JOURNAL
0 I?
APPLIED
Vol. 38, No. 4,
PHYSlOLOFY
April 19 75.
Printed
in U.S.A.
Effects of moderate hypoxemia and hypocapnia on CSF [H+] and ventilation in man J’. A. DEMPSEY, H. V. FORSTER, N. GLEDHILL, AND Pulmonary Physiolugy Laboratory, Department of Prevenfive Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53705
DEMPSEY,
J.
A.,
EL
V.
FORSTER,
N.
GLEDHILL,
AND
G.
We were concerned with the application of these findings and theories to the regulation of ventilatory acclimatization to chronic hypoxemia of “moderate” degree. We recently demonstrated that ventilatory acclimatization to 3,100 m altitude in man (6) and to 3,400 m in ponies (16) was unrelated to the accompanying changes in lumbar (man) or cisternal (pony) CSF pH. That is, both arterial blood and CSF pH after 34 wk at these moderately high altitudes were significantly alkaline to levels obtained in either acute hypoxia or chronic normoxia; and the decrease in [HCO 3-1 and compensation of pH were similar in blood and CSF. We concluded, then, that ventilatory acclimatization to these moderate degrees of hypoxia was not mediated by CSF [H+] st imulation; and postulated that no mechanisms were available under these combinations of hypocapnra and hypoxemia for the “specific” or local regulation of CSF [HCO&J and pH. The present study has examined the independent effects of moderate hypoxemia on CSF pH regulation in healthy man, by contrasting the effects of prolonged hypocapnia alone with those of prolonged hypocapnia plus hypoxemia. Furthermore, the question of a relationship between CSF pH regulation and ventilatory acclimatization was reexplored by comparing the spontaneous ventilation obtained in recovery from each of these imposed conditions,
A.
~oPrco. Effects of moderate hypoxemia and hypocapnia on CSF [H+] and ventilation in man. J- Appl. Physiol. 38(4): 665-674. 1975.--The effects of 26 h of normoxic hypocapnia (Paoo2 , 3 II mmHg) vs. 26 h of hypocapnia + hypobaric hypoxia (Pacon 32, PaOz 57 mmHg) were compared with respect to: a) CSF acid-base status; and 6) the spontaneous ventilation (at P1oz 145 mmHg) which followed the imposed (voluntary) hyperventilation. For each condition of prolonged hypocapnia, Pitoo, was held constant throughout and pH, and [IX0 a-la were constant over the final 6-10 h. We assumed that measured changes in lumbar CSF acid-base status paralleled those in cisternal CSF. Spontaneous hyperventilation followed both normoxic and hypoxic h ypocapnia but was significantly greater following hypoxic hypocapnia. In the CSF, pH compensation after 26 h of hyperventilation was incomplete (~45-50 o/b), was similar to that in arterial blood, and was unaffected by a superimposed hypoxemia. These data were inconsistent with current theory which proposes the regulation of CSF [HCOa-] via local mechanisms and, in turn, the mediation of ventilatory acclimatization to hypoxemia and/or hypocapnia via CSF [II+]. Alternative mediators oi ventilatory acclimatization were postulated, including mechanisms both dependent on and independent of “chemoreceptor” stimuli. ventilatory and severity of hypoxemia
acclimatization; of hypocapnia
dual and
chemoreceptor hypoxemia;
theory; independent
G. A. D~PICO
duration effects
METHODS
of ventilatory ” acclimatization” to prolonged hypoxemia and to acid-base derangements of respiratory origin is well known Mitchell, Severinghaus and colleagues (30, 39) proposed that the mediation of this process was critically dependent upon precise adjustments in cerebroof the despinal fluid (CSF) [H+] d uring the time-course rangement and their accompanying effects on ventilation via medullary chemoreceptors. This theory was based on a combination of three sets of findings: I) the high sensitivity of alveolar ventilation to small variations in CSF [H+] in awake animals (9, 32) and man (10); 2) the relatively precise compensation of CSF [H+] via local regulation of CSF [HCO a-1, as shown experimentally during chronic metabolic acid-base derangements in man and animals (9, 10) and during short-term hypoxemia and/or hypocapnia in anesthetized animals (23); and 3) the conclusion from limited data in healthy man sojourning at 3,800 m altitude, that ventilatory acclimatization was positively correlated to changes in CSF [H+] (39) THE
PROCESS
A total informed and no disease. arterial were all
of eight volunteer male subjects were studied with consent. All had normal resting ECG, chest X ray, previous history or evidence of cardiopulmonary Routine pulmonary function tests and resting acid-base status and hemoglobin concentration within the normal range (Table X)”
Procedures Experimental of acid-base fluid under period, with 745, (P Bhyperventilation PI02- 145, 26-h period
design. The study consisted of an analysis status in arterial blood and in lumbar spinal three conditions: I) A 24- to 26-h control the subject breathing ambient air throughout PIOZ - 145) ; 2) a 26-h period of controlled under ambient conditions (PB 745, and 3) an additional PacOz - 30-33 mmHg); of controlled hyperventilation during simula-
665
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DEMPSEY,
666
Subj
Age, yr
I-It, cm
-.--JJ
22
GB
20
RS l-m L>s 7-R TN
21 24 29 22 22 23
Ri;M
Mea11 GEM
23 ztl .O
Wt, kg
TLC, 1
FEVl.os, 1
--
Single-Breath Hb, DLco, W - g/A; min)/mmHig
79.3 79.8 62.1 65.7 76.2 83.9 61.7 81.6
7.24
4.81
36.1
6.72 6.74 6.61 6.25 6.46 7.08
4.55 4.06 4.70 3.74 4.95 5.53
25.8 38.2 33.3 34.0 30.8 40.2
177 jA.5
73.8 fr3.2
6.73 49.12
4.62 Ito.
15.6 15.4 14.6 13.7 14.0 15.0 14.5 15.5
34.1 14.8 AA .70 zto.3
tion of 3,100 m altitude in a hypobaric chamber (PB 530, PIED - 100, PaGo, - 30-33 mxnHg). In addition, each subject was studied -during spontaneous (uncontrolled) ventilation (PB - 745, PloZ 145) for 1-2 h immediately after each condition of prolonged hyperventilation. Subjects were required to remain awake throughout all sessions. The three conditions were applied in a random order over a total 3.5~mo period. There were some individual exceptions to this standard protocol. Two of the eight subjects were studied for only 17-18 h under each of the three conditions. Of the remaining six subjects, complete data (CSF and blood) in all three 26-h conditions were obtained in five. An attempt was made to standardize conditions and testing protocol throughout the three testing sessions. The subjects spent the evening and night preceding each session in the laboratory. All sessions began between 7: 00 and 9100 A.M. and finished between 1O:OO A.M. and 1200 noon the following day for the 26-h sessions, and between 1: 00 and 2 : 00 A.M. for the 18-h sessions. Both during and for 3 days prior to each session, all subjects were required to follow a standard diet. The diet consisted of 2,400~2,800 total kcal/day with 24 and 35 70 of the total caloric content as protein and carbohydrate, respectively. Fluids (water and “ski& milk) were taken ad libitum throughout each session. Over the course of each of the three sessions no significant variations were observed in body weight, blood glucose, and hemoglobin concentrations or in oral ternperature. Xone of the subjects experienced any detectable symptoms as a result of the hyperventilation or hypoxic exposure. Sump&g procedures. The techniques for anaerobic saxnpling of arterialized venous blood and lumbar spinal fluid under steady-state conditions for ventilation have been described in detail (6). Arterialized blood acid-base status was measured in Z- to 3-ml samples obtained from an indwelling needle in a dorsal hand vein, with the hand heated to 43°C. Details of the sampling procedures and the close agreement between brachial arterial and “ arterialized” acid-base status have been described (14). Brachial arterial blood was sampled under local anesthesia to determine the arterial Pop during the final hour of hypoxic hyperventilation. Lumbar cerebrospinal fluid (CSF) (6-7 ml) was sampled through a Z-gauge needle placed percutaneously under local anesthesia in the fourth intervertebral
GLEDHILL,
AND
DOPICO
over 8-12 breaths space . All blood samples were drawn with the subject in a relative steady state for ventilation as determined by continuous monitoring of end-tidal Pco 2 (PETCOd
180 175 169 177 177 179 179 182
FORSTER,
l
Control of arterial Pco2. Throughout the periods of prolonged hyperventilation Paco2 was controlled between 29 and 33 mmHg in each subject. This level of hyperventilation corresponded to that spontaneously achieved during 1-8 wk sojourn at 3,100 m altitude (5, 6). Each subject achieved and maintained this level of Pace, almost exclusively through voluntary hyperventilation. A negative pressure “ chest-shell” respirator was used sparingly on two occasions to aid the subject in maintaining the desired breathing frequency. Nasal catheters fitted with gas sarnpling lines were attached to the subject throughout each session, which permitted continuous measurement of PETcoz for display on the meter face of an infrared analyzer (to guide th e subject) and on a polygraph recording (to provide a continuous guide for the investigators). During the initial 15-20 min of each hyperventilation session, each subject hyperventilated to a predetermined PETITE and two or three arterialized blood samples were obtained to ensure that the specified PETIT% produced the desired Pacr-, 2. Over the remaining period arterialized blood samples Wf3X 0 btained at hourly int ervals and when necessary, pull sonar Y ventilation . was readj usted to produce the desired The subjects remained in a sernirecum bent or supme position throughout except for the collection of urine samples every 1-2 h. Each collection required a total of 7-10 min including a Z- to 3-min walk at a slow pace during which time the subjects attempted to maintain the hyperventilation. Considerable care was taken throughout the hyperventilation sessions to ensure that the subjects maintained PETIT, at the desired constant level. Almost continuous surveillance of the recorded PETALS together with freq uent verba 1 reminders to the subjects were required to maintain this consistencv as fatigue and boredom becar ne apparent over the final 6-8 h of each session. Recovery periods. Between the 25th and 26th h of each of the three sessions the subject was prepared for the spinal fluid sampling. The PETIT), was continuously monitored and controlled during CSF sampling and three-to-four arterialized blood samples were drawn immediately before and after the spinal puncture. The average values frown these three samples were used to represent the arterial acid-base status at the time of the spinal puncture. For 20-30 min after the spinal tap, PETIT, was maintained at the desired level while one or two additional blood sarnples were obtained with the subject remaining in a supine position. The subject was then informed that the experiment had terminated. The end-tid al sampling aPPa ratus was removed and, in the hypoxic h .yperven til ation condition, the subject was removed from the hypobaric chamber. A recovery period of 1-2 h followed, during which the subject breathed room air spontaneously (Pro2 - 145), in a supine position, with sampling of arterialized blood at 15-min intervals. The subjects remained in an awake but noticeably relaxed state throughout this recovery period.
pacoy
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CSF
[H+]
IN
HYPOCAPNIA
,4ND
667
HYPOXEhW4
of grouped data were tested by conventional, paired t-test analyses (7). Differences which produced J) values TO.05 were accepted as statistically significant. Ninety-five percent confidence intervals for group mean values were calculated using small-sample statistical criteria (11). RESULTS
Time Coum of Blood Acid-BaseChanges
l
pco2CSF
- ( ELECTRODE
FIG. 1. Comparison of manometric and electrode of lumbar CSF Pco2 (N = 33). “Indirect” manometric derived from measurements of COgr and pH. “Direct” determined from electrode measurements (see text).
