Clinical Science (1970) 39, 391-406.
T H E EFFECT O F D I C H L O R P H E N A M I D E O N BLOOD
A N D CEREBROSPINAL F L U I D A C I D - B A S E STATE
I N C H R O N I C VENTILATORY F A I L U R E
D. J. L A N E , J. B. L. HOWELL
AND
T . B. S T R E T T O N
Department of Medicine, Manchester Royal Injirniary, Manchester
(Received 10 September 1969)
SUMMARY
1. Pco,, [HCO;] and [H'] have been measured in arterial blood and CSF in
twenty-three patients with chronic airways obstruction and five patients without chest
disease.
2. Through a range of Pco, in the CSF from normal to 79 mmHg there was a
direct linear relation between Pco, and [H']. The slope of this relation (0-41 nmol
1-l mmHg-') was similar to that reported in experimental studies in animals and
would appear to represent the extent to which regulatory mechanisms can protect
CSF [H'] against the acidosis of chronic hypercapnia.
3. There was also a direct linear relation between CSF [HCO,] and arterial
plasma [HCO;], the rise in [HCO;] in the CSF being less than that in the blood.
4. Thirteen patients were re-studied after receiving the carbonic anhydrase inhibitor
dichlorphenamide for 1 week. A metabolic acidosis developed in the arterial blood.
In the CSF Pco, and [HCO;] fell but [H'] did not change. CSF [H'] is maintained
constant and normal in other forms of chronic metabolic acidosis but it seems likely
that the constancy observed in the present study was fortuitous. Possible reasons for
this are discussed, and it is concluded that variability in responsiveness to ventilatory
stimuli between patients is the most likely explanation.
Studies of the changes in cerebrospinal fluid (CSF) acid-base state in a variety of experimental
and pathological disturbances of blood acid-base have shown that CSF pH remains relatively
normal in chronic metabolic disorders and in chronic respiratory alkalosis (Agrest & Roehr,
1963; Bradley & Semple, 1962; Buhlmann, Scheitlin & Rossier, 1963; Cowie, Lambie & Robson, 1962; Mitchell, Carman, Severinghaus, Richardson, Singer & Shnider, 1965a; Mitchell &
Singer, 1965; Pauli & Reubi, 1963; Pauli, Vorburger & Reubi, 1962; Posner, Swanson &
Plum, 1965;Schwab, 1962a;Severinghaus & Carcelen, 1964;Severinghaus, Mitchell, Richardson & Singer, 1963). By contrast, most reports have shown a marked deviation from normal of
the CSF pH in patients with chronic respiratory acidosis. (Alroy & Flenley, 1967; Agrest &
Correspondence: Dr D. J. Lane, Nuffield Department of Medicine, The Radcliffe Idrmary, Oxford.
39 1
392
D. J. Lane, J. B. L. Howell and T. B. Stretton
Roehr, 1963; Buhlmann et al., 1963; Huang & Lyons, 1966; Kawiak, 1963; Merwarth, Seiker
8z Manfredi, 1961; Rossier & Buhlmann, 1961;van Heijst & Visser, 1964). This difference is
not satisfactorily explained by current concepts of CSF acid-base regulation and the present
study was undertaken to investigate the problem further. It reports firstly further data on
arterial blood and CSF acid-base variables in patients with chronic respiratory acidosis and
secondly the changes in these variables, which occur following the administration of a carbonic
anhydrase inhibitor (dichlorphenamide) to these patients.
METHODS
Patients
All patients had chronic diffuse obstructive disease of the airways associated with
chronic bronchitis, emphysema or allergic airways disease. The nature and purpose of the
investigations to be carried out was explained to them and their permission obtained before
proceeding with the study.
The physical characteristics of the patients studied are detailed in Table 1. All but one patient
TABLE
1. Physical characteristics of patients studied
Patient
Age
Sex
F.A.
J.B.
J.Br.
C.C.
P.C.
A.C.
G.F.
C.F.
J.F.
R.H.
E.L.
V.L.
R.M.
J.N.
M.P.
H.R.
S.R.
S.S.
H.T.
E.T.
48
64
45
M
M
M
M
M
F
M
M
M
M
M
M
M
M
F.D.
C.H.
T.P.
64
43
50
56
58
48
45
61
55
59
54
44
58
58
59
61
65
55
57
59
F
M
M
M
F
M
M
M
M
Height
(cm)
166
174
170
163
173
160
173
177
176
178
181
176
180
180
147
168
173
175
152
181
178
170
178
Weight
Vital
(kg)
capacity (1)
65
67
68
45
65
50
85
89
66
74
48
69
63
69
35
70
67
86
43
73
80
65
64
1.98
2.37
3.56
1.69
2.28
-
1.95
2.60
3.74
2.03
2.74
2.01
4.23
1.91
1*57
1.78
2.33
0.99
1.63
4.08
2,75
2.22
FEVl (1)
0.88
0.72
0.77
0.89
1.14
0.65
1.61
1.54
0.60
0.83
-
0.49
0.71
0.39
0.54
0.68
0.62
0.5 1
0.44
0.83
0.66
0.98
(S.S.), who was admitted overnight for the specific purpose of the study, had been in hospital
for an average of 33 weeks (range 2-10 weeks) before the study was undertaken. All were
considered to be in a steady state following recovery from an acute dyspnoeic or infective
episode with attendant acute respiratory acidosis ;progress towards a steady state was followed
CSF in ventilatory failure
393
by routine spirometry and in seventeen patients with serial Pco, measurements (rebreathing
technique or Astrup interpolation technique) until there was no further tendency for the Pco,
to fall.
Twenty patients were judged to be in chronic steady state ventilatory failure having an arterial Pco, (Pa,co,) of greater than 47 mmHg (mean 58.3, range 48-71 mmHg). One patient (M.P.)
was studied on two separate occasions. Three patients had a Pa,co, within normal limits.
Five patients with neurological disorders but without chest disease were included to provide
control values.
