Clinical Science (1970) 39, 169-182.
A N APPROACH TO T H E PROBLEMS OF ACID-BASE
BALANCE
C. T . K A P P A G O D A , R . J . L I N D E N
AND
H. M. SNOW
Cardiovascular Unit, Department of Physiology, University of Leeds
(Received 30 July 1969)
SUMMARY
1. The existing methods for assessing states of acidosis are discussed with particular
reference to non-respiratory acidosis. Most of these methods are based either on the
Henderson-Hasselbalch equation or on the direct extrapolation of in vitro studies on
blood to the whole animal. The evidence available shows that these methods cannot
be used to obtain an accurate assessment of disturbances of acid-base balance in the
whole animal.
2. The experiments were designed to investigate the acid-base parameters of an
animal when a respiratory acidosis was superimposed on a non-respiratory acidosis
caused by the infusion of N HC1; from these experiments it was possible to construct
COz titration curves at various levels of non-respiratory acidosis.
3. A scheme which is based upon the C 0 2 titration curves, has been proposed for
assessing an acute acid-base disturbance in terms of its respiratory and non-respiratory components.
4. The use of sodium bicarbonate to correct a non-respiratory acidosis was investigated, and it was shown that the amount of sodium bicarbonate required varied
with the rate of infusion. No firm predictions could be made regarding the dose of
bicarbonate required, but from the results of the present experiments an infusion
rate of 0.1 mEq kgg' min-' is recommended in dogs.
INTRODUCTION
Acid-base balance is an aspect of physiology which has engaged the attention of biochemists,
clinicians and physiologists. Unfortunately due to defects in communication between these
disciplines there has been a considerable degree of confusion over both the terminology and
the concepts involved.
A basic difficulty is that it is not possible to measure either the hydrogen ion concentration
or its activity in physiological fluids. The pH numbers provided by electrometricmeasurements
Correspondence : Professor R. J. Linden, Department of Physiology Medical School, University of Leeds,
Yorkshire.
169
170
C. T . Kappagoda, R. J. Linden and H . M . Snow
do not have a precise fundamental definition but are defined instead by an operational scale
based upon standard buffer solutions (Bates, 1954). Previous methods of assessing acid-base
balance (Singer & Hastings, 1948 ; Davenport, 1958 ;Astrup, Jorgensen, Siggaard Andersen &
Engel, 1960; Campbell, 1962; Owen, Dudley & Masterton, 1965) have depended upon the use
of the Henderson-Hasselbalch equation linking pH to the molar concentrations of carbonic
acid and bicarbonate ions in plasma. It is now appreciated that the constants in this equation
cannot be predicted with sufficient accuracy to warrant its use (Linden & Norman, 1966;
Trenchard, Noble & Guz, 1967; Norman, 1969; Linden & Norman, unpublished observations).
Finally some of the existing concepts (buffer base, standard bicarbonate, base excess and base
deficit) which have evolved from studies conducted on blood in vitro are at best misleading
and at their worst frankly untenable when applied to changing states within the whole animal.
It is known that titration of the whole animal with CO, produces titration curves significantly
different from those obtained by the titration of blood in vitro (Cunningham, Lloyd & Michel,
1962; Cohen, Brackett & Schwartz, 1964; Brackett, Cohen & Schwartz, 1965; Norman &
Linden, 1965; Linden & Norman, 1966).
In order to avoid much of the confusion relating to this subject, the terms which we propose
to use are defined in a manner similar to that of Creese, Neil, Ledingham & Vere (1962). In
this context it is important briefly to define some of the terms used here.
Acidosis is a state of the whole body reflected as an acidaemia in the blood where the pH of
arterial blood is below 7-36 (normal 7.36-7.46) (Singer & Hastings, 1948). Alkalosis is a state
of the whole body where the pH of arterial blood is above 7.46. Acidosis as defined above, can
be either respiratory or non-respiratory in origin and it can occur either in a pure form or as a
mixed disorder.
Respiratory acidosis
Respiratory acidosis results from a retention of CO, (carbonic acid) and the sequence of
chemical changes are as follows:
COZ+H,O =$ H,CO,
$ H+3+HC03-
1
H++BA- e H B A
Non-respiratory acidosis
This refers to states of acidosis caused by the addition of acids other than (i.e. stronger than)
carbonic acid and these are handled by the body in the following manner.
HA e H + + A I
J.