Analysis
1 -j 4
determinations PCO~
was
PCO~ was
Techniques
Analyses of acid-base status was completed within 6-8 min aft& sampling for CSF and within 15-20 min for blood. Three basic measurements of acid-base status were carried out on all samples : I) CO2 total in CSF in the van Slyke manometric apparatus (48) ; 2) pH and PCO~ with conventional electrodes (Radiometer, Copenhagen) (at 37.0”(Z), calibrated with tonometered blood of known PCOZ and tonometered artificial CSF of known PCO~and [HCOJ ; and 3) lactic acid concentration in plasma and CSF by a modified colorometric technique (1). In addition, in vitro “buffer slopes” of blood and CSF (A log Pco,,‘A pH) f or each subject were obtained by microtonometry. A previous report has detailed these analytic procedures and includes a quantitative description of acidbase measurement validity and reproducibility (6).
A trend for the time course of arterial Pcoz and pH over the 26 h of each condition was estimated by averaging 15-25 values at each 2-5-h interval (Fig. 2). a) Throughout the control condition no systematic variations in Pacoz or pH, were observed. Mean [HCO& varied between 24 and 25 meq/l throughout the control session. b) PacOa was controlled at 30-33 mmHg throughout each session of prolonged voluntary hyperventilation. A small, yet systematic, increase of approximately 1 mmHg Pcoz was evident in each session over the final 9-12 h. Mean Pacoz was 0.5-l .5 mmHg higher during the hypoxic hyperventilation condition, but these differences were not significant. c) Arterial pH rose immediately at the onset of hyperventilation, remained unchanged further (in normoxia) or fell slightly (in hypoxia) during the initial 12-14 h, and was reduced to within 0.03-0.05 units of normocapnic control levels over the final 6-10 h of hyperventilation. Blood und CSF )H Regulation The acid-base status of arterial blood and CSF under control conditions and at the 26th h of each hyperventilation session is shown in Tables 2 and 3. The changes in acid-base status between control and hyperventilation conditions are described. All references tY grouz) mean U
Calculations Calculations of [ HCO 3-1 in blood and CSF used published values for pKI and/or COP solubility (31). All reported values of CSF Peon, pH and [HCOZ-] for each subject represent the average of values obtained by manometric and electrode measurements. Figure 1 compares these two techniques with respect to CSF Peon. Total pH compensation in arterial blood and in CSF achieved as a result of prolonged hyperventilation was calculated after Siesjij (41)
7-50
7-45
% pH compensation =
A (pH at 26 h hyperventilation-maximum A (control pH-maximum pH)
pH)
7-40
x
100
--L~--i-1 0
“Maximum” pH represents that pH achieved if the system contained only the [HCOZ-] - H&OS buffers and could not exchange ‘[Hi-l or [HCO3-1 ions with its environment. Maximum UPH was calculated; then, using the [HCOZ-] observed under control conditions and the Pcoz observed at + 26 h of each hyperventilation session. Statistical probability of differences between the means
1
5
I5
to
20
I
I
I
I
I
i
I
J
25
HOURS 2. Time course of changes in arterial pH and Pco2 in control conditions and during 26 h of voluntary hyperventilation in normoxia and hypobaric hypoxia. Plotted values are mean j, 95% confidence interval (N = 8). Vertical arrows designate the time of lumbar fluid sampling in all three conditions (see METHODS). Extreme right-hand panel is the “recovery period” of spontaneous ventilation and is shown in detail in Fig. 4. FIG.
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668 TABLE
DEMPSEY,
2. Arterial
blood and lumbar spinal fluid acid-base status: individual Subj
Control (+26 h), ,- 745, PIoIl P 14:)
JJ Gl3 RS RO m TR TAq RMS
50.0 47.8 50.0 51.5 49.4 51 .o 50.7 48.5
Arterial Lactate
PI-I
49.7 &0.6
24.6 zto.2
1.58 +0.07
7.365 7.380 7.351 7.363 7.395 7.328 7.325 7.310
41.3 43.1 42.7 43.1 39.0 45.5 46.5 47.6
22.8 23.7 22.3 22.9 22.8 23.1 23.2 22.9
1.70 1.63 1.92 1.79 1.74 1.47 2.17 1.75
7 -434 7.472 7.449 7 -437 7.448 7.444 7.431 7.440
7.370 Ito -008
41 A ztO.8
22.9 +0.2
1.75
7.411 7.364 7.339 7.356 7.391 7.353
37.1 41.5 41.7 42.1 38.4 44.5
22.8 22.3 21.7 22.5 22.5 23.6
7.372 Ito.
40.2 -41 .o
P
O.lO>
+0.27 zto.09 ( 0.05 >O.lO
>o. 10 >O.lO
>0.05
o. >o.
Pt
>O.lO
>0.05
10 10
40 1
ALK. 1 /4-{RECOVERY II t y/L---q. --u---L +23 24 25 26 I5
HOURS
60
-52-z
4. Changes in arterial Pc&@n exfwimentat and control conditions after prolonged hyperventilation --.--. ---- -----
TABBET;
Recovery Subj
Mean
Post R alk
JJ GB BS RO DS
33.1 37.4 35.5 37.0 35.6
TR
PaGo.,* Post R AIB + hypox
&EM
A Pacot Post
from ConErol R alk
35.9
32.6 33.0 32.6 31.8 37,2 33.1
-6.1 -0.5 -3.6 -5.5 -3.7 -2.9
35.8
33.4
-3.7 (P < 0.05) bl.8
zt0.6
ho.8
Post R alk + hYPox -6.6 -4.9 -6.5 -10.7 -2.1 -5.7 -611 ztI.1
APacOs from Hnervent “A Post
R alk
+2.0 +6.9 +4.1 +4.8 +3.8 +4.9
-/- 26 h Post R Alk + bpox +1,8 +0.3 +1.2 +1.1 +2.8 t-1.4
-54.4 (P < 0.01) zto.7
+r
.5
hO.4 -.-~
T
I
I
1
PCO, (mmHgr1 40
50
30
FIG. 3. pH compensation in arterial blood and CSF as a result of prolonged normoxic and hypoxic hyperventilation. “Maximum” pH values were calculated using PCO~ obtained with each of the hyperventilation conditions and the [HCOS-] obtained in control conditions METHODS).
45
FIG. 4. Group mean changes in arterial PCOS while breathing spontaneously (Pro2 145 mmHg), after 26 h of normoxic and hypoxic hyperventilation (iv = 6). Measurelnents were obtained and averaged at 15-min intervals during the first hour following prolonged hyperventilation.
* Recovery PacOa (mmHg) refers to the mean of two to three ments per subject obtained during spontaneous ventilation (Pr o2 30 and 60 min after 26 h of normoxic and hypoxic hyperventilation.
-
Paco2 measure145) between
that (physicochemical) buffering accounted for 50 to 60 % of the total pH compensation in blood, but a negligible amount in CSF (< 5 %). Recovery of Arterial
(See
30
MINUTES
(P < 0.05)
7 3o
50
PERIOD(F~~~l45)~----)/
/
Y
/ 1 J -,30 I ’ -
tRESP
30
+o .44 AO.12
Pco2 in mmHg; [HCOa-] and Iactic acid concentration in meq/l. * These P values refer to the differences between CSF and arterial blood. 1 These P values refer to the effect of each of the conditions on the differences between CSF and arterial blood. I
40
Pco:!
After Prolonged
Hyperventilation
The average and individual subject changes in PacOp while breathing spontaneously (Pro2 145), during 1-2 h recovery from prolonged normoxic and hypoxic hyperventilation, are shown in Fig. 4 and Table 4 (N = 6). a) At 15 min of recovery group mean PaGo rose 3 mmHg (P < 0.05) following 26 h of normoxic hyperventilation but remained unchanged from 26-h values following hypoxic hyperventilation (t-O.3 mmHg, P > 0.10). The immediate rise in Paco2 was evident in all six subjects following the normoxic hyperventilation. After hypoxic hyperventilation, only two of the six subjects showed a measurable increase in Pace, (+ 1.5 and +Z.O mmHg) above 26-h values. b) At 30 min of recovery from both conditions of hyperventilation, group mean Pace 2 rose further but showed no further systematic changes throughout the remaining 30-W min of study. Three of the twelve individual recovery curves (not shown)-two following normoxic and one
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670
DEMPSEY,
following hypoxic hyperventilation-showed a continuous rise in PacOz throughout the recovery periods. c) Arterial PCO~ measurements obtained during the relatively stable period at +30 to 60 min of recovery were used to quantify the differences between the two conditions (Table 4). i) PacoZ remained significantly below control values during recovery from both conditions of prolonged hyperventilation. However, the recovery of Pace., toward control levels was significantly more complete following normoxic than hypoxic hyperventilation. ii) Considering the slightly higher level of PacOz obtained in the final hour of normoxic over hypoxic hyperventilation, the most meaningful assessment of the relative amounts of spontaneous hyperventilation was the change in Pacod, between the end of voluntary hyperventilation and +30 to 60 rnin of recovery (Table 4, final 2 columns). In five of the six subjects, the increase in PacOz after normoxic hyperventilation exceeded that following hypoxic hyperventilation. DISCUSSION
Thwy
and Fz’ndings
The data showed that spontaneous hyperventilation persisted after a prolonged period of imposed hyperventilation and hypocapnia, and that the degree of spontaneous hyperventilation was significantly increased when hypobaric hypoxia was superimposed over the duration of the period of voluntary hyperventilation. This ventilatory acclimatization to prolonged hypocapnia has been shown previously in awake man using either passive or active means of hyperventilation, and the magnitude of the spontaneous hyperventilation appeared to be somewhat dependent upon the severity of the imposed hypocapnia (2, 4, 8, 28, 45). The independent effects of a superimposed hypoxia on spontaneous hyperventilation were also demonstrated by Eger et al. (8) in terms of an augmented leftward shift in the CO2 response curve. Somewhat analogous to this effect is the observation commonly reported at high altitude, where hyperventilation continues at a slightly reduced level when the acclimatized subject is acutely returned to sealevel normoxia (5, 13, 39). The current explanation for each of these observations has focused on the local regulation of CSF [HCOS-1, with stimulation of chemoreceptors near the medullary surface via CSF [H+] as the mediator of ventilatory acclimatization (30, 39). For example, during prolonged hypocapnia it is suggested that CSF [HCOS-] is reduced to the point where CSF pH is returned to normal or to near-normal control levels. Then, when the primary stimulus to the prolonged hyperventilation-in this case a voluntary act-is removed, PCO~ rises immediately in arterial blood and in turn in CSF. The resultant fall in pH below normal control levels in the poorly buffered CSF elicits the added stimulus for the observed spontaneous hyperventilation which persists, possibly for many hours, until CSF [HCOS-] and pH are restored to normal. In turn, the explanation for the additional or independent effects of the superimposed hypoxia on spontaneous hyperventilation is identical-except that the CSF [HCOS-] would have fallen further during hypoxic than normoxic hypocapnia because of the ac-
FORSTER,
GLEDHILL,
AND
DOPICO