Procedures
Some 3 h post-prandially and after a minimum of 30 min resting in bed, the left brachial
artery was cannulated with a Cournand needle. A lumbar puncture needle was then inserted
with the patient lying on the left side. A 15 ml sample of blood and a 4 ml sample of CSF were
withdrawn simultaneously into greased dry-sterilized syringes. A similar pair of samples were
withdrawn a few minutes later. The syringes were capped and placed immediately in crushed
ice. Great care was taken to ensure that the CSF was collected anaerobically. Before sampling
sufficient CSF was drawn into the syringe to fill the dead space and eject the air bubble. For
blood sampling the syringe dead space was filled with heparin (5000 units/ml).
Dichlorphenamide was administered orally to twelve of the twenty patients in ventilatory
failure and to one of the bronchitics with a normal Pa,co,, in a dose of 50-100 mg bd according
to body size and tolerance; measurements of arterial blood and CSF were repeated after 1 week.
Analytical techniques
Analyses were made as soon as possible after sampling, and were usually completed within
2 h. Whole blood was used for pH and Pco, measurements, plasma for the total CO, content.
pH was measured at 37" with an E.I.L. electrode or (later in the series) a Radiometer microelectrode, using in both instances an E.I.L. 48A pH meter. Like others (Leusen, 1963) we found
that the method of measuring pH in CSF was critical; any trace of buffer or distilled water in
the capillary of the electrode altered the measured reading considerably. The procedure adopted
to avoid this was to set the meter with standard buffer (Radiometer pH, 7.381), then after
washing with distilled water, to dry the capillary by sucking through air. Several drops of CSF
were drawn individually through the capillary before a full quantity was sucked in for measurement. Duplicate measurements were required to agree within 0.005 pH unit and repeated
measurements were made until this degree of reproducibility was achieved. pH values were
then converted to hydrion concentration [H'] in nmol/l.
Pco, was measured with a Severinghaus CO, electrode calibrated with humidified mixtures
of 5% and 10% CO, in oxygen. Duplicates were required to agree to within 1 mmHg. In some
instances there was insufficientCSF for satisfactory direct determination of Pco, and this was
calculated from the Henderson-Hasselbalch equation using the pH dependent pK of Cowie
et al. (1962): such instances are marked $.
Total CO, content was measured initially by the manometric method of Van Slyke & Neil
(1924) and later by the Natelson technique (Microgasometer model 600): duplicates were
required to agree to within 0.2 mmol/l. Blood was transferred anaerobically under para&
into centrifugetubes and spun at 3000 r.p.m. for 10 min to obtain plasma, which was then transferred under paraffin to the manometric apparatus.
Bicarbonate concentration [HCO;] was calculated from measured total CO, and a solubility
D. J . Lane, J. B. L. Howell and T. B. Stretton
394
coefficient of 0.0303 mmol 1-1 mmHg-' at 37" for plasma (Severinghaus, Stupfel & Bradley,
1956) and 0.0312 mmol/l at 37" for CSF (Mitchell, Herbert & Carman, 1965b).
Twenty-four-hour urine collections were made under paraffin in eleven of the patients
throughout the period before and during dichlorphenamide administration. Aliquots of these
specimens were analysed for CO, content by the method of Van Slyke & Neil (1924) or using
the Natelson microgasometer, for sodium and potassium by flame photometry and for chloride
by an autoanalyser.
RESULTS
The observed values for arterial blood and CSF pH, [H'], Pco, and [HCO;] in twenty-four
resting patients with chronic obstructive airways disease and five patients with neurological disorders are given in Table 2. Graphical representation of the results is given in Figs. 1-3.
TABLE
2. Acid-base state of arterial blood and CSF in twenty-one patients with chronic hypercapnia and
eight controls (F.D., C.H., T.P., B.H., J.J., R.P., M.T. and J.W.)
CSF
Arterial blood
-
Patient
pH
[H+] PCOz [HCO;]
(nmol/l) (mmHg) (mmol/l)
pH
~
F.A.
J.B.
J.B.
C.C.
P.C.
A.C.
G.F.
C.F.
J.F.
R.H.
E.L.
V.L.
R.M.
J.N.
M.P.
M.P.
H.R.
S.R.
S.S.
H.T.
E.T.
F.D.
C.H.
T.P.
B.H.
J.J.
R.P.
M.T.
J.W.
7.315
7.430
7.385
7.370
7.396
7.370
7.380
7.347
7.351
7.340
7.389
7.426
7.385
7.346
7.424
7.367
7.392
7.370
7.364
7.330
7.375
7.405
7.457
7.369
7.372
1.439
7.396
7,383
7.410
48.4
37.2
41.2
42.6
40.1
42.6
41.6
45.0
44.5
45.7
40.8
37.5
41.2
45.1
37.7
43.0
40.5
42.6
43.2
46.8
41.1
39.3
34.9
42.7
42.5
36.4
40.2
41.1
38.9
71
52
62
57
53
48
56
55
50
65
63
63
55
64
57
60
62
63
59
64
59
41
46
46
45
38
45
42
40
34.9
33.5
35.6
31.8
31.7
29.3
32.2
29.8
25.3
34.2
37.0
38.5
30.2
34.2
36.3
33.6
36.2
35.0
31.5
32.1
34.0
25.2
31.1
28.0
24.7
23.6
26.3
24.6
25.4
7.247
7.267
7.249
7.257
7.264
7.319
7.287
7.281
7.271
7,262
7.259
7.249
7.266
7.228
7.277
7.274
7.264
7.288
7.283
7.232
7.313
7.337
7.289
7.318
7.311
7.352
7.342
7.324
7.349
[H+] PCO2 [HCO;]
(nmol/l) (mmHg) (mmol/l)
56.6
53.0
56.4
55.3
54.5
48.0
51.6
52.4
53.5
54.7
55.0
56.4
54.2
59.1
52.9
53.2
57.5
51.5
52.1
58.6
48.6
46.0
51.4
48.1
48.9
44.5
45.5
47.4
44.8
74
62
73$
70
67$
56
64
61
58
71
72
70
64
79$
70
66
72
69
66
73
66
49
57
52
53
461
51
54
47
APco,
Blood-CSF
(mmHg)
30.5
28.9
30.4
29.8
30.0
27.9
29.4
27.8
24.8
31.3
32.3
31.8
29.3
32.5
31.8
30.8
31.4
32.4
29.2
29.6
32.6
26.5
28.1
25.8
25.8
24.5
24.4
26.9
24.5
$ Instances in which CSF Pco, was calculated and not measured directly (see text).