H+ +HCO,- 2 H,CO,
=$
H,O+COz
It is often found that respiratory and non-respiratory forms of acidosis occur together and
it is necessary to be in a position to assess the severity of each component in order to adopt
a rational form of therapy. It must be emphasized at this stage that the changes referred to
above are acute and primary. If these changes are permitted to persist for any length of time
compensatory (Astrup et al., 1960) or secondary (Creese et al., 1962) changes occur. The secondary changes caused by a chronic acid-base disturbance represent a more complex clinical
problem which awaits elucidation.
Acid-base balance
171
In the case of respiratory acidosis the arterial PC02 (Pa,C02) is taken as a reliable index of
its severity but it must be borne in mind that even transient changes in ventilation can affect
this value. There is unfortunately no general agreement on the method of assessing a nonrespiratory acidosis but several important contributions have been made in the past (Singer &
Hastings, 1948; Jorgenson & Astrup, 1957; Siggaard Andersen & Engel, 1960; Siggaard
Andersen, 1962).
Implicit in these methods of assessing a non-respiratory acidosis is the belief that data
derived from the in vitro titration of blood can be applied directly to the whole animal. In other
words, for all conditions of acid-base balance in the whole animal the pK’ of the HendersonHasselbalch equation should be a constant, or vary within predictable limits; and the titration
curve of the whole animal with CO, should be the same as that obtained by the titration of
blood in vitro. But in the event neither of these assumptions proves to be correct. The form of
in vivo titration curves in man and animal are significantly different from those obtained in
vitro (Cunningham, et al., 1962; Cohen, et al., 1964; Brackett et al., 1965; Norman & Linden,
1965;Linden &Norman, 1966; Norman, 1969). Alsoit has been shown by in vitro measurements
that, whereas the apparent first dissociation constant of carbonic acid (pK’) varies inversely
with pK (Severinghaus, Stupfel & Bradley, 1956) the in vivo measurements show pK‘ to vary
directly with pH (Norman & Linden, 1965;Linden &Norman, 1966; Linden & Norman, 1970).
In addition a large significant variation in pK’ at any one pH and temperature has been
observed in studies on the whole animal (Norman, 1969; Linden & Norman, 1970).
These observations indicate that methods of deriving acid-base parameters which are based
upon either the constancy of p K , or its variation in vitro, lead to an inaccurate assessment of
the acid-base status of the whole animal especially when the pH is outside the normal range.
The Singer-Hastings nomogram (1948) which is based on the Henderson-Hasselbalch equation
and a constant pK’ is an example of the former approach while the Siggaard Andersen nomogram (Siggaard Andersen & Engel, 1960) is one of the latter.
As a consequence of the disparity between the in vitro and in vivo studies, other workers have
advocated a more physiological approach to the problem of assessing the non-respiratory
component of an acidosis by considering the plasma bicarbonate with respect to the whole
clinical history of the patient (Schwartz & Relman, 1963). In a series of recent publications
(Brackett et al., 1965 ; Arbus, Herbert, Levesque, Elsten & Schwartz, 1969; Brackett, Wingo,
Muren & Solano, 1969) measurements of acid-base parameters in states of acute hypocapnia,
hypercapnia and chronic hypercapnia have been reported. Since the primary disturbance in
these experiments was respiratory, the relationship between arterial blood PCO, and pH
defined the acid-base state and deviations from the ranges given were taken as indicating the
existence of a non-respiratory acid-base balance disturbance. The relationship between arterial
blood pH and PC02 in acute and chronic hypercapnia are, however, different (Brackett et al.,
1969) and this serves to emphasize the point that the history of the disturbance is of the utmost
importance in interpreting the results obtained by examining the blood. Unfortunately some
of the data on which the above relationships between pH and Pa,CO, are based has been
derived using the Henderson-Hasselbalch equation with a constant p K .
Therefore the main criticism of the present methods of assessing the non-respiratory component of an acidosis can be summarized as follows:
(i) Buffer base, standard bicarbonate, base excess and base deficit precisely quantitate
172
C. T. Kappagoda, R. J. Linden and H. M . Snow
the acid-base changes in blood in vitro. The practical problem however involves changes in
the whole animal and direct extrapolation from in vitro to the whole animal is not warranted.
(ii) The constants in the Henderson-Hasselbalch equation vary in a manner which cannot
be predicted with sufficient accuracy when applied to the whole animal. Buffer base and
standard bicarbonate are usually derived from nomograms based upon this equation.