companying hypoxemia and cerebral tissue hypoxia. Hence, CSF pH would be relatively more acid both at the end of the prolonged hyperventilation period and during spontaneous hyperventilation in recovery. This explanation largely depends on the following basic premises 1) that the decrease in CSF [HCOS-] in prolonged hypocapnia is primarily regulated by local mechanisms-such as an active transport of [HCOS-] from CSF to capillary plasma (39)-which are suficient to return CSF [H+] to normocapnic control levels, and 2) that a superimposed hypoxemia exerts additional local regulatory effects, independent of hypocapnia alone-such as a cerebral lactacidosis (46)-which results in even greater reductions in CSF [HCO 3-1. These basic premises were not supported by present findings. That is, the finding that reductions in CSF [HCOs-] did not exceed those in plasma in either normoxic or hypoxic hypocapnia is inconsistent with the concept of a significant contribution to CSF [HCOZ-] regulation via local mechanisms, and a superimposed hypoxemia showed no independent effect on pH compensation in the CSF. The result was, that at the end of prolonged hyperventilation, CSF and plasma pH remained significantly alkaline to normocapnic control values. Hence, contrary to theory, the spontaneous hyperventilation which persisted during the “recovery” periods was not attributable to the corresponding degree of [HCOZ-] regulation or pH compensation in CSF which occurred during the preceding conditions of controlled hypoxemia and/or hypocapnia. Th e present st u d y represents a more direct testing of current theory, regarding CSF chemoreceptor mediation of ventilatory acclimatization to hypoxemia and/or hypocapnia, than has previously been reported. On the other hand, interpretation of the data is restricted by both the narrow scope of the experimental design and the methods used. Limitations Use of lumbar CSF. Our study required the assumption that the observed changes in lumbar CSF acid-base status with normoxic and hypoxic hyperventilation reflected the changes in cisternal CSF. With this in mind, the study was designed to provide minimum periods of 25 h constant hypocapnia (and hypoxemia) and 6-10 h of fairly constant arterial blood pH and [HCO 3-1, prior to the spinal fluid sampling. Two types of findings are relevant to the application of the assumption to these experimental conditions. 1) [HC&-] was similar in cisternal and lumbar CSF both in healthy subjects and in acid-base disorders which were 5 24 h in duration (12, 17, 37). Furthermore, changes in lumbar CSF [HCOJ p aralleled those in cisternal CSF during l-6 h of induced metabolic acidosis or alkalosis in dog (33) and man (36). Pcos and pH in the ‘%teady-state” of health or disease were significantly different between the two compartments, i.e., the Pco2 was -1-3 mmHg higher and the pH -0.02-0.04 units lower in the lumbar CSF (12, 17, 37). H owever, changes in lumbar CSF pH have been shown to parallel those in cisternal CSF during primary metabolic acid-base derangements and in patients 24 h after initiating a variety of moderate changes in
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CSF
[II+]
IN
HYPOCAPNIA
AND
671
HYPOXEMM
systemic acid-base balance (37; F. Plum, personal communication). These reports and others (3) have emphasized the importance to this parallelism of achieving “steadystate” levels for Pace,, prior to the spinal fluid sampling. Finally, it has recently been shown in the anesthetized dog (18) that 6 h of hypocapnia (Pacog - 19 mmHg) with controlled levels of constant arterial [HCOS-] and pH, resulted in nearly identical changes in cisternal and lumbar CSF pH, Pcoz, and [HCOa-1. 2) Changes in cisternul CSF ;bH and [HCO 3-1 were not different from those in arterial blood after 7-16 h of “ modcrate” hypocapnia or hypoxemia in anesthetized dogs (19, 20, 34) and after 6-24 h exposure to 3,400 m altitude in awake ponies (16). These findings in cisternal CSF were consistent with those presently found in lumbar CSF in man under conditions of nearly identical combinations of hypoxemia and/or hypocapnia. After 3-5 wk sojourn to 3,100 m the changes in lumbar CSF pH and [HCOa-] bore a relationship to corresponding changes in arterial blood which was similar to that presently found after 26 h simulation of these exposure conditions (6) (see below). In summary, the avilable evidence supports our assumption of parallel changes in lumbar and cisternal CSF [HCOS-] after 26 h of relatively moderate hyperventilation. Extension of this assumption to changes in CSF PCQ and pH also appears justified from data in experimental animals but is based on less comprehensive findings in man. Xo direct evidence was available on the question of whether a superimposed hypoxemia might violate this assumption; but comparisons of data obtained in man and pony were consistent with the premise that changes in lumbar CSF pH after 26 h of moderate hypoxemia and hypocapnia reflected those in cisternal CSF.’ Duration of hypocupniu and hyfioxemia. It is clear that 26 h of hyperventilation cannot be classified as a truly ” chronic” condition of change. It may be argued, then, that longer durations of hypoxemia and/or hypocapnia would have confirmed current theories, i.e., CSF pH would have been completely compensated and, in turn, positively related to the spontaneous hyperventilation in recovery. Certainly the duration of change is important to acidbase regulation, as shown by the findings that 3-5 wk exposure to 3,100 m altitude (6) resulted in a more complete compensation of CSF pH (66 & 8 %) than was presently observed after 26 h exposure (50 =t: 9 “r,). However, the elf‘ects of chronic exposure conditions do not contradict the key points of disagreement with current theory concerning ventilatory acclimatization. That is, after 3-5 wk at 3,100 m, the decrease in [HCOS-] and compensation of 1.Theoretically, the superimposed hypoxemia may have violated the assumption of parallel changes in lumbar and cisternal CSF Pco:! (and PI-I) : a) if the hypoxemia caused an acute increase in cerebral blood flow (CBF) and thereby a fall in brain ISF Pcoe which exceeded that in cisternal CSF (38) ; and b) if this acute decrease in ISF PCOZ required periods of steady-state hypoxemia longer than 26 h before it was reflected in cisternal and lumbar CSF. It seems unlikely that these circumstances occurred: a) 10 min to 1 h of arterial hypoxemia in the range of SO-60 mmHg Paoz causes no significant change in CBF or in the jugular venous to arterial difference for Pco:! (6, 22, 40) ; and b) the duration of hypoxic exposure extended well beyond the acute period when any effects of a changing CBF on the disequilibrium between ISF and CSF Pcoz would be maxi11111111(38). L
pH was not different between arterial blood and CSF, CSF pH still remained significantly alkaline (to sea-level control values), and changes in CSF pH bore no positive relationship to ventilatory acclimatization. Concerning this latter point, it is also relevant to point out a) that the during spontaneous small increases in obtained hyperventilation after 26 h of hypoxic hyperventilation were similar in magnitude to those observed when acute normoxia was imposed during l-8 wk acclimatization to 3,100 m altitude (5, 13); and b) that even periods of irnposed hypocapnia as brief as 6 h duration were shown by Eger et al. (8) to produce marked aftereRects on spontaneous ventilation. Seuerily of 1lypoxemiu und hyfiocupniu. Contrary to our findings in moderate hypocapnia and hypoxemia, experimental data in anesthetized animals studied over 6-10 h have clearly demonstrated that more severe hypocapnia (< 20 mmHg PacO,) (21, 23, 34, 35, 49) or hypoxemia ( ” Extrachemoreceptors. ” Potential mediators of ventilatory acclimatization which might operate independently or even in spite of brain [H+] levels are numerous and almost completely unexplored (15, 47). Some indirect findings in man have been reported in support of a purely mechanical effect of prolonged hyperventilation, possibly dependent on an aff‘erent pathway originating in lung and/or chest wall receptors (44). During prolonged exposure to hypoxia, preliminary findings in the decerebrate cat point to facilitory suprapontine influences on medullary control centers as a potential contributor of significance to ventilatory acclimatization (47). Currently available knowledge does not permit any quantitation of the relative contributions of these postulated mechanisms as mediators of ventilatory acclimatization. Indeed, even the existence of such mechanisms is based on only limited evidence. We can, then, only postulate on the basis of present findings that the effects of prolonged hypocapnia and the independent effects of a superimposed hypoxemia on ventilatory acclimatization are mediated by a more complex scheme of mechanisms than that originally proposed by the dual CSF + arterialchemoreceptor theory.
pacogc;;;n--I : 1
RESP. AM.
30-
:23P
24I 25’
i k----[RECOVERY I t 15 I
Pm00
301
451
~PIO~145#---~
601
,
T
HOURS
j
MINUTES
FIG. 5,. Estimated CSF pH during the “recovery” periods of spontaneous ventilation. i\t any point in time during “recovery,” CSF pH was estimated by assuming that 1) CSF [HCOZ-] remained equal to that obtained at the 26th h of each hyperventilation session; and 2) that CSF Pcoz was changed from 26-h values by an amount equal to the corresponding change in arterial Pco~. CSF pH during recovery would have been Q) lower than shown here if CBF had fallen during “recovery” (see text); or /I) higher than shown here if either CBF or CSF [HCOS-] had risen during “recovery.”
CSF pH between the end of voluntary hyperventilation and the recovery period were determined solely by the influence of a rising Pace, (see legend to Fig. 5). These estimates of CSF pH were not positively correlated to the accompanying levels of spontaneous hyperventilation, i.e., the CSF pH remained alkaline or equal to normocapnic control values after normoxic hyperventilation and even more alkaline after hypoxic hyperventilation. However, as PacOz and Paoz increased during “recovery,” it is likely that changes occurred in CBF (38) and therefore in the CSF-to-arterial difference for Pco 2. Accordingly, appropriate changes in CSF [H+] would have accompanied the spontaneous hyperventilation in recovery; if the rise in CSF Pcoz exceeded the rise in PacOz, secondary to immediate and progressive reductions in CBF.2 Reported findings are not consistent with this hypothesis, e.g., acute changes in CBF from Pacoz 55-60 mmHg to normoxia are not accompanied by significant changes in CBF (6, 22, 40) and the rise in Paco2 after both normoxic and hypoxic hyperventilation would, if anything, be associated with a slight increase in CBF (38) and therefore an even more hypocapnic and alkalotic CSF pH than shown in Fig. 5. Furthermore, it has been shown that, after a step change in Pacop a new steady-state for cisternal CSF PCO~is not reached before 10 (24) to 25 min (3). This evidence also points to lower PCO~ and higher pH in CSF-at any point in time during ~recovery”than the estimates shown in Fig. 5. It does not appear, then, that appropriate adjust2 The required increases in the CSF to arterial difference from the 26-h values to + 15 min recovery, were +2.2 +20y0) after normoxic hypocapnia and +5.4 mmHg after hypoxic hypocapnia. These changes would yield CSF pH at +I5 min recovery which were ~0.01 and respectively, below mean control values.
for Pco~, mmHg (or (or +65%) values for 0.015 units,
It is a pleasure to acknowledge the expert technical assistance provided by Ms. Deborah Grouse, Ms. Jean Vaughn, Ms. Monique Buehnlann, and Mr. David Scherr. We are indebted to Dr. John Rankin and to Dr. Eric Kindwall and his staff (St. Luke’s Hospital, Milwaukee, Wis.) who so generously provided facilities for this study. Ms. Helena Andersson provided invaluable assistance in the preparation of the manuscripts. This study was supported in part by grants from the k\merican Lung Association, National Institutes of Health (1 -RO 1 -HI, i546’3), and the Wisconsin Heart Association. This work was presented in part at the Federation of American Societies for Experimental Biology National Meeting, Atlantic City, N. J., April 1973. H. V. Forster and N. Gledhili were National Institutes of Health Graduate Trainees. Received
for
publication
26 July
1974.
3 These required changes in [HC08-] were based on control values estimated from Siesjo’s data for intracellular (ic) pH and [HCO:i-] in rat brain (43). con&ol: 7.04 pH, 12.0 [HCO,-j and 47.7 Pco:!;. normoxic hypocapnia: Pcoz fell 7.9 mmHg and to maintain pHi, at 7.04, [HC03jic would be 10.0 meq/l; hypoxic hypocupnia: Pco:! fell 9.5 mmHg and to bring pHi, to 7.03, [HCOz*]ic would be 9.4 meq/l. It is assumed here that observed changes in CSF PCOZ approximated those in intracellular Pcog (43).