3
10
11
13
14
8
8
6
8
6
9
7
9
15
13
6
10
6
7
9
7
8
11
6
8
8
6
12
7
CSF in ventilatory failure
395
Fig. 1 shows the relation between arterial [H'] and Pa,co,. Although this shows a tendency
for arterial [H'] to rise with increasing Pa,co2 only three patients had an arterial [H'] greater
than 45 nmol/l and the scatter of points is wide. The correlation coefficient is 0.54 (<0*01);
the regression line calculated by the method of least squares has the formula:
[H+],a = 0.19 Pa,CO,
+ 30.9
There was by contrast a much closer correlation between [H'] and Pco, in the CSF (correlation coefficient = 0.92, P<O.OOl) (Fig. 2), the regression line having the formula:
[H'], CSF
=
+
0.41 PCSF,C02 26.4
The slope is steeper than that of the corresponding relation in the arterial blood and the
development of marked acidosis in the CSF with increasing hypercapnia is evident.
"i
1
45-
E
C
+-I
Y
o
._
L
al
+
<
40-
c e
35
I
I
40
I
50
Arterial PCO, (rnmHg)
1
I
60
70
FIG. 1. Relationship between arterial [H+] and Pa,co, in twenty-one patients with chronic
ventilatory failure and eight controls.
The relationship between arterial and CSF [HCO;] is shown in Fig. 3. In the normal
subjects the two [HCO;] levels were similar but the rise in arterial [HCO;] which accompanies
hypercapnia was greater than the associated rise in CSF [HCO;]. The relation between the
two [HCOJ] values may be represented linearly; the regression line calculated by the method
of least squares has a correlation coefficient of 0.93. The divergence of this line (B, Fig. 3)
from the line of equality (A, Fig. 3) is demonstrated.
The arterial blood to CSF Pco, gradient was not statistically different in the more hypercapnic patients from those with normal Pa,co,. However, when compared to arterial [H']
396
D. J. Lane, J. B. L. Howell and T. B. Stretton
I
I
I
50
I
I
60
CSF
I
80
I
70
P C O (rnrnHg)
~
FIG. 2. Relationship between CSF [H+] and CSF Pcoz in twenty-one patients with chronic
ventilatory failure and eight controls. The regression line has the formula :
[H+] CSF = 0.41 PCSF,
co2+26.1(r = 0.92: P<O.OOl)
I
I
I
I
25
30
35
40
A r t e r i a l [HCO;]
(rnmol/l)
FIG.3. Relationship between arterial and CSF [HCO;]
A = line of equality between arterial and CSF [HCO;]
B = regression line through data calculated by method of least squares (r = 0.93: P<O.OOl)
CSF in ventilatory failure
397
there was a significant correlation between blood-CSF Pcoz gradient and arterial acidity (Fig.
4, r = -0.34, 0.02<P<0.05).
The effect of the administration of dichlorphenamide can be judged from a comparison of
mean values of the acid-base variables found in thirteen patients before and at the end of 1
week on the drug (Table 3). The acidosis which developed in the arterial blood was attributable
to a fall in [HCO;] and associated with a fall in Pa,co,.
15-
-I"
E
E
y
0
..
..
0
.
10-
v)
0
0
*.
0
i
m
0
O."
0
.O
O
..
0" 5-
c
0
O
o
o
0
QJ
OL
1
I
I
x)
34
38
I
42
Arterial [H'] (nrnol/L)
1
I
I
46
50
54
FIG.4. Relationship between arterial blood-CSF Pco2 difference and arterial [H+]. 0 = Basal
data (patients and controls); o = Data on dichlorphenamide.
I
I
I
25
30
35
Arterial [HCO;]
(mmol/l)
FIG. 5 . Relationship between CSF [HCO;] and arterial [HCO;] in thirteen patients at the end of
7 days on dichlorphenamide,showing no significant differencefrom the regression line under basal
conditions (Fig. 3) which is shown for comparison.
7.332
0.046
7.316
0.038
7.343
0.025
On DCP
Basal
On DCP
Significance
Difference on DCP
On DCP
P<O.Ool
-0445
7.339
0.037
7.384
0.047
7.384
0.039
Basal
ALLPATIENTSBasal
GROUP
II
GROUPI
a
PH
NS
a = arterial blood, mean and SD
c = cerebrospinal fluid, mean and SD
P<Oa02
P<O.Ool
P<O.Ool
P<O.Oo2
- 2.9
P<O.Ool
NS
- 5.0
+0.4
+4.5
-0.004
- 6.3
27.5
2.4
29.0
3.5
63.1
7.5
55.6
1.4
55.4
3.8
46.0
4.0
7.256
0.024
- 3.3
30.4
1.3
34.0
2.2
69.4
5.7
59.5
6.8
26.8
2.9
28.2
1-7
60.0
8.0
55.0
2.4
52.5
7.8
30.1
1.2
33.5
2.1
69.3
6.2
41.5
4.1
53.5
3.9
45.4
2.9
7.272
0.033
59.7
7.4
28.1
2.0
30.7
1.4
C
7.260
0.024
2.4
42.0
4.2
55.0
29.8
2.9
65.8
6.3
58.2
6.5
57.0
3.1
46.5
4.9
34.5
2.4
69.4
5.8
59.4
6.9
54.9
2.6
41.1
4.3
a
[HCO;] (mmol/l)
C
Pcoz (mmHg)
a
C
a
7.259
0.024
7.260
0.025
7.243
0.027
C
W + I (nmol/l)
TABLE
3. Arterial blood and CSF acid-base changes at the end of 1 week's treatment with dichlorphenamide (DCP) compared with basal values.
