A, Morrison RB, Relman AS: Acid-base behavior of separated canine renal tubule cells. Am J Physiol 214: 1155. 1968.
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