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
CSF
[H+]
IN
HYPOCAPNIA
AND
673
HYPOXEMM:A
REFERENCES 1. BARKER,
18.
S, B., AND W. H. SUMMERSON. The calorimetric determination of lactic acid in biological material. J. Biol. Chem. 35: 535-541, 1941. BOOTHBY, W. M. Absence of apnoea after forced breathing. J. Physiol., Lmdon 45: 328-334, 1912. BRADLEY, R. D., AND S. J. G. SEMPLE. A comparison of Certain acid-base characteristics of arterial blood, jugular venous blood and cerebrospinal Auid in man, and the effect on them of some acute and chronic acid-base disturbances. J. physiol., London 160: 381-391, 1962. BROWN, E. B., G. S. CAMPBELL, M. N. JOHNSON, A. HEMINGWAY, AND M. B. VISSCHRE. Changes in response to inhalation of CO2 before and after 24 hours of hyperventilation in inan. J. &$Z. Physiol. 1: 333-338, 1948. DEMPSEY, J. A., H. V. FORSTER, M. L. BXRNBAUM, W. G. REDDAN, J. THODEN, R. F. GROVER, AND J. RANKIN. Control of exercise hyperpnea under varying durations of exposure to moderate hypoxia. Respiration Physiol. 16: 213-231, 1972. L)EMPSEY, J. A., H. V. FORXER, AND G. A. DOPICO, Ventilatory acclimatization to moderate hypoxemia: role of spinal fluid [H+j. J. C&n. Invest. 53: 1091-l 100, 1974. EDWARDS, i-1. L. Statistical bfethods for the Behavioral Sciences. New York : Rinehart, 1954. EGER, E. I., R. H. KELLOGG, A. H. MINES, M. LIMA-OSTOS c. E. ~/~ORILL, AND D. W. KENT. Influence of CO2 on ventila-, tory acclimatization to altitude. J. A#. Physiol. 24: 607-6 15, 1968. FENCL, V., T. B, MILLER, AND J* R, PAPPENHEIMER. Studies on the respiratory response to disturbances of acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid. Am. J. Physiol. 200 : 459-472, 1966. FENCL, V., J. R. VALE, AND J, A. BROCH. Respiration and cerebral blood flow in metabolic acidosis and alkalosis in humans. J. Appl. Physiol. 27 : 67-76, 1969. FERGUSON, G. A. Statistical Analysis in Psychology and Education, New York: McGraw, 1959. FISHER, V. J ., AND L. C. CHRISTIANSON. Cerebrospinal fluid acidbase balance during a changing ventilatory state in man. J. A#. Physiol. 18: 712-716, 1963. FORS'I'ER, H.V,,J. &DEMPSEY, M.L. BIRNBAUM, W. G. REDDAN, J- THODEN, R. F. GROVER, AND J. RANKIN. The effect of chronic exposure to hypoxia on ventilatory response to CO? and hypoxia. J, A@[. Physiol. 31: 586-592, 197 1. FORS~ER, J3. V., J+ A. DEMPSEY, J, THOMSON, E. VIDRUK, AND G. A. DOPXCO. Estimation of arterial Paz, Pco~, pH, and lactate from arterialized venous blood. J. A#. Physiol. 32 : 134-137, 1972. FORSTER, H.V.,J.A. DEMPSEY&H. VIDRUK,AND G. A. DOPICO. Evidence of altered regulation of ventilation during exposure to hypoxia. Respiration Physiol. 20 : 379-392, 1974. FORSTER, H. V., L. HAMILTON, AND J. WILL. Effect of altitude sojourn (3400112) on ventilation and CSF and arterial acid-base status (Abstract). Federation Proc. 32 : 857, 1973. HEIJS’~ A. N. P. VAN, A. H. J- MAAS, AND B. P. VISSER. Comparison of the acid-base balance in cisternal and lumbar cerebrospinal fluid. PJuegers Arc/z. 287 : 242-246, 1966. HORNBEIN, T. F., AND E. G. PAVLIN. Distribution of [H’] and
19.
[HCOs-] between CSF and blood during respiratory in dogs. Am. J. Physiol. 228: 393-394, 1975. KAZEMI, H., D. C. SHANNON, AND E. CARVALLO-GIL.
2. 3.
4.
5.
6.
7. 8.
9,.
10.
11. 12.
13.
14.
15.
16,
17.
buffering Physiol. 20.
KAZEMI, Brain ApPl.
21.
22.
capacity 22 : 241-245,
H.,
organic Physiol.
in
respiratory 1967.
acidosis
and
23. 24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
34.
35. 36.
37.
1343-1351, 38. 39.
J.
CO2 41.
N.
S. SHORE, V. E. buffers in respiratory 34 : 478-482, 1973.
SHIH, AND D. acidosis and
SIESJ~,
42. 43.
Intern. SIE~@,
1969.
44.
AND
R,
J. .Ajt$d.
Busru. f%ysioZ.
P. SCHEINBERG, i&lechanisms 29:
223-229,
M. P. REINMUTI~, of cerebral vasodilation 0.
1970,
J. RUJISHIMA, in hypoxia. 45.
B.
RICHARDSON,
W.
control at high altitudes of CSF pH. J. ApPl.
166, 19fj3. W. h., J. WASSERMAN, J. P. BAKER, AND SON. Cerebrovascular response to acute hypocapnia
AND B. K. Smqij. The regulation KJALLQUIS~, A., M. NARDINI, of extraand intracellular acid-base parameters in the rat brain during hyperand hypocapnia. Acta Physiol. &and. 76: 485-4-94, K.,
London:
sugl?zysioE.
1155-l
1971. Sr~s~ii,
KOGURE,
MITCHELL,
SHAPIRO,
in 8,
normal Quantification
hypocapnia
C. SHANNON. alkalosis. J.
circulation.
1972,
hypoxia
&$.
of the cerebral
physiology
p. 2 15-2 16. SEVERXNGHAUS, J. W., R. ;\. AND M. M. SINGER. Respiratory gesting active transport regulation 18:
40.
alkalosis.
1973.
PURVES, M. J. The Cambridge,
alkalosis Brain
LEUSEN, I. Regulation of cerebrospinal fluid with reference to breathing. physiol. Rev. 52 : l-56, 1972, LOESCHCKE, H. H., AND K. SUGIOKA. pH of the cerebrospinal fluid in the cisterna magna and on the surface of the choroid plexus of the 4th ventricle and its effect on ventilation in experimental disturbances of acid-base balance; transient and steady states. Pjuegers Arch. 3 12: 161-188, 1969. LIPSCOMB, W. T., AND I. L. BOYARSKY. Neurophysiological investigation of Medullary chemosensitive areas of Respiration. Respiration Physiol. 16 : 362-376, 1972. MACMLLLAN, V., AND B. K. SIESJ~. The influence of hypocapnia upon intracellular pH and upon some carbohydrate substrates, amino acids and organic phosphates in the brain. J. Neurochem. 21: 1283-1299, 1973. MACMILLAN, V., AND B. K. SIESJ~. Intra-cellular pH of the brain in arterial hypoxemia, evaluated with the GOa method and from the creatine phosphokinase equilibrium. &and. J. Clin. Lab. Invest. 30 : 117-125, 1972. MILLS, J . N. Hyperpnea induced by forced breathing. J. Physiol., London 45: 328-334, 1912. MINES, -4. H., AND S. C. S@RENSEN. Changes in the electrochemical potential difference for HCOZbetween blood and CSF and in CSF lactate concentration during isocarbic hypoxia. Acta Physiol. &and. 8 I : 225-233, 197 1. MITCHELL, R. A., C. T, CARMAN, J. W. SEVERINGHAUS, B. W. RICHARDSON, h/r. M. SINGER, AND S. SCHNIDER. Stability of cerebrospinal fluid pH in chronic acid-base disturbances in blood. J. A$#. Physiol. 20: 443-452, 1965. MITCHELL, R. A., D. A. HERBERT, AND C. T. CARMAN. Acid-base constants and temperature coefficients for cerebrospinal fluid. J. A@ Physiol. 20 : 27-30, 1965. PAPPENHEIMER, J. R., V. FENCL, S. R, HEISEY, AND D. HELD. Role of cerebral fluids in control of respiration as studied in unanesthetized goats. Am. J. Physiol. 208: 436-450, 1965. PAVLIN, E. E., AND T. F. HORNBEIN. Regulation of CSF (H+> and HCOZin metabolic acidosis (Abstract). Federation Proc. 32 : 856, 1973. PELLIGRINO, D. A., C. G. IRVIN, S. M. MASTENBROOK, AND J. A. DEMPSEY. Dependence of CSF (H+) regulation on plasma (HCO3-) in respiratory alkalosis and hypoxemia (Abstract). Federation Proc. 33 : 1369, 1974. PLUM, F., AND J. B. POSNER. Blood and cerebrospinal fluid lactate during hyperventilation. Am. J. Physiol. 2 12 : 864-870, 1969. Inhomogeneity of cisternal and PLUM, F., AND J. B. POSNER. lumbar CSF acid-base balance during acute metabolic alterations in CBF and CSF (Abstract). &and. J. C&n. Lab, Invest. SupPl. 102: lB, 1968. PLUM, F., AND R. W. PRICE. Acid-base balance of cisternal lumbar cerebrospinal fluid in hospital patients. Iv. Engl. J. Med. 289:
man.
(Editorial). 13. K.
The
J. C/in. blest. of pli regulation &and.
J.
regulation
1 : 360-374, 1972. B. K. hletabolic
G&n.
of
control
J. L. PNYTERand eucapnic
Lab.
cerebrospinal of intracellular
Invest.
artificial ,A. C.,
ventilation. [. M. K.
and
28 : 1 13-l
fluid ~1-1
&and, J. Gin. Lab. Incest. 3 1 : 97-104, 1973. SMITH, A. C., J‘. M. K. SPALDING, AND W. E. WATSON. tion volume as a stimulus to spontaneous ventilation longed SMITH,
1970.
49 : 2362-2368, in hypercapnia
pl-1.
15,
Kidney
(Editorial).
Ventilaafter
pro-
J. Physiol.,
SPPALIIING,
London 160: 22-27, 1962. AND W. E. WATSON. CO2 as
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
674
46.
47.
DEMPSEY, stimulus to spontaneous ventilation after prolonged artificial ventilation. J. Physiol., London 160 : 27-3 1, 1962. Effect of cerebral S#RENSEN, S. C., AND J. Wm SEVERXNGHAUS. acidosis on the CSF-blood potential difference. Am. J. Physiol. 219: 68-71, 1970. TENNEY, S. M., P. SCOTTO, L. C. Ou, D. BARTLETT, AND J. E. REMMERS. Suprapontine influences on hypoxic ventilatory control In : High Altitude Physiology-Curdiac and Respiratory Aspects,
48.
49.
FORSTER,
GLEDHILL,
AND
DOPICO
edited by R. Panter and J. Knight. Edinburgh 8L London: Churchill-Livingstone, 197 1. VAN SLYKE, D. D. Studies in acidosis: Method for determination of carbon dioxide and carbonates in solution. J. Biol. Chem. 30: 347-354, 1917. VAN VAERENBERGH, P. J. J., G. DEMEESTER, AND J. LEUSEN. Lactate in cerebrospinal fluid during hyperventilation. Arch, Intern. Physiol. 73 : 738-745, 1965.