The division of patients into two groups with similar degrees of metabolic acidosis but strikingly different responses in CSF [H+] and Pa,co2 is
shown (see text)
*pY
.Y
4
CSF in ventilatory failure
399
In the CSF the fall in Pco, was greater than that in the blood and the blood-CSF Pco,
difference was narrowed but not to a statistically significant degree (0-05
< P <0.10). The relation of blood-CSF Pco, difference to arterial [H'] noted in the basal data was similar after
dichlorphenamide (Fig. 4). The decrease in CSF [HCO;] was less than that in the blood but
the relationship of arterial to CSF [HCO;] did not alter (Fig. 5). The distribution ratio for
bicarbonate (RCSF,HCO; = [HCO;]CSF/[HCO;] plasma) altered from 0.83 before dichlorphenamide to 0.88 after 1 week on the drug.
The resultant effect of these changes in CSF Pco, and [HCO;] was that mean CSF [H'] did
not alter from pre-dichlorphenamide levels (Table 3). Individual patients however sometimes
showed an appreciable shift in CSF [H'] and the group of thirteen patients may be divided
into seven patients in whom the CSF became more acid and six patients in whom the CSF [H']
remained constant or fell (Table 3). The degree of metabolic acidosis achieved in the two
groups expressed in terms of the fall in arterial [HCO,] produced was almost identical 4.7 SD
1.6 nmol/l and 5.3 SD 3.2 mmol/l respectively (P>0*05).The response to this metabolic
acidosis differed markedly in the two groups however. Those in whom the CSF [H+] rose
showed a mean fall in Pa,coz of only 1.2 SD 1.8 mmHg whereas the remainder showed a mean
fall in Pa,co, of 7.2 SD 1.7 mmHg (P<O-OOl).
Urine analyses confirmed changes noted by previous investigators. A brisk diuresis with
HCO; loss was obvious in the first 24-48 h on dichlorphenamide but volume and electrolyte
excretion then returned to normal.
DISCUSSION
CSF acidity in chronic respiratory acidosis
Although there are some reports in the literature of only minor deviations of CSF pH from
normal in chronic respiratory acidosis (Mitchell et al., 1965a; Schwab, 1962b), other reports
have documented a significant CSF acidosis in this condition (Alroy & Flenley, 1957; Agrest &
Roehr, 1963; Buhlmann et al., 1963; Huang & Lyons, 1966; Kawaik, 1963; van Heijst &
Visser, 1964). Our data confirm the latter observations and show that the relation between
CSF [H'] and CSF Pco, may be represented linearly through the whole range of deviation
from normal to severe chronic hypercapnia. A similar linear relation has been reported by
Alroy & Flenley (1967) although the slope of the regression line through their data is lower and
the correlation coefficientless significant. There does not appear in our data any suggestion that
CSF pH is regulated back to normal up to a certain level of Pco, after which adaptive
mechanisms fail as suggestedby Huang & Lyons (1966). Indeed if the data of these workers is
replotted as [H'] v Pco, instead of pH v Pco, then a more linear relation is revealed with a
slope similar to that shown in Fig. 2.
Chronic adaptation of the CSF to hypercapnia appears to follow a similar pattern in animal
studies where a degree of buffering comparable to that seen in man following prolonged hypercapnia viz. around 0.4 nmol 1-lmmHg-' is achieved in about 8 to 12 h (Bleich, Berkman
& Schwartz, 1964; Michel, 1964, Pontbn, 1966; Swanson & Rosengren, 1962). This figure would
appear to represent, both in man and experimental animals, the ability of non-respiratory
factors to buffer CSF [H'] against the hypercapnia caused by a primary respiratory disturbance.
E
400
D. J. Lane, J. B. L. Howell and T. B. Stretton
There seems no reason to suppose that CSF [H'] buffering in response to rising Pa,co, is
any different in chronic respiratory disease from that in any other experimental or pathological
state of primary respiratory acid-base disturbance; only the method of producing the altered
level of Pa,co, is different. In experimental studies of hypercapnia the natural mechanism of
response in the form of increased ventilation is frustrated because of the continuous supply of
CO, in the inspired air. In chronic obstructive airways disease this response is, in certain
patients, hindered by the sheer magnitude of the mechanical problem presented by the airways
obstruction and, in others, is reduced because of loss of CO, sensitivity (Lane & Howell,
unpublished observations).
CSF [H'] in chronic metabolic acidosis
A discussion of the effect of dichlorphenamide must be seen against the background of
studies of CSF and blood acid-base state in chronic metabolic acidosis. Deviations of CSF
pH from normal are far less marked and it was from an examination of CSF acid-base state in
uraemic patients that the concept of the constancy of CSF [H'] in chronic acid-base disorders
first arose (Bradley & Semple, 1962; Pauli, Vorburger & Reubi, 1962; Schwab, 1962a). In
order to assess compensation within the CSF for the primary metabolic disturbance it would be
logical to ascertain the relation between CSF [H'] and an index of metabolic change such as
[HCO;]. However, to make these data comparable with those for respiratory disturbances the
relation between CSF [H'] and CSF Pco, has been determined in metabolic acid base disturbances. In this instance the relation will be inverse, in that the higher the [H'] then the
greater the metabolic acidosis and the lower will be the Pco,.
From the data in the literature the relationship between CSF [H'] and Pco, in metabolic
acid-base disturbances has been examined. Human studies suggest an effective buffering of
CSF [H'] of the order of 0.10 nmoll-' mmHg Pco,-', although it is not possible to calculate
the statistical significance of this figure because of the heterogeneous and incomplete nature
of the data. This relative constancy of CSF [H'] is all the more remarkable when it is compared
with the change in blood [H+]which, in metabolic disturbances, is of the order of 1.0 nmol 1-'
mmHg Pco,-l or possibly ten times the magnitude of the CSF [H'] change.