(iii) A single estimate of the acid-base parameters of blood does not take into consideration
the time-course of an acid-base disturbance, which is an important factor in assessing its
severity.
Present study
In view of the doubtful value of the existing methods of assessing a non-respiratory acidosis,
a study has been made of the behaviour of the whole animal when titrated with COz whilst
in different states of non-respiratory acidosis. From this study it was possible to evolve a
method for assessing the severity of each component in a mixed acidosis within defined experimental conditions. As a secondary exercise we investigated the administration of sodium
bicarbonate in non-respiratory acidotic states in order to ascertain whether one could predict
the doses of sodium bicarbonate required to compensate for the acidosis. Briefly, CO, titration
curves were obtained in normal anaesthetized dogs by altering the Pa,CO, by hyperventilation
and by adding CO, to the inspired air. After sufficient time had elapsed to permit equilibration,
the pH and PCOz of the arterial blood were determined. The log Pa,CO, was plotted against
pH and a titration curve obtained which was found to be linear in the physiological range,
as observed in vitro by Brewin, Gould, Nashat & Neil (1955). A series of COz titration curves
was also obtained at various levels of non-respiratory acidosis produced by the infusion of N HC1
and these were compared with the control titration curve obtained from a previous series of
experiments on normal anaesthetized dogs (Linden & Norman, 1970).
MATERIALS A N D METHODS
Dogs weighing 8-21 kg were given a subcutaneous injection of morphine sulphate (0.5 mg/kg).
Half an hour later, under local anaesthesia (2% Decicain), a catheter was introduced into the
inferior vena cava through the right long saphenous vein. Nine dogs were anaesthetized by an
intravenous infusion of a 1% solution of chloralose in normal saline (0.1 gm/kg) and one dog
by an intravenous infusion of pentobarbitone sodium, B.Vet.C. (20 mg/kg). Subsequently
during the experimental procedure a steady state of light anaesthesia was maintained by infusion
of chloralose every 15 min (1 mg/kg). In the case of the dog anaesthetized with pentobarbitone
sodium the supplementary dose was 1 mg/kg every half hour. After induction a tracheal cannula was inserted and respiration maintained with 40% oxygen in air using a ‘Starling Ideal
Pump’ so as to maintain an Pa,CO, of 40+3 mmHg (Ledsome, Linden & Norman, 1967).
Cannulae were inserted into both femoral arteries and the left femoral vein. The arterial
pressure was recorded by connecting one femoral arterial cannula to a Statham manometer
(Model P23 Gb) and a carrier amplifier (S.E. Laboratories, Feltham, Middlesex), the output
of which was recorded on a U.V. recorder (S.E. Laboratories). The carrier amplifier output
was also used to drive a cardiotachometer (Gilford Instrument Laboratories Inc., Oberlin,
Ohio, U.S.A.). The ECG was recorded from leads connected to the left hind leg and the right
foreleg.
Acid-base balance
173
End-tidal PCO, was monitored using a URAS 4 CO, analyser (Hartmann and Braun,
Frankfurt, Main, Western Germany). The ECG, end-tidal PCO, and the respiratory pressure were also recorded on the same U.V. recorder.
Throughout the experiment, all infusions of N HC1 and 8.4% NaHCO, were given intravenously using Braun infusion pumps (Braun Mellsungen, Western Germany). The second
femoral arterial cannula was used for obtaining samples for estimating the acid-base parameters, Pa,o, and the packed cell volume. The blood was collected in syringes in which the
dead space was filled with a solution of heparin (‘Pularin’, Evans Medical Ltd., 100 i.u./ml of
0.9% NaCl) and the blood was transferred to an E.I.L. electrode system for measuring the
pH, Pa,CO, and Pa,o, (Ledsome, Linden, Norman & Snow, 1967b). The CO, concentration in
blood and urine was measured by the method of Linden, Ledsome & Norman (1965). The
packed cell volume was obtained using a micro-haematocrit centrifuge (Hawksley & Sons Ltd.,
London).
The temperature of the animal was monitored throughout using an oesophageal thermistor
probe (Yellow Spring Instrument Co. Inc., Yellow Springs, Ohio).
In five dogs the ureters were cannulated and samples of urine were analysed for CO, concentration using the PCO, electrode (Ledsome, Linden & Norman, 1967a).
The animal was made acidotic by an intravenous infusion of N HC1 at a rate not greater
than 2.0 mEq/min. Once a particular level of acidosis was achieved and the necessary blood
samples obtained for analysis the pH was restored to the control value by an intravenous
infusion of 8.4% NaHCO,. A total of ten experiments in eight dogs was completed. In five of
these dogs the urine was examined to ascertain the point during the infusion at which bicarbonate appeared in the urine.