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0 I?
APPLIED
Vol. 38, No. 4,
PHYSlOLOFY
April 19 75.
Printed
in U.S.A.
Effects of moderate hypoxemia and hypocapnia on CSF [H+] and ventilation in man J’. A. DEMPSEY, H. V. FORSTER, N. GLEDHILL, AND Pulmonary Physiolugy Laboratory, Department of Prevenfive Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53705
DEMPSEY,
J.
A.,
EL
V.
FORSTER,
N.
GLEDHILL,
AND
G.
We were concerned with the application of these findings and theories to the regulation of ventilatory acclimatization to chronic hypoxemia of “moderate” degree. We recently demonstrated that ventilatory acclimatization to 3,100 m altitude in man (6) and to 3,400 m in ponies (16) was unrelated to the accompanying changes in lumbar (man) or cisternal (pony) CSF pH. That is, both arterial blood and CSF pH after 34 wk at these moderately high altitudes were significantly alkaline to levels obtained in either acute hypoxia or chronic normoxia; and the decrease in [HCO 3-1 and compensation of pH were similar in blood and CSF. We concluded, then, that ventilatory acclimatization to these moderate degrees of hypoxia was not mediated by CSF [H+] st imulation; and postulated that no mechanisms were available under these combinations of hypocapnra and hypoxemia for the “specific” or local regulation of CSF [HCO&J and pH. The present study has examined the independent effects of moderate hypoxemia on CSF pH regulation in healthy man, by contrasting the effects of prolonged hypocapnia alone with those of prolonged hypocapnia plus hypoxemia. Furthermore, the question of a relationship between CSF pH regulation and ventilatory acclimatization was reexplored by comparing the spontaneous ventilation obtained in recovery from each of these imposed conditions,
A.
~oPrco. Effects of moderate hypoxemia and hypocapnia on CSF [H+] and ventilation in man. J- Appl. Physiol. 38(4): 665-674. 1975.--The effects of 26 h of normoxic hypocapnia (Paoo2 , 3 II mmHg) vs. 26 h of hypocapnia + hypobaric hypoxia (Pacon 32, PaOz 57 mmHg) were compared with respect to: a) CSF acid-base status; and 6) the spontaneous ventilation (at P1oz 145 mmHg) which followed the imposed (voluntary) hyperventilation. For each condition of prolonged hypocapnia, Pitoo, was held constant throughout and pH, and [IX0 a-la were constant over the final 6-10 h. We assumed that measured changes in lumbar CSF acid-base status paralleled those in cisternal CSF. Spontaneous hyperventilation followed both normoxic and hypoxic h ypocapnia but was significantly greater following hypoxic hypocapnia. In the CSF, pH compensation after 26 h of hyperventilation was incomplete (~45-50 o/b), was similar to that in arterial blood, and was unaffected by a superimposed hypoxemia. These data were inconsistent with current theory which proposes the regulation of CSF [HCOa-] via local mechanisms and, in turn, the mediation of ventilatory acclimatization to hypoxemia and/or hypocapnia via CSF [II+]. Alternative mediators oi ventilatory acclimatization were postulated, including mechanisms both dependent on and independent of “chemoreceptor” stimuli. ventilatory and severity of hypoxemia
acclimatization; of hypocapnia
dual and
chemoreceptor hypoxemia;
theory; independent
G. A. D~PICO
duration effects
METHODS
of ventilatory ” acclimatization” to prolonged hypoxemia and to acid-base derangements of respiratory origin is well known Mitchell, Severinghaus and colleagues (30, 39) proposed that the mediation of this process was critically dependent upon precise adjustments in cerebroof the despinal fluid (CSF) [H+] d uring the time-course rangement and their accompanying effects on ventilation via medullary chemoreceptors. This theory was based on a combination of three sets of findings: I) the high sensitivity of alveolar ventilation to small variations in CSF [H+] in awake animals (9, 32) and man (10); 2) the relatively precise compensation of CSF [H+] via local regulation of CSF [HCO a-1, as shown experimentally during chronic metabolic acid-base derangements in man and animals (9, 10) and during short-term hypoxemia and/or hypocapnia in anesthetized animals (23); and 3) the conclusion from limited data in healthy man sojourning at 3,800 m altitude, that ventilatory acclimatization was positively correlated to changes in CSF [H+] (39) THE
PROCESS
A total informed and no disease. arterial were all
of eight volunteer male subjects were studied with consent. All had normal resting ECG, chest X ray, previous history or evidence of cardiopulmonary Routine pulmonary function tests and resting acid-base status and hemoglobin concentration within the normal range (Table X)”
Procedures Experimental of acid-base fluid under period, with 745, (P Bhyperventilation PI02- 145, 26-h period
design. The study consisted of an analysis status in arterial blood and in lumbar spinal three conditions: I) A 24- to 26-h control the subject breathing ambient air throughout PIOZ - 145) ; 2) a 26-h period of controlled under ambient conditions (PB 745, and 3) an additional PacOz - 30-33 mmHg); of controlled hyperventilation during simula-
665
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DEMPSEY,
666
Subj
Age, yr
I-It, cm
-.--JJ
22
GB
20
RS l-m L>s 7-R TN
21 24 29 22 22 23
Ri;M
Mea11 GEM
23 ztl .O
Wt, kg
TLC, 1
FEVl.os, 1
--
Single-Breath Hb, DLco, W - g/A; min)/mmHig
79.3 79.8 62.1 65.7 76.2 83.9 61.7 81.6
7.24
4.81
36.1
6.72 6.74 6.61 6.25 6.46 7.08
4.55 4.06 4.70 3.74 4.95 5.53
25.8 38.2 33.3 34.0 30.8 40.2
177 jA.5
73.8 fr3.2
6.73 49.12
4.62 Ito.
15.6 15.4 14.6 13.7 14.0 15.0 14.5 15.5
34.1 14.8 AA .70 zto.3
tion of 3,100 m altitude in a hypobaric chamber (PB 530, PIED - 100, PaGo, - 30-33 mxnHg). In addition, each subject was studied -during spontaneous (uncontrolled) ventilation (PB - 745, PloZ 145) for 1-2 h immediately after each condition of prolonged hyperventilation. Subjects were required to remain awake throughout all sessions. The three conditions were applied in a random order over a total 3.5~mo period. There were some individual exceptions to this standard protocol. Two of the eight subjects were studied for only 17-18 h under each of the three conditions. Of the remaining six subjects, complete data (CSF and blood) in all three 26-h conditions were obtained in five. An attempt was made to standardize conditions and testing protocol throughout the three testing sessions. The subjects spent the evening and night preceding each session in the laboratory. All sessions began between 7: 00 and 9100 A.M. and finished between 1O:OO A.M. and 1200 noon the following day for the 26-h sessions, and between 1: 00 and 2 : 00 A.M. for the 18-h sessions. Both during and for 3 days prior to each session, all subjects were required to follow a standard diet. The diet consisted of 2,400~2,800 total kcal/day with 24 and 35 70 of the total caloric content as protein and carbohydrate, respectively. Fluids (water and “ski& milk) were taken ad libitum throughout each session. Over the course of each of the three sessions no significant variations were observed in body weight, blood glucose, and hemoglobin concentrations or in oral ternperature. Xone of the subjects experienced any detectable symptoms as a result of the hyperventilation or hypoxic exposure. Sump&g procedures. The techniques for anaerobic saxnpling of arterialized venous blood and lumbar spinal fluid under steady-state conditions for ventilation have been described in detail (6). Arterialized blood acid-base status was measured in Z- to 3-ml samples obtained from an indwelling needle in a dorsal hand vein, with the hand heated to 43°C. Details of the sampling procedures and the close agreement between brachial arterial and “ arterialized” acid-base status have been described (14). Brachial arterial blood was sampled under local anesthesia to determine the arterial Pop during the final hour of hypoxic hyperventilation. Lumbar cerebrospinal fluid (CSF) (6-7 ml) was sampled through a Z-gauge needle placed percutaneously under local anesthesia in the fourth intervertebral
GLEDHILL,
AND
DOPICO
over 8-12 breaths space . All blood samples were drawn with the subject in a relative steady state for ventilation as determined by continuous monitoring of end-tidal Pco 2 (PETCOd
180 175 169 177 177 179 179 182
FORSTER,
l
Control of arterial Pco2. Throughout the periods of prolonged hyperventilation Paco2 was controlled between 29 and 33 mmHg in each subject. This level of hyperventilation corresponded to that spontaneously achieved during 1-8 wk sojourn at 3,100 m altitude (5, 6). Each subject achieved and maintained this level of Pace, almost exclusively through voluntary hyperventilation. A negative pressure “ chest-shell” respirator was used sparingly on two occasions to aid the subject in maintaining the desired breathing frequency. Nasal catheters fitted with gas sarnpling lines were attached to the subject throughout each session, which permitted continuous measurement of PETcoz for display on the meter face of an infrared analyzer (to guide th e subject) and on a polygraph recording (to provide a continuous guide for the investigators). During the initial 15-20 min of each hyperventilation session, each subject hyperventilated to a predetermined PETITE and two or three arterialized blood samples were obtained to ensure that the specified PETIT% produced the desired Pacr-, 2. Over the remaining period arterialized blood samples Wf3X 0 btained at hourly int ervals and when necessary, pull sonar Y ventilation . was readj usted to produce the desired The subjects remained in a sernirecum bent or supme position throughout except for the collection of urine samples every 1-2 h. Each collection required a total of 7-10 min including a Z- to 3-min walk at a slow pace during which time the subjects attempted to maintain the hyperventilation. Considerable care was taken throughout the hyperventilation sessions to ensure that the subjects maintained PETIT, at the desired constant level. Almost continuous surveillance of the recorded PETALS together with freq uent verba 1 reminders to the subjects were required to maintain this consistencv as fatigue and boredom becar ne apparent over the final 6-8 h of each session. Recovery periods. Between the 25th and 26th h of each of the three sessions the subject was prepared for the spinal fluid sampling. The PETIT), was continuously monitored and controlled during CSF sampling and three-to-four arterialized blood samples were drawn immediately before and after the spinal puncture. The average values frown these three samples were used to represent the arterial acid-base status at the time of the spinal puncture. For 20-30 min after the spinal tap, PETIT, was maintained at the desired level while one or two additional blood sarnples were obtained with the subject remaining in a supine position. The subject was then informed that the experiment had terminated. The end-tid al sampling aPPa ratus was removed and, in the hypoxic h .yperven til ation condition, the subject was removed from the hypobaric chamber. A recovery period of 1-2 h followed, during which the subject breathed room air spontaneously (Pro2 - 145), in a supine position, with sampling of arterialized blood at 15-min intervals. The subjects remained in an awake but noticeably relaxed state throughout this recovery period.
pacoy
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CSF
[H+]
IN
HYPOCAPNIA
,4ND
667
HYPOXEhW4
of grouped data were tested by conventional, paired t-test analyses (7). Differences which produced J) values TO.05 were accepted as statistically significant. Ninety-five percent confidence intervals for group mean values were calculated using small-sample statistical criteria (11). RESULTS
Time Coum of Blood Acid-BaseChanges
l
pco2CSF
- ( ELECTRODE
FIG. 1. Comparison of manometric and electrode of lumbar CSF Pco2 (N = 33). “Indirect” manometric derived from measurements of COgr and pH. “Direct” determined from electrode measurements (see text).