Animal studies confirm these small deviations of CSF [H'] from normal in chronic experimental metabolic disorders. Fencl, Miller & Pappenheimer (1966) found the CSF to be
slightly but significantly acid during metabolic acidosis in goats and less significantly alkaline
during metabolic alkalosis. Chazan, Appleton, London & Schwartz (1969) on the other hand
found in dogs that, when care had been taken to establish a steady state, CSF [H'] showed no
significant change during metabolic acidosis but fell slightly during metabolic alkalosis. It
seems reasonable therefore to accept that CSF [H'] changes little from normal valuesin chronic
metabolic acidosis in comparison with the obvious divergence of CSF [H'] from normal in
chronic respiratory acidosis.
Eflects of dichlorphenamide
The observation of no net change in CSF [H'] despite decreases in both CSF Pco, and CSF
[HCO;] following dichlorphenamide (Table 3) suggests that the buffering of CSF [H+] in
response to this form of chronic metabolic acidosis in patients with chronic ventilatory failure
follows the pattern seen in chronic metabolic acidosis in general. A similar trend has been
CSF in ventilatory failure
401
noted in other reports in the literature on the effects of carbonic anhydrase inhibition. Schwab
(1962b) followed blood and CSF acid-base variables in two groups of patients with chronic
but mild (mean Pa,co, 52 mmHg) ventilatory failure given acetazolamide for 2-3 days and
2-3 weeks respectively. The latter group (nine patients) is comparable with our patients and
the pattern of response is similar to that seen in our data. Following acetazolamide CSF [H']
remained nearly constant (the mean change in pH was from 7.309 to 7.317), despite a fall in
CSF Pco, of 10.2 mmHg and a fall in CSF [HCO;] of 4.3 mmol/l. Naimark & Cherniack
(1966) reported on the effects of dichlorphenamide in a small group of patients with mild
ventilatory failure (mean Pa,co, 50.1 mmHg); CSF pH fell from 7.28 to 7.26 but the change
was not significant.
Despite this constancy of mean CSF [H'] following carbonic anhydrase inhibition, which is
reminiscent of the constancy of CSF [H'] during other forms of metabolic acidosis, it is not
possible to draw an exact parallel between the two situations for two reasons. Firstly, the
complex nature of the total body response to carbonic anhydrase inhibition may introduce
variables other than those due to a simple metabolic acidosis: the possibility of changes in the
transport of CO, by red cells or the secretion of [H'] or [HCO;] ions into the CSF must be
considered. Secondly, the situation differs from an uncomplicated metabolic acidosis in that
CSF [H'] remains constant at an abnormal level rather than remaining constant within the
normal range.
The pattern of acid-base change in the arterial blood following carbonic anhydrase inhibition
is that of a metabolic acidosis, there being a decrease in [HCO;] and an increase in [H'].
The [HCO;] decrease may be attributed to the demonstrated renal loss of this ion caused by
inhibition of renal tubular carbonic anhydrase. Arterial metabolic acidosis stimulates ventilation and this mechanism would seem a reasonable explanation for a fall in Pa,co, on treatment
with dichlorphenamide.
An alternative mechanism for lowering Pa,co, would be by a reduction in CO, production.
This could be of some importance in patients with CO, retention and occasionally a normal
individual shows a marked fall in CO, production with a lowering of Pa,co, without change
in minute ventilation (Chiesa, Stretton, Massoud & Howell, 1969). However a statistically
significant fall in CO, production in a whole group of subjects was seen in only one out of five
reports of ventilatory changes following the clinical use of carbonic anhydrase inhibitors
(Naimark, Brodovsky & Cherniack, 1960). In animal studies a transient fall in CO, production
is often seen (Mithoefer, 1959) but this rarely persists. Furthermore in animals when large
doses of carbonic anhydrase inhibitors are given equilibration between the various components
of the carbonic acid buffer system fails to take place during the time required for passage of
blood through the lungs (Cain & Otis, 1961; Maren, 1967). This could lead to difficulties in
interpreting Pco, changes but it seems unlikely that such a situation obtains in the lesser degrees
of inhibition achieved with the dosage used in human studies (Chiesa et al., 1969). With these
reservations in mind it seems possible to interpret the overall effect of dichlorphenamide in
terms of a metabolic acidosis which results in a fall in Pco, in both the arterial blood and the
CSF. The effect of this fall in CSF Pco, on CSF [H'] will depend on other factors.
It has been noted that in uncomplicated metabolic acidosis regulatory mechanisms seem to
be brought into play to stabilize CSF [H'] within the normal range. In the present study CSF
[H'] was stabilized during a metabolic acidosis but at an abnormal level viz. that due to the
underlying respiratory acidosis. This suggests that either the regulatory mechanisms are geared
402
D. J. Lane, J. B. L. Howell and T. B. Stretton
to stability of CSF [H'] rather than normality of CSF [H'] or that the apparent stabilization
of CSF [H'] found was fortuitous.
The former suggestion would imply some sort of re-setting of the ventilatory regulatory
apparatus but insufficient information is available concerning the normal mechanism to allow
speculation on this point. One other report exists in the literature in which blood and CSF
measurements have been made whilst an established acid-base disturbance has been complicated by carbonic anhydrase inhibition. In this instance a respiratory alkalosis was induced in
normal subjects by simulated ascent to altitude and the effect on this of carbonic anhydrase
inhibition with benzolamide was observed (Kronenberg & Cain, 1968). Subjects receiving
the drug showed a slightly lower CSF pH at 72 h than those receiving the placebo but all values
appear to be rather alkaline, and no observations are available a t one week.