RESULTS
The relationship between pH and Pa,CO, produced by an alteration of inspired PCO, and
ventilation was investigated in four dogs with differing degrees of non-respiratory acidosis
produced by the infusion of N HCl. The arterial Pa,CO, was maintained at 40+3 mmHg
during the infusion of acid until the selected pH value was reached. The Pa,CO, was then raised
by adding CO, to the inspired mixture or lowered by hyperventilation. Blood samples were
taken for assessment of acid-base parameters at a mean time of 7 min (range 4-12) after the
onset of the change in Pa,CO,. Samples taken at 10-12 min gave rise to points which lay on
the same titration curves as those from samples taken at 4-5 min. The Pa,CO, was returned
to the control value after the titration and the estimations repeated; only the titration curves
in which the initial and final blood pH values at a Pa,CO, of 40 were within 0.03 pH units
(mean difference+0.005, n = 12). The slope of the CO, titration curve was the same whether
the points were obtained as the Pa,CO, was increased or as the Pa,CO, was decreased. An
example of the titration curves obtained in one dog are shown in Fig. 1. As the degree of nonrespiratory acidosis is increased (as estimated by the pH at a Pa,C02 of 40 mmHg) the curves
become steeper and move to the left; twelve titration curves were completed in four dogs.
Regression lines were calculated for each titration curve. The regression lines obtained were
considered along with the regression line for the titration curve in the normal anaesthetized
dog (Linden & Norman, unpublished observations). Two parameters of the curves were
examined: the slope and the pH at a Pa,CO, of 40 mmHg. A significant correlation was found
to exist between the pH at a Pa,CO, of 40 mmHg and the slope of the titration curve (Fig. 2).
174
C. T. Kappagoda, R . J. Linden and H . M . Snow
Using these results it was possible to construct mean titration curves at different values of pH
at a Pa,CO, of 40 mmHg (Fig. 3). The value for the pH at a Pa,CO, of 40 mmHg is termed
the non-respiratory pH. This chart allows the assessment of an acid-base disturbance in terms of
the pH at a Pa,CO, of 40 mmHg. It in no way allows an assessment of the amount of sodium
bicarbonate or any other base necessary to correct a non-respiratory acidosis (see Discussion).
100
9oL
80 70 -
60 -
I"
50-
E
E
0"
40
-
30
-
Ll
c
2ot
PH
A
B
C
pH 7 4 at PCOz 40rnrnHg
pH 7 2 at PCOz40rnrnHg
pH 71 at PCOz40mrn Hg
FIG.1.'C02 titration curves. A = Normal anaesthetized dogs (Norman, 1969; Linden & Norman,
1970) B and C = Curves obtained in one dog at two different levels of non-respiratoryacidosis.
0
I
7.I
I
I
I
72
7.3
7.4
Non-respi ratory pH
FIG.2. The relationshipbetween the non-respiratory pH (PH at a Pa,C02of 40 mmHg) and slopes
of the CO, titration curves (twelve observations in four dogs).
175
Acid-base balance
Titration of the animal with sodium bicarbonate.
In eight dogs an acid-base disturbance was produced by the infusion of N HC1 at rate of
0.375-2.0 mEq/min. The arterial Pa,CO, was maintained at 40 mmHg and the pH at this
Pa,CO, was taken as an index of the degree of non-respiratory acidosis. In six experiments on
five dogs (Nos. 3, 4, 5 & 8) the pH at a Pa,CO, of 40 mmHg was reduced to pH 6-95-7.05
and in four experiments in four dogs (Nos. 2 , 4 , 7 & 10) to pH 7.1 1-7-26. In six dogs the N HC1
."6%
6.9 70
7.1
7.2
7.3
74
7.5
7.6
7.7
PH
FIG.3. C 0 2 titration curves constructed from the regression line shown in Fig. 2. The nonrespiratory pH during an acute acidosis can be obtained from the arterial pH and Pa,C02 as
follows. The relevant point is plotted on this diagram and the titration curve is drawn through it.
The pH value on this curve, corresponding to a Pa,COt of 40 mmHg is the non-respiratory pH.
was infused and the onset of the infusion of NaHCO, was delayed for periods varying between
10 min to 1 h to estimate the degree of spontaneous return towards a normal pH. The average
rate of return after termination of the acid infusion was 0.1 pH units/h from a pH value of
6.95-7.00.