Analysis
1 -j 4
determinations PCO~
was
PCO~ was
Techniques
Analyses of acid-base status was completed within 6-8 min aft& sampling for CSF and within 15-20 min for blood. Three basic measurements of acid-base status were carried out on all samples : I) CO2 total in CSF in the van Slyke manometric apparatus (48) ; 2) pH and PCO~ with conventional electrodes (Radiometer, Copenhagen) (at 37.0”(Z), calibrated with tonometered blood of known PCOZ and tonometered artificial CSF of known PCO~and [HCOJ ; and 3) lactic acid concentration in plasma and CSF by a modified colorometric technique (1). In addition, in vitro “buffer slopes” of blood and CSF (A log Pco,,‘A pH) f or each subject were obtained by microtonometry. A previous report has detailed these analytic procedures and includes a quantitative description of acidbase measurement validity and reproducibility (6).
A trend for the time course of arterial Pcoz and pH over the 26 h of each condition was estimated by averaging 15-25 values at each 2-5-h interval (Fig. 2). a) Throughout the control condition no systematic variations in Pacoz or pH, were observed. Mean [HCO& varied between 24 and 25 meq/l throughout the control session. b) PacOa was controlled at 30-33 mmHg throughout each session of prolonged voluntary hyperventilation. A small, yet systematic, increase of approximately 1 mmHg Pcoz was evident in each session over the final 9-12 h. Mean Pacoz was 0.5-l .5 mmHg higher during the hypoxic hyperventilation condition, but these differences were not significant. c) Arterial pH rose immediately at the onset of hyperventilation, remained unchanged further (in normoxia) or fell slightly (in hypoxia) during the initial 12-14 h, and was reduced to within 0.03-0.05 units of normocapnic control levels over the final 6-10 h of hyperventilation. Blood und CSF )H Regulation The acid-base status of arterial blood and CSF under control conditions and at the 26th h of each hyperventilation session is shown in Tables 2 and 3. The changes in acid-base status between control and hyperventilation conditions are described. All references tY grouz) mean U
Calculations Calculations of [ HCO 3-1 in blood and CSF used published values for pKI and/or COP solubility (31). All reported values of CSF Peon, pH and [HCOZ-] for each subject represent the average of values obtained by manometric and electrode measurements. Figure 1 compares these two techniques with respect to CSF Peon. Total pH compensation in arterial blood and in CSF achieved as a result of prolonged hyperventilation was calculated after Siesjij (41)
7-50
7-45
% pH compensation =
A (pH at 26 h hyperventilation-maximum A (control pH-maximum pH)
pH)
7-40
x
100
--L~--i-1 0
“Maximum” pH represents that pH achieved if the system contained only the [HCOZ-] - H&OS buffers and could not exchange ‘[Hi-l or [HCO3-1 ions with its environment. Maximum UPH was calculated; then, using the [HCOZ-] observed under control conditions and the Pcoz observed at + 26 h of each hyperventilation session. Statistical probability of differences between the means
1
5
I5
to
20
I
I
I
I
I
i
I
J
25
HOURS 2. Time course of changes in arterial pH and Pco2 in control conditions and during 26 h of voluntary hyperventilation in normoxia and hypobaric hypoxia. Plotted values are mean j, 95% confidence interval (N = 8). Vertical arrows designate the time of lumbar fluid sampling in all three conditions (see METHODS). Extreme right-hand panel is the “recovery period” of spontaneous ventilation and is shown in detail in Fig. 4. FIG.
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668 TABLE
DEMPSEY,
2. Arterial
blood and lumbar spinal fluid acid-base status: individual Subj
Control (+26 h), ,- 745, PIoIl P 14:)
JJ Gl3 RS RO m TR TAq RMS
50.0 47.8 50.0 51.5 49.4 51 .o 50.7 48.5
Arterial Lactate
PI-I
49.7 &0.6
24.6 zto.2
1.58 +0.07
7.365 7.380 7.351 7.363 7.395 7.328 7.325 7.310
41.3 43.1 42.7 43.1 39.0 45.5 46.5 47.6
22.8 23.7 22.3 22.9 22.8 23.1 23.2 22.9
1.70 1.63 1.92 1.79 1.74 1.47 2.17 1.75
7 -434 7.472 7.449 7 -437 7.448 7.444 7.431 7.440
7.370 Ito -008
41 A ztO.8
22.9 +0.2
1.75
7.411 7.364 7.339 7.356 7.391 7.353
37.1 41.5 41.7 42.1 38.4 44.5
22.8 22.3 21.7 22.5 22.5 23.6
7.372 Ito.
40.2 -41 .o
P
O.lO>
+0.27 zto.09 ( 0.05 >O.lO
>o. 10 >O.lO
>0.05
o. >o.
Pt
>O.lO
>0.05
10 10
40 1
ALK. 1 /4-{RECOVERY II t y/L---q. --u---L +23 24 25 26 I5
HOURS
60
-52-z
4. Changes in arterial Pc&@n exfwimentat and control conditions after prolonged hyperventilation --.--. ---- -----
TABBET;
Recovery Subj
Mean
Post R alk
JJ GB BS RO DS
33.1 37.4 35.5 37.0 35.6
TR
PaGo.,* Post R AIB + hypox
&EM
A Pacot Post
from ConErol R alk
35.9
32.6 33.0 32.6 31.8 37,2 33.1
-6.1 -0.5 -3.6 -5.5 -3.7 -2.9
35.8
33.4
-3.7 (P < 0.05) bl.8
zt0.6
ho.8
Post R alk + hYPox -6.6 -4.9 -6.5 -10.7 -2.1 -5.7 -611 ztI.1
APacOs from Hnervent “A Post
R alk
+2.0 +6.9 +4.1 +4.8 +3.8 +4.9
-/- 26 h Post R Alk + bpox +1,8 +0.3 +1.2 +1.1 +2.8 t-1.4
-54.4 (P < 0.01) zto.7
+r
.5
hO.4 -.-~
T
I
I
1
PCO, (mmHgr1 40
50
30
FIG. 3. pH compensation in arterial blood and CSF as a result of prolonged normoxic and hypoxic hyperventilation. “Maximum” pH values were calculated using PCO~ obtained with each of the hyperventilation conditions and the [HCOS-] obtained in control conditions METHODS).
45
FIG. 4. Group mean changes in arterial PCOS while breathing spontaneously (Pro2 145 mmHg), after 26 h of normoxic and hypoxic hyperventilation (iv = 6). Measurelnents were obtained and averaged at 15-min intervals during the first hour following prolonged hyperventilation.
* Recovery PacOa (mmHg) refers to the mean of two to three ments per subject obtained during spontaneous ventilation (Pr o2 30 and 60 min after 26 h of normoxic and hypoxic hyperventilation.
-
Paco2 measure145) between
that (physicochemical) buffering accounted for 50 to 60 % of the total pH compensation in blood, but a negligible amount in CSF (< 5 %). Recovery of Arterial
(See
30
MINUTES
(P < 0.05)
7 3o
50
PERIOD(F~~~l45)~----)/
/
Y
/ 1 J -,30 I ’ -
tRESP
30
+o .44 AO.12
Pco2 in mmHg; [HCOa-] and Iactic acid concentration in meq/l. * These P values refer to the differences between CSF and arterial blood. 1 These P values refer to the effect of each of the conditions on the differences between CSF and arterial blood. I
40
Pco:!
After Prolonged
Hyperventilation
The average and individual subject changes in PacOp while breathing spontaneously (Pro2 145), during 1-2 h recovery from prolonged normoxic and hypoxic hyperventilation, are shown in Fig. 4 and Table 4 (N = 6). a) At 15 min of recovery group mean PaGo rose 3 mmHg (P < 0.05) following 26 h of normoxic hyperventilation but remained unchanged from 26-h values following hypoxic hyperventilation (t-O.3 mmHg, P > 0.10). The immediate rise in Paco2 was evident in all six subjects following the normoxic hyperventilation. After hypoxic hyperventilation, only two of the six subjects showed a measurable increase in Pace, (+ 1.5 and +Z.O mmHg) above 26-h values. b) At 30 min of recovery from both conditions of hyperventilation, group mean Pace 2 rose further but showed no further systematic changes throughout the remaining 30-W min of study. Three of the twelve individual recovery curves (not shown)-two following normoxic and one
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670
DEMPSEY,
following hypoxic hyperventilation-showed a continuous rise in PacOz throughout the recovery periods. c) Arterial PCO~ measurements obtained during the relatively stable period at +30 to 60 min of recovery were used to quantify the differences between the two conditions (Table 4). i) PacoZ remained significantly below control values during recovery from both conditions of prolonged hyperventilation. However, the recovery of Pace., toward control levels was significantly more complete following normoxic than hypoxic hyperventilation. ii) Considering the slightly higher level of PacOz obtained in the final hour of normoxic over hypoxic hyperventilation, the most meaningful assessment of the relative amounts of spontaneous hyperventilation was the change in Pacod, between the end of voluntary hyperventilation and +30 to 60 rnin of recovery (Table 4, final 2 columns). In five of the six subjects, the increase in PacOz after normoxic hyperventilation exceeded that following hypoxic hyperventilation. DISCUSSION
Thwy
and Fz’ndings
The data showed that spontaneous hyperventilation persisted after a prolonged period of imposed hyperventilation and hypocapnia, and that the degree of spontaneous hyperventilation was significantly increased when hypobaric hypoxia was superimposed over the duration of the period of voluntary hyperventilation. This ventilatory acclimatization to prolonged hypocapnia has been shown previously in awake man using either passive or active means of hyperventilation, and the magnitude of the spontaneous hyperventilation appeared to be somewhat dependent upon the severity of the imposed hypocapnia (2, 4, 8, 28, 45). The independent effects of a superimposed hypoxia on spontaneous hyperventilation were also demonstrated by Eger et al. (8) in terms of an augmented leftward shift in the CO2 response curve. Somewhat analogous to this effect is the observation commonly reported at high altitude, where hyperventilation continues at a slightly reduced level when the acclimatized subject is acutely returned to sealevel normoxia (5, 13, 39). The current explanation for each of these observations has focused on the local regulation of CSF [HCOS-1, with stimulation of chemoreceptors near the medullary surface via CSF [H+] as the mediator of ventilatory acclimatization (30, 39). For example, during prolonged hypocapnia it is suggested that CSF [HCOS-] is reduced to the point where CSF pH is returned to normal or to near-normal control levels. Then, when the primary stimulus to the prolonged hyperventilation-in this case a voluntary act-is removed, PCO~ rises immediately in arterial blood and in turn in CSF. The resultant fall in pH below normal control levels in the poorly buffered CSF elicits the added stimulus for the observed spontaneous hyperventilation which persists, possibly for many hours, until CSF [HCOS-] and pH are restored to normal. In turn, the explanation for the additional or independent effects of the superimposed hypoxia on spontaneous hyperventilation is identical-except that the CSF [HCOS-] would have fallen further during hypoxic than normoxic hypocapnia because of the ac-
FORSTER,
GLEDHILL,
AND
DOPICO