A fortuitously stable CSF [H'] might arise if regulatory mechanisms designed to achieve
normality of CSF [H'] have been partially or completely disrupted because of carbonic
anhydrase inhibition. It has been postulated that CSF [H'] is regulated by an active transport
process (Severinghaus & Mitchell, 1963). This postulate is based partly on observations relating
to the distribution of ions between plasma and CSF. If no active transport is involved the
distribution ratio of an ion is that across a semipermeable membrane and is determined by the
electrical potential across the membrane. Measurements of this potential in man give a value
of about 4mV CSF positive (Severinghaus, 1965). The distribution ratio for bicarbonate
(RCSF,HCO,) which is the same as that for chloride (RCSF,Cl-) should have a value of 1.16
at this electrical potential. However, Mitchell et al. (1965a) have shown that RCSF, HCO;
varies with arterial pH in a predictable manner ranging from 0-71 in metabolic alkalosis to
2.18 in metabolic acidosis but is only in equilibrium as defined by the Nernst equation at an
arterial pH of around 7.30. C1- ion distribution on the other hand varies little (Mitchell et
al., 1965a; Bradbury, Stubbs, Hughes & Parker, 1963). It is argued that since C1- and HCO;
are both subjected to the same electrical potential and neither is bound, then the wide variation in the distribution ratio for HCO; compared to that for C1- suggests active regulation
of CSF [HCO;] either resulting from or responsible for active regulation of CSF [H'].
The presence of carbonic anhydrase in choroid plexus and glia has suggested a role for this
enzyme in H + secretion into the CSF (Maren, 1967). Experimental studies have shown that its
inhibition results in a reduction in CSF formation in animals (Ames, Higashi & Nesbett, 1965;
Oppelt, Patlak & Rall, 1964; Welch, 1963) and man (Maren & Robinson, 1960). There is also
a fall in the rate of turnover of 24Na (Davson & Luck, 1957), and a marked acute rise in
RCSF, HCO; (Maren, 1962). However in more chronic studies in man (Birzis, Carter &
Maren, 1958) and in the present study the change in RCSF,HCO; when referred to arterial
pH is no different from that described by Mitchell et al. (1965a) for various acid-base disorders
not involving carbonic anhydrase inhibition. The absence of any change in the relation between
CSF and plasma [HCOJ during dichlorphenamide administration is also evident from Fig. 5.
This either means that insufficient inhibitor was given to effect significantly the transport
system or that active transport of HCO; is unlikely to be an important factor in the regulation
of CSF [H'] as suggested by Loeschcke (1965) and by Kjallquist & Siesjo (1968). In either
event the possible disruption of regulatory transport mechanisms by the dichlorphenamide
seems an unlikely explanation for a fortuitously stable CSF [H'] under the conditions of this
study.
An alternative explanation would be that the group of patients under study was in some
403
CSF in ventilatory failure
respect heterogeneous, those showing an increased CSF [H' ] fortuitously balancing those
showing a fall in CSF [H']. The observation that the patients may be divided into two groups
showing strikingly different responses to similar degrees of metabolic acidosis supports this
explanation and suggests a variation in sensitivity to the ventilatory stimulation produced by a
metabolic acidosis amongst the patients studied.
Eight of the patients from the present study were also included in a previous study (Lane &
Howell, 1970) in which CO, sensitivity in terms of the inspiratory mechanical work rate response to increasing concentrations of inhaled COz was measured. A clear correlation was
obtained between this index of CO, sensitivity (S %7,/COz)and the fall in Pa,co, on treatment
with dichlorphenamidein the same subjects (r = - 0.88;P< 0.01 ;Fig. 6 ) .This fall in Pa,co, may
+2 r
00
-
-2
0
0
0
I
E
ON
,$
v
40
6-
4
8-
0
0
0
10
12
04
0.2
sf,/C02 (kg M min" mmHg-')
0.3
FIG.6. Sensitivity to CO,, as assessed by the slope of the inspiratory mechanical work rate response
to CO, (SW,/CO, kg M min-' mmHg-': Lane & Howell, 1970), compared with the fall in
arterial Pco, during dichlorphenamidetherapy in eight patients, showing that patients with a poor
response to COz also have a poor response to dichlorphenamide.
be taken as an index of the response of ventilatory control mechanisms to the metabolic
acidosis induced by dichlorphenamide. Those patients who retained reasonable sensitivity to
COz showed a large fall in Pa,co, and a return of CSF [H'] towards normal during dichlorphenamide administration, whereas those patients who had lost COz sensitivity showed only a
small fall in Pa,co, and a further increase in CSF acidity beyond that already caused by the
respiratory acidosis, Since neurological disturbances including coma may be related to CSF
acidosis rather than arterial acidosis (Posner & Plum, 1967) it is important to recognize that
in some patients with chronic ventilatory failure carbonic anhydrase inhibition may lead to
further CSF acidosis without significant change in Pa,co,.
It would appear therefore that the concept of 'sensitivity' of the respiratory regulatory
404
D.J. Lane, J. B. L. Howell and T, B. Stretton
apparatus may be applied not only to the acute response to CO, inhalation but also to the
chronic response to the metabolic acidosis associated with dichlorphenamide administration.
The degree of impairment of CO, sensitivity has been shown to have an important bearing on
the clinical presentation of patients with chronic obstructive airways disease. A discussion of
this and of the pathogenesis of the loss of sensitivity are beyond the scope of this paper and are
published elsewhere (Lane & Howell, 1970).
Blood-CSF PCO, gradient
The arterial-CSF Pco, difference has been held to reflect cerebral blood flow on the grounds
that CSF and jugular venous blood are in equilibrium for CO, (Bradley & Semple, 1962).
Variations in this gradient should then reflect variations in cerebral blood flow provided CO,
production remains constant. Although an acute rise in CO, causes an increase in cerebral
blood flow and so a reduction in the arterial-CSF Pco, difference (Kety & Schmidt, 1948) the
data obtained in this study showed that during chronic CO, retention the Pco, gradient
was not significantly different from that obtained in the subjects with normal Pco,. However,
when referred to arterial [H'] it is seen that there is a reduction in the Pco, difference with
increasing acidity (Fig. 4). This finding is in accordance with recent experimental work in
animals and man which suggests that cerebral blood flow is affected to an important degree by
brain extra-cellular fluid [H+] although in animal studies it appears that CSF [H'] levels are
more important in this respect than arterial [H+] levels (Severinghaus, 1968).
ACKNOWLEDGMENTS
We wish to thank Professor D. A. K. Black, Dr C. S . D. Don, Dr H. Howat and Dr Morgan
Jones for permission to study patients under their care. The skilled technical assistance of Mrs
B. Giblin is gratefully acknowledged. One of us (D.J.L.) was in receipt of a research grant from
the Board of Governors of the Manchester Royal Infirmary.