companying hypoxemia and cerebral tissue hypoxia. Hence, CSF pH would be relatively more acid both at the end of the prolonged hyperventilation period and during spontaneous hyperventilation in recovery. This explanation largely depends on the following basic premises 1) that the decrease in CSF [HCOS-] in prolonged hypocapnia is primarily regulated by local mechanisms-such as an active transport of [HCOS-] from CSF to capillary plasma (39)-which are suficient to return CSF [H+] to normocapnic control levels, and 2) that a superimposed hypoxemia exerts additional local regulatory effects, independent of hypocapnia alone-such as a cerebral lactacidosis (46)-which results in even greater reductions in CSF [HCO 3-1. These basic premises were not supported by present findings. That is, the finding that reductions in CSF [HCOs-] did not exceed those in plasma in either normoxic or hypoxic hypocapnia is inconsistent with the concept of a significant contribution to CSF [HCOZ-] regulation via local mechanisms, and a superimposed hypoxemia showed no independent effect on pH compensation in the CSF. The result was, that at the end of prolonged hyperventilation, CSF and plasma pH remained significantly alkaline to normocapnic control values. Hence, contrary to theory, the spontaneous hyperventilation which persisted during the “recovery” periods was not attributable to the corresponding degree of [HCOZ-] regulation or pH compensation in CSF which occurred during the preceding conditions of controlled hypoxemia and/or hypocapnia. Th e present st u d y represents a more direct testing of current theory, regarding CSF chemoreceptor mediation of ventilatory acclimatization to hypoxemia and/or hypocapnia, than has previously been reported. On the other hand, interpretation of the data is restricted by both the narrow scope of the experimental design and the methods used. Limitations Use of lumbar CSF. Our study required the assumption that the observed changes in lumbar CSF acid-base status with normoxic and hypoxic hyperventilation reflected the changes in cisternal CSF. With this in mind, the study was designed to provide minimum periods of 25 h constant hypocapnia (and hypoxemia) and 6-10 h of fairly constant arterial blood pH and [HCO 3-1, prior to the spinal fluid sampling. Two types of findings are relevant to the application of the assumption to these experimental conditions. 1) [HC&-] was similar in cisternal and lumbar CSF both in healthy subjects and in acid-base disorders which were 5 24 h in duration (12, 17, 37). Furthermore, changes in lumbar CSF [HCOJ p aralleled those in cisternal CSF during l-6 h of induced metabolic acidosis or alkalosis in dog (33) and man (36). Pcos and pH in the ‘%teady-state” of health or disease were significantly different between the two compartments, i.e., the Pco2 was -1-3 mmHg higher and the pH -0.02-0.04 units lower in the lumbar CSF (12, 17, 37). H owever, changes in lumbar CSF pH have been shown to parallel those in cisternal CSF during primary metabolic acid-base derangements and in patients 24 h after initiating a variety of moderate changes in
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CSF
[II+]
IN
HYPOCAPNIA
AND
671
HYPOXEMM
systemic acid-base balance (37; F. Plum, personal communication). These reports and others (3) have emphasized the importance to this parallelism of achieving “steadystate” levels for Pace,, prior to the spinal fluid sampling. Finally, it has recently been shown in the anesthetized dog (18) that 6 h of hypocapnia (Pacog - 19 mmHg) with controlled levels of constant arterial [HCOS-] and pH, resulted in nearly identical changes in cisternal and lumbar CSF pH, Pcoz, and [HCOa-1. 2) Changes in cisternul CSF ;bH and [HCO 3-1 were not different from those in arterial blood after 7-16 h of “ modcrate” hypocapnia or hypoxemia in anesthetized dogs (19, 20, 34) and after 6-24 h exposure to 3,400 m altitude in awake ponies (16). These findings in cisternal CSF were consistent with those presently found in lumbar CSF in man under conditions of nearly identical combinations of hypoxemia and/or hypocapnia. After 3-5 wk sojourn to 3,100 m the changes in lumbar CSF pH and [HCOa-] bore a relationship to corresponding changes in arterial blood which was similar to that presently found after 26 h simulation of these exposure conditions (6) (see below). In summary, the avilable evidence supports our assumption of parallel changes in lumbar and cisternal CSF [HCOS-] after 26 h of relatively moderate hyperventilation. Extension of this assumption to changes in CSF PCQ and pH also appears justified from data in experimental animals but is based on less comprehensive findings in man. Xo direct evidence was available on the question of whether a superimposed hypoxemia might violate this assumption; but comparisons of data obtained in man and pony were consistent with the premise that changes in lumbar CSF pH after 26 h of moderate hypoxemia and hypocapnia reflected those in cisternal CSF.’ Duration of hypocupniu and hyfioxemia. It is clear that 26 h of hyperventilation cannot be classified as a truly ” chronic” condition of change. It may be argued, then, that longer durations of hypoxemia and/or hypocapnia would have confirmed current theories, i.e., CSF pH would have been completely compensated and, in turn, positively related to the spontaneous hyperventilation in recovery. Certainly the duration of change is important to acidbase regulation, as shown by the findings that 3-5 wk exposure to 3,100 m altitude (6) resulted in a more complete compensation of CSF pH (66 & 8 %) than was presently observed after 26 h exposure (50 =t: 9 “r,). However, the elf‘ects of chronic exposure conditions do not contradict the key points of disagreement with current theory concerning ventilatory acclimatization. That is, after 3-5 wk at 3,100 m, the decrease in [HCOS-] and compensation of 1.Theoretically, the superimposed hypoxemia may have violated the assumption of parallel changes in lumbar and cisternal CSF Pco:! (and PI-I) : a) if the hypoxemia caused an acute increase in cerebral blood flow (CBF) and thereby a fall in brain ISF Pcoe which exceeded that in cisternal CSF (38) ; and b) if this acute decrease in ISF PCOZ required periods of steady-state hypoxemia longer than 26 h before it was reflected in cisternal and lumbar CSF. It seems unlikely that these circumstances occurred: a) 10 min to 1 h of arterial hypoxemia in the range of SO-60 mmHg Paoz causes no significant change in CBF or in the jugular venous to arterial difference for Pco:! (6, 22, 40) ; and b) the duration of hypoxic exposure extended well beyond the acute period when any effects of a changing CBF on the disequilibrium between ISF and CSF Pcoz would be maxi11111111(38). L
pH was not different between arterial blood and CSF, CSF pH still remained significantly alkaline (to sea-level control values), and changes in CSF pH bore no positive relationship to ventilatory acclimatization. Concerning this latter point, it is also relevant to point out a) that the during spontaneous small increases in obtained hyperventilation after 26 h of hypoxic hyperventilation were similar in magnitude to those observed when acute normoxia was imposed during l-8 wk acclimatization to 3,100 m altitude (5, 13); and b) that even periods of irnposed hypocapnia as brief as 6 h duration were shown by Eger et al. (8) to produce marked aftereRects on spontaneous ventilation. Seuerily of 1lypoxemiu und hyfiocupniu. Contrary to our findings in moderate hypocapnia and hypoxemia, experimental data in anesthetized animals studied over 6-10 h have clearly demonstrated that more severe hypocapnia (< 20 mmHg PacO,) (21, 23, 34, 35, 49) or hypoxemia ( ” Extrachemoreceptors. ” Potential mediators of ventilatory acclimatization which might operate independently or even in spite of brain [H+] levels are numerous and almost completely unexplored (15, 47). Some indirect findings in man have been reported in support of a purely mechanical effect of prolonged hyperventilation, possibly dependent on an aff‘erent pathway originating in lung and/or chest wall receptors (44). During prolonged exposure to hypoxia, preliminary findings in the decerebrate cat point to facilitory suprapontine influences on medullary control centers as a potential contributor of significance to ventilatory acclimatization (47). Currently available knowledge does not permit any quantitation of the relative contributions of these postulated mechanisms as mediators of ventilatory acclimatization. Indeed, even the existence of such mechanisms is based on only limited evidence. We can, then, only postulate on the basis of present findings that the effects of prolonged hypocapnia and the independent effects of a superimposed hypoxemia on ventilatory acclimatization are mediated by a more complex scheme of mechanisms than that originally proposed by the dual CSF + arterialchemoreceptor theory.
pacogc;;;n--I : 1
RESP. AM.
30-
:23P
24I 25’
i k----[RECOVERY I t 15 I
Pm00
301
451
~PIO~145#---~
601
,
T
HOURS
j
MINUTES
FIG. 5,. Estimated CSF pH during the “recovery” periods of spontaneous ventilation. i\t any point in time during “recovery,” CSF pH was estimated by assuming that 1) CSF [HCOZ-] remained equal to that obtained at the 26th h of each hyperventilation session; and 2) that CSF Pcoz was changed from 26-h values by an amount equal to the corresponding change in arterial Pco~. CSF pH during recovery would have been Q) lower than shown here if CBF had fallen during “recovery” (see text); or /I) higher than shown here if either CBF or CSF [HCOS-] had risen during “recovery.”
CSF pH between the end of voluntary hyperventilation and the recovery period were determined solely by the influence of a rising Pace, (see legend to Fig. 5). These estimates of CSF pH were not positively correlated to the accompanying levels of spontaneous hyperventilation, i.e., the CSF pH remained alkaline or equal to normocapnic control values after normoxic hyperventilation and even more alkaline after hypoxic hyperventilation. However, as PacOz and Paoz increased during “recovery,” it is likely that changes occurred in CBF (38) and therefore in the CSF-to-arterial difference for Pco 2. Accordingly, appropriate changes in CSF [H+] would have accompanied the spontaneous hyperventilation in recovery; if the rise in CSF Pcoz exceeded the rise in PacOz, secondary to immediate and progressive reductions in CBF.2 Reported findings are not consistent with this hypothesis, e.g., acute changes in CBF from Pacoz 55-60 mmHg to normoxia are not accompanied by significant changes in CBF (6, 22, 40) and the rise in Paco2 after both normoxic and hypoxic hyperventilation would, if anything, be associated with a slight increase in CBF (38) and therefore an even more hypocapnic and alkalotic CSF pH than shown in Fig. 5. Furthermore, it has been shown that, after a step change in Pacop a new steady-state for cisternal CSF PCO~is not reached before 10 (24) to 25 min (3). This evidence also points to lower PCO~ and higher pH in CSF-at any point in time during ~recovery”than the estimates shown in Fig. 5. It does not appear, then, that appropriate adjust2 The required increases in the CSF to arterial difference from the 26-h values to + 15 min recovery, were +2.2 +20y0) after normoxic hypocapnia and +5.4 mmHg after hypoxic hypocapnia. These changes would yield CSF pH at +I5 min recovery which were ~0.01 and respectively, below mean control values.
for Pco~, mmHg (or (or +65%) values for 0.015 units,
It is a pleasure to acknowledge the expert technical assistance provided by Ms. Deborah Grouse, Ms. Jean Vaughn, Ms. Monique Buehnlann, and Mr. David Scherr. We are indebted to Dr. John Rankin and to Dr. Eric Kindwall and his staff (St. Luke’s Hospital, Milwaukee, Wis.) who so generously provided facilities for this study. Ms. Helena Andersson provided invaluable assistance in the preparation of the manuscripts. This study was supported in part by grants from the k\merican Lung Association, National Institutes of Health (1 -RO 1 -HI, i546’3), and the Wisconsin Heart Association. This work was presented in part at the Federation of American Societies for Experimental Biology National Meeting, Atlantic City, N. J., April 1973. H. V. Forster and N. Gledhili were National Institutes of Health Graduate Trainees. Received
for
publication
26 July
1974.
3 These required changes in [HC08-] were based on control values estimated from Siesjo’s data for intracellular (ic) pH and [HCO:i-] in rat brain (43). con&ol: 7.04 pH, 12.0 [HCO,-j and 47.7 Pco:!;. normoxic hypocapnia: Pcoz fell 7.9 mmHg and to maintain pHi, at 7.04, [HC03jic would be 10.0 meq/l; hypoxic hypocupnia: Pco:! fell 9.5 mmHg and to bring pHi, to 7.03, [HCOz*]ic would be 9.4 meq/l. It is assumed here that observed changes in CSF PCOZ approximated those in intracellular Pcog (43).