REFERENCES
AMES,A. 111, HIGASHI,
K. & NESBETT,
F.B. (1965) Effects of PC02 acetazolamide, and ouabain on volume and
composition of choroid-plexus fluid. Journal of Physiology, 181, 51 6-524.
AGREST,A. & ROEHR,E.E. (1963) Relation Electrolitica y acido-basica entre sangre arterial y liquid0 cefalorraquides en trastornos del equilibro acido-base. Medicina (Beunos Aires), 23, 173-1 87.
ALROY,G.G. & FLENLEY,
D.C. (1967) The acidity of the cerebrospinal fluid in man with particular reference to
chronic ventilatory failure. Clinical Science, 33, 335-343.
BIRZIS,L., CARTER,
C.H. & MAREN,
T.H. (1958) Effect of acetazolamide on C.S.F. pressure and electrolytes in
hydrocephalus. Neurology, 8, 522-528.
BLEICH,H.L., BERKMAN,
P.M. & SCHWARTZ,
W.B. (1964) The response of cerebrospinal fluid composition to
sustained hypercapnia. Journal of Clinical Investigation, 43, 11-16.
BRADBURY,
M.W.B., STUBBS,
J., HUGHES,
I.E. & PARKER,
P. (1963) The distribution of K+, N a + and C1- and
urea between lumbar C.S.F. and blood in human subjects. Clinical Science, 25,97-105.
BRADLEY,
R.D. & SEMPLE,
S.J.G. (1962) A comparison of certain acid-base characteristics of arterial blood,
jugular venous blood, and cerebrospinal fluid in man, and the effect on them of some acute and chronic
acid-base disturbance. Journal of Physiology, 160, 381-391.
BUHLMANN,
A., SCHEITLIN,
W. & ROSSIER,
P.H. (1963) Die Beziehungen nvischen Blut und Liquor cerebrospinalis bei Storungen des Saure-Basen-Gleichgewichtes. Schweizerische Medizinische Wochenschrif, 93,
427432.
CSF in ventilatory failure
405
CAW,S.M. & Ons,A.B. (1961)Carbon dioxide transport in anaesthetised dogs during inhibition of carbonic
anhydrase. Journal of Applied Physiology, 16,1023-1028.
CHAZAN,
J.A., APPLETON,
F.M., LONDON,A.M. & SCHWARTZ,
W.B. (1969)Effects of chronic metabolic acidbase disturbanceson the composition of cerebrospinalfluid in the dog. Clinical Science, 36,345-358.
CHIESA, A., STRETTON,
T.B., M m m , A.A.E. & HOWELL,
J.B.L. (1969)The effects of inhibition of carbonic
anhydrase with dichlorphenamide on ventilatory control at rest and on exercise in normal subjects. Clinical
Science, 37,689-706.
Cow,J., LAMBIE,
A.T. & ROBSON,
J.S. (1962)The influence of extracorporealdialysis on the acid-base composition of blood and cerebrospinal fluid. Clinical Science, 23, 397404.
DAVSON,
H. & LUCK,C.P. (1957)The effect of acetazoleamide on the chemical composition of the aqueous
humor and cerebrospinal fluid of some mammalian species and on the rate of turnover of 24Na in these
fluids. Journal of Physiology, 137,279-293.
FENCL,
V., MILLER,T.B. & PAPPENHEIMER,
J.R. (1966)Studies on the respiratory response to disturbances of
acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid. American
Journal of Physiology, 210,459-472.
HUANG,
C.T. & LYONS,
H.A. (1966)The maintenanceof acid-basebalance between cerebrospinalfluid and arterial blood in patients with chronic respiratory disorders. Clinical Science, 31,273-284.
KAWIAK,
W. (1963)H + and alkali reserve in C.S.F. and blood in patients with cor pulmonale. Polski Tygodnik
hkarski, 18,982-984.
KEn, S.S. & SCHMIDT, C.F. (1948)The effects of altered arterial tensions of carbon dioxide and oxygen on
cerebral blood flow and cerebral oxygen consumption of normal young men. Journal of Clinical Znvestigation, 27,484-492.
K~ALLQUIST,
A. & SIESIB,B.K. (1968) Regulation of C.S.F. pH-influence of the C.S.F./plasma potential.
Scandinavian Journal of Laboratory and Clinical Investigation, Suppl. 102, 1 :C.
KRONENBERG,
R.S. & C m , S.M. (1968)Hastening Respiratory Acclimatization to Altitude with Benzolarnide
(CL 11,366)Aerospace Medicine, 39, 296-300.
LANE,D.J. & HOWELL,
J.B.L. (1970)Relationship between sensitivity to carbon dioxide and clinical features in
patients with chronic airways obstruction. Thorax, 25,150-159.
LEUSEN,
I. (1963)Aspects of the chemosensitivityof the Respiratory Centres. The Regulation of Human Respiration (Ed. by D. J. C. Cunningham and B. B. Lloyd), p. 207. Blackwell Scientific Publications, Oxford.
LOESCHCKE,H.H. (1965)A concept of the role of intracranial chemosensitivity in respiratorycontrol. In: Cerebrospinal Fluid and the Regulation of Ventilation (Ed. by C. McC. Brooks, F. F. Kao, and B. B. Lloyd) p. 195.
Blackwell Scientific Publications, Oxford.
MAREN,
T.H. (1962)Ionic composition of cerebrospinal fluid and aqueous humor of the dogfish, Squalus acanthias. 11. Carbonic anhydrase activity and inhibition. Comparative Biochemistry and Physiology, 5,201-215.
MAREN,
T.H. (1967)Carbonic anhydrase: Chemistry, physiology and inhibition.Physiological Reviews, 47,595781.
MAREN,
T.H. & ROBINSON,
B. (1960). The pharmacology of acetazolamide as related to cerebrospinal fluid and
the treatment of hydrocephalus. Bulletin of the Johns Hopkins Hospital, 106, 1-24.