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CSF
[H+]
IN
HYPOCAPNIA
AND
673
HYPOXEMM:A
REFERENCES 1. BARKER,
18.
S, B., AND W. H. SUMMERSON. The calorimetric determination of lactic acid in biological material. J. Biol. Chem. 35: 535-541, 1941. BOOTHBY, W. M. Absence of apnoea after forced breathing. J. Physiol., Lmdon 45: 328-334, 1912. BRADLEY, R. D., AND S. J. G. SEMPLE. A comparison of Certain acid-base characteristics of arterial blood, jugular venous blood and cerebrospinal Auid in man, and the effect on them of some acute and chronic acid-base disturbances. J. physiol., London 160: 381-391, 1962. BROWN, E. B., G. S. CAMPBELL, M. N. JOHNSON, A. HEMINGWAY, AND M. B. VISSCHRE. Changes in response to inhalation of CO2 before and after 24 hours of hyperventilation in inan. J. &$Z. Physiol. 1: 333-338, 1948. DEMPSEY, J. A., H. V. FORSTER, M. L. BXRNBAUM, W. G. REDDAN, J. THODEN, R. F. GROVER, AND J. RANKIN. Control of exercise hyperpnea under varying durations of exposure to moderate hypoxia. Respiration Physiol. 16: 213-231, 1972. L)EMPSEY, J. A., H. V. FORXER, AND G. A. DOPICO, Ventilatory acclimatization to moderate hypoxemia: role of spinal fluid [H+j. J. C&n. Invest. 53: 1091-l 100, 1974. EDWARDS, i-1. L. Statistical bfethods for the Behavioral Sciences. New York : Rinehart, 1954. EGER, E. I., R. H. KELLOGG, A. H. MINES, M. LIMA-OSTOS c. E. ~/~ORILL, AND D. W. KENT. Influence of CO2 on ventila-, tory acclimatization to altitude. J. A#. Physiol. 24: 607-6 15, 1968. FENCL, V., T. B, MILLER, AND J* R, PAPPENHEIMER. Studies on the respiratory response to disturbances of acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid. Am. J. Physiol. 200 : 459-472, 1966. FENCL, V., J. R. VALE, AND J, A. BROCH. Respiration and cerebral blood flow in metabolic acidosis and alkalosis in humans. J. Appl. Physiol. 27 : 67-76, 1969. FERGUSON, G. A. Statistical Analysis in Psychology and Education, New York: McGraw, 1959. FISHER, V. J ., AND L. C. CHRISTIANSON. Cerebrospinal fluid acidbase balance during a changing ventilatory state in man. J. A#. Physiol. 18: 712-716, 1963. FORS'I'ER, H.V,,J. &DEMPSEY, M.L. BIRNBAUM, W. G. REDDAN, J- THODEN, R. F. GROVER, AND J. RANKIN. The effect of chronic exposure to hypoxia on ventilatory response to CO? and hypoxia. J, A@[. Physiol. 31: 586-592, 197 1. FORS~ER, J3. V., J+ A. DEMPSEY, J, THOMSON, E. VIDRUK, AND G. A. DOPXCO. Estimation of arterial Paz, Pco~, pH, and lactate from arterialized venous blood. J. A#. Physiol. 32 : 134-137, 1972. FORSTER, H.V.,J.A. DEMPSEY&H. VIDRUK,AND G. A. DOPICO. Evidence of altered regulation of ventilation during exposure to hypoxia. Respiration Physiol. 20 : 379-392, 1974. FORSTER, H. V., L. HAMILTON, AND J. WILL. Effect of altitude sojourn (3400112) on ventilation and CSF and arterial acid-base status (Abstract). Federation Proc. 32 : 857, 1973. HEIJS’~ A. N. P. VAN, A. H. J- MAAS, AND B. P. VISSER. Comparison of the acid-base balance in cisternal and lumbar cerebrospinal fluid. PJuegers Arc/z. 287 : 242-246, 1966. HORNBEIN, T. F., AND E. G. PAVLIN. Distribution of [H’] and
19.
[HCOs-] between CSF and blood during respiratory in dogs. Am. J. Physiol. 228: 393-394, 1975. KAZEMI, H., D. C. SHANNON, AND E. CARVALLO-GIL.
2. 3.
4.
5.
6.
7. 8.
9,.
10.
11. 12.
13.
14.
15.
16,
17.
buffering Physiol. 20.
KAZEMI, Brain ApPl.
21.
22.
capacity 22 : 241-245,
H.,
organic Physiol.
in
respiratory 1967.
acidosis
and
23. 24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
34.
35. 36.
37.
1343-1351, 38. 39.
J.
CO2 41.
N.
S. SHORE, V. E. buffers in respiratory 34 : 478-482, 1973.
SHIH, AND D. acidosis and
SIESJ~,
42. 43.
Intern. SIE~@,
1969.
44.
AND
R,
J. .Ajt$d.
Busru. f%ysioZ.
P. SCHEINBERG, i&lechanisms 29:
223-229,
M. P. REINMUTI~, of cerebral vasodilation 0.
1970,
J. RUJISHIMA, in hypoxia. 45.
B.
RICHARDSON,
W.
control at high altitudes of CSF pH. J. ApPl.
166, 19fj3. W. h., J. WASSERMAN, J. P. BAKER, AND SON. Cerebrovascular response to acute hypocapnia
AND B. K. Smqij. The regulation KJALLQUIS~, A., M. NARDINI, of extraand intracellular acid-base parameters in the rat brain during hyperand hypocapnia. Acta Physiol. &and. 76: 485-4-94, K.,
London:
sugl?zysioE.
1155-l
1971. Sr~s~ii,
KOGURE,
MITCHELL,
SHAPIRO,
in 8,
normal Quantification
hypocapnia
C. SHANNON. alkalosis. J.
circulation.
1972,
hypoxia
&$.
of the cerebral
physiology
p. 2 15-2 16. SEVERXNGHAUS, J. W., R. ;\. AND M. M. SINGER. Respiratory gesting active transport regulation 18:
40.
alkalosis.
1973.
PURVES, M. J. The Cambridge,
alkalosis Brain
LEUSEN, I. Regulation of cerebrospinal fluid with reference to breathing. physiol. Rev. 52 : l-56, 1972, LOESCHCKE, H. H., AND K. SUGIOKA. pH of the cerebrospinal fluid in the cisterna magna and on the surface of the choroid plexus of the 4th ventricle and its effect on ventilation in experimental disturbances of acid-base balance; transient and steady states. Pjuegers Arch. 3 12: 161-188, 1969. LIPSCOMB, W. T., AND I. L. BOYARSKY. Neurophysiological investigation of Medullary chemosensitive areas of Respiration. Respiration Physiol. 16 : 362-376, 1972. MACMLLLAN, V., AND B. K. SIESJ~. The influence of hypocapnia upon intracellular pH and upon some carbohydrate substrates, amino acids and organic phosphates in the brain. J. Neurochem. 21: 1283-1299, 1973. MACMILLAN, V., AND B. K. SIESJ~. Intra-cellular pH of the brain in arterial hypoxemia, evaluated with the GOa method and from the creatine phosphokinase equilibrium. &and. J. Clin. Lab. Invest. 30 : 117-125, 1972. MILLS, J . N. Hyperpnea induced by forced breathing. J. Physiol., London 45: 328-334, 1912. MINES, -4. H., AND S. C. S@RENSEN. Changes in the electrochemical potential difference for HCOZbetween blood and CSF and in CSF lactate concentration during isocarbic hypoxia. Acta Physiol. &and. 8 I : 225-233, 197 1. MITCHELL, R. A., C. T, CARMAN, J. W. SEVERINGHAUS, B. W. RICHARDSON, h/r. M. SINGER, AND S. SCHNIDER. Stability of cerebrospinal fluid pH in chronic acid-base disturbances in blood. J. A$#. Physiol. 20: 443-452, 1965. MITCHELL, R. A., D. A. HERBERT, AND C. T. CARMAN. Acid-base constants and temperature coefficients for cerebrospinal fluid. J. A@ Physiol. 20 : 27-30, 1965. PAPPENHEIMER, J. R., V. FENCL, S. R, HEISEY, AND D. HELD. Role of cerebral fluids in control of respiration as studied in unanesthetized goats. Am. J. Physiol. 208: 436-450, 1965. PAVLIN, E. E., AND T. F. HORNBEIN. Regulation of CSF (H+> and HCOZin metabolic acidosis (Abstract). Federation Proc. 32 : 856, 1973. PELLIGRINO, D. A., C. G. IRVIN, S. M. MASTENBROOK, AND J. A. DEMPSEY. Dependence of CSF (H+) regulation on plasma (HCO3-) in respiratory alkalosis and hypoxemia (Abstract). Federation Proc. 33 : 1369, 1974. PLUM, F., AND J. B. POSNER. Blood and cerebrospinal fluid lactate during hyperventilation. Am. J. Physiol. 2 12 : 864-870, 1969. Inhomogeneity of cisternal and PLUM, F., AND J. B. POSNER. lumbar CSF acid-base balance during acute metabolic alterations in CBF and CSF (Abstract). &and. J. C&n. Lab, Invest. SupPl. 102: lB, 1968. PLUM, F., AND R. W. PRICE. Acid-base balance of cisternal lumbar cerebrospinal fluid in hospital patients. Iv. Engl. J. Med. 289:
man.
(Editorial). 13. K.
The
J. C/in. blest. of pli regulation &and.
J.
regulation
1 : 360-374, 1972. B. K. hletabolic
G&n.
of
control
J. L. PNYTERand eucapnic
Lab.
cerebrospinal of intracellular
Invest.
artificial ,A. C.,
ventilation. [. M. K.
and
28 : 1 13-l
fluid ~1-1
&and, J. Gin. Lab. Incest. 3 1 : 97-104, 1973. SMITH, A. C., J‘. M. K. SPALDING, AND W. E. WATSON. tion volume as a stimulus to spontaneous ventilation longed SMITH,
1970.
49 : 2362-2368, in hypercapnia
pl-1.
15,
Kidney
(Editorial).
Ventilaafter
pro-
J. Physiol.,
SPPALIIING,
London 160: 22-27, 1962. AND W. E. WATSON. CO2 as
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
674
46.
47.
DEMPSEY, stimulus to spontaneous ventilation after prolonged artificial ventilation. J. Physiol., London 160 : 27-3 1, 1962. Effect of cerebral S#RENSEN, S. C., AND J. Wm SEVERXNGHAUS. acidosis on the CSF-blood potential difference. Am. J. Physiol. 219: 68-71, 1970. TENNEY, S. M., P. SCOTTO, L. C. Ou, D. BARTLETT, AND J. E. REMMERS. Suprapontine influences on hypoxic ventilatory control In : High Altitude Physiology-Curdiac and Respiratory Aspects,
48.
49.
FORSTER,
GLEDHILL,
AND
DOPICO
edited by R. Panter and J. Knight. Edinburgh 8L London: Churchill-Livingstone, 197 1. VAN SLYKE, D. D. Studies in acidosis: Method for determination of carbon dioxide and carbonates in solution. J. Biol. Chem. 30: 347-354, 1917. VAN VAERENBERGH, P. J. J., G. DEMEESTER, AND J. LEUSEN. Lactate in cerebrospinal fluid during hyperventilation. Arch, Intern. Physiol. 73 : 738-745, 1965.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 16, 2019.