MERWARTH,
C.R., SIEKER,
H.O. & MANFREDI,
F. (1961)Acid-base relations between blood and cerebrospinal
fluid in normal subjects and patients with respiratory insufficiency. New England Journal of Medicine,
265, 310-313.
MICHEL,
C.C. (1964)C.S.F. HCO; during respiratory acid-base disturbance. Journal of Physiology, 170,6&67P.
MITCHELL,
R.A., CARMAN,
C.T., SEVERINGHAUS,
J.W., RICHARDSON,
B.W., SINGER,
M.M. &SHNWER,
S. (1965a)
Stability of cerebrospinal fluid pH in chronic acid-base disturbancesin blood. Journal of Applied Physiology,
20,443452.
MITCHELL,
R.A., HERBERT,
D.A. & CARMAN,
C.T. (1965b).Acid-base constants and temperaturecoefficients for
C.S.F. Journal of Applied Physiology, 20,27-30.
MITCHELL,
R.A. & SINGER,
M.M. (1965) Respiration and cerebrospinal fluid pH in metabolic acidosis and
alkalosis, Journal of Applied Physiology, 20, 905-91 1.
MITHOEFER,
J.C. (1959)Inhibition of Carbonic Anhydrase: its effect on CO, elimination by lungs. Journal of
Applied Physiology, 14, 109-1 15.
NAIMARK,
A., BRODOVSKY,
D.M. & CHERNIACK
R.M. (1960).The effect of a new carbonic anhydrase inhibitor
(dichlorphenamide)in respiratory insufficiency. American Journal of Medicine, 28, 368-375.
D. J. Lane, J. B. L. Howell and T. B. Stretton
NAIMARK,
A. & CHERNIACK,
R.M. (1966) Effect of dichlorphenamide on gas exchange and C.S.F. acid-base state
in chronic respiratory failure. Canadian Medical Association Journal, 94, 164-170.
OPPELT,W., PATLAK,
C.S. & RALL,D.P. (1964) Effect of certain drugs on cerebrospinal fluid production in the
dog. American Journal of Physiology, 206,247-250.
PAULI,H.G. & REUBI,F. (1963) Respiratory control in uraemic acidosis. Journal of Applied Physiology, 18,717721.
PAULI,H.G., VORBURGER,
C. & REUBI,F. (1962) Chronic derangements of cerebrospinal fluid acid-base components in man. Journalof AppliedPhysiology, 17,993-998.
P O N T ~ U.
N , (1966) Consecutive acid-base changes in blood, brain tissue and cerebrospinal fluid during respiratory acidosis and baseosis. Acta Neurologica Scandinavica,42,455471.
POSNER,
J.B. & PLUM,F. (1967). Spinal fluid pH and neurologic symptoms in systemic acidosis. New England
Journal of Medicine, 277, 605-613.
POSNER,
J.B., SWANSON,
A.G. &PLUM,F. (1965). Acid-base balance in cerebrospinal fluid. Archives of Neurology,
12,479496.
ROSIER,P.N. & BUHLMANN,
A. (1961) Die Beeinflussung des intrakraniellan druckes und der elektrolyte im
liquor cerebrospinalis durch karboanhydrasehemmung. Munchener medizinische Wochenschrif, 103,21882190.
SCHWAB,
M. (1962a) Das Saure-Basen-Gleichgewichtim arteriellen blut und liquor cerebrospinalis bei chronischer niereninsuffizienz. Klinische Wochenschrift, 40,765-772.
SCHWAB,
M. (1962b) Das Saure-Basen-Gleichgewichtim arteriellen blut und liquor cerebrospinalis bei herzinsuffizienzund core pulmonale und seine beeinflussung durch carboanhydrase-hemmung. Klinische Wochenschrift, 40, 1233-1245.
SEVERINGHAUS,
J.W. (1965) Electrochemical gradients for hydrogen and bicarbonate ions across the bloodC.S.F. barrier in response to acid-base balance changes. In: CerebrospinalFluidand the Regulation of Ventilation (Ed. by C. McC. Brooks, F. F. Kao and B. B. Lloyd), p. 247. Blackwell Scientific Publications, Oxford.
SEVERINGHAUS,
J.W. (1968) Outline of H+-blood flow relationship in brain. Scandinavian Journal of Laboratory
and Clinical Investigation, Suppl. 102, VIII :K
B.A. (1964) Cerebrospinal fluid in man native to high altitude. Journal of
SEVERINGHAUS,
J.W. & CARCELEN,
Applied Physiology, 19, 319-321.
SEVERINGHAUS,
J.W. & MITCHELL,
R.A. (1963) Evidence for active transport regulation of cerebrospinal fluid
pH and its effect on the regulation of respiration. Journal of Clinical Investigation, 42,977-978.
SEVERINGHAUS,
J.W., MITCHELL,
R.A., RICHARDSON,
B.W. & SINGER,
M.M. (1963) Respiratory control at high
altitude suggesting active transport regulation of C.S.F. pH. Journal of Applied Physiology, 18, 1155-1 166.
SEVERINGHAUS,
J.W., STUPFEL,
M. &BRADLEY
Jr., A.F. (1956) Variations of serum carbonic acid pK with pH
and temperature. Journal of Applied Physiology, 9, 187-200.
SWANSON,
A.G. & ROSENGREN,
H. (1962) Cerebrospinal fluid buffering during acute experimental respiratory
acidosis. Journal of Applied Physiology, 17, 812-814.
VAN HEIJST,A.N.D. & VISSER,
B.F. (1964). L'Equilibre acido-basique dans le sang et le C.S.F. dans I'hypercapnie chronique. Entretiens de Physiopathologie Respiratoire, 6, 19-22.
VAN SLYKE,
D.D. & NEILL,J.M. (1924) Determination of gases in blood and other solutions by vacuum extraction and manometric measurement. Journal of Biological Chemistry, 61, 523-573.
WELCH,K . (1963) Secretions of cerebrospinal fluid by choroid plexus of rabbit. American Journal of Physiology,
205, 617-624.