The dogs were titrated back to the normal pH range (7-36-7-46) by infusing NaHCO, at
rates between 0.1-0-33 mEq kg-' min-'. The results obtained from two dogs are shown in
Fig. 4. The pH at a Pa,C02 of 40 mmHg was obtained from the relationship demonstrated in
Fig. 3 and this pH was plotted against time. At the higher rate of infusion (0-2 mEq kg- min- ')
a normal pH was reached in 29 min (Fig. 4). At the lower rate of infusion 72 min were required.
The total amount of bicarbonate infused at the higher rate was 9.2 mEq/kg and at the lower
rate the amount was 6.9 mEq/kg. Despite the larger amount of bicarbonate infused in the former instance the pH at aPa,CO, at 40 mmHg decreased rapidly after the infusion was stopped.
During the infusion of bicarbonate Pa,CO, rises unless the ventilation is increased as the
buffering of acids stronger than carbonic acid takes place. The Pa,CO, tends to rise sharply at
the higher rates of infusion; an example is shown in Fig. 5 where the Pa,C02 rose to 75 mmHg
176
C. T. Kappagoda, R. J. Linden and H. M . Snow
in spite of an increase in the respiratory minute volume from 5.4 l/min to 6.4 l/min. The total
amount of bicarbonate infused in this experiment was 8.9 mEq/kg.
100
Infused at 0 lmEq kf'min-' 0
Infused at 02mEq kq'min-l o
Time from onset of NaHCO,infusion
(min)
FIG.4. The effect of infusions of NaHC03 at two different rates on Pa,C02, pH and nonrespiratory pH. Above: log Pa,CO,/pH plot for two rates of infusion. Below: corresponding
non-respiratory pH values plotted against time. Note that at the faster rate of infusion the nonrespiratory pH is corrected earlier, but there is a subsequent drop after termination of infusion.
The ventilation was adjusted in an attempt to maintain the Pa,CO, at 40 mmHg throughout the
bicarbonate infusion.
The amount of acidosis produced by the infusion of acid can be expressed in terms of pH at
a Pa,CO, of 40 mmHg and also in terms of the total amount of acid infused. The effectiveness
of the bicarbonate infusion is judged either as the amount of bicarbonate required to cause a
unit rise in the pH at a Pa,CO, of 40 mmHg or as the ratio of the bicarbonate infused to the
amount of acid infused. The results obtained are shown in Table 1. There is a significant
positive correlation between the amount of bicarbonate required to produce a unit change in
the pH at a Pa,CO, of 40 mmHg and the rate at which it is infused (Fig. 6). If the rate of
infusion is increased from 0.1 to 0.3 mEq kg- min- the amount of bicarbonate required to
cause a unit change in the pH at a Pa,CO, of 40 mmHg is more than doubled.
At a bicarbonate infusion rate of 0.1 mEq kg-I min-' the amount of bicarbonate required
'
'
177
Acid-base balance
I5m
7.1
30
69
7.2
7.3
74
75
76
7.7
-
75L
7.5
z
7
.
4
'F 1
5 73 )
I
._
e
n
g 72
72
c
2 7.1 -
7
7.
.0
0L
-20 -I0
I
0
I
10
I
20
NoHC03 infused at 0
. 2 6 m E ~kg-l
0.26mEq
kg-'mid
mid
I
I
I
I
I
I 1
I
I
30 40 50 60 70 80 90
90 loo
100
Time from opset of N a H q infusion (min)
FIG.5. Effect of a rapid infusion of NaHC03 on Pa,CO, pH and non-respiratory pH. The
ventilation was adjusted in an attempt to maintain the Pa,CO, at 40 mmHg throughout the
bicarbonate infusion.
TABLE
1. Details of infusions administered
Non-respiratory
Non-respiratory
pH before
NaHC03
pH after
APH
Dog Wt NHCI infused
NaHC03
NaHC03
(noninfused Rate of NaHC03
infusion
respiratory)
(mEq/kg)
(mEq/kg) (mEq min- kg- ')
infusion
no. (kg)
2
3
4
4
5
5
6
7
8
10
20.5
16.0
8.0
8.0
17-0
17.0
20.0
12.3
19.6
21.0
6.6
6.1
64
6.4
5.9
5.3
7.2
3.2
5.6
4.0
7.11
7.01
7.05
7.12
7.02
6.98
6.95
7.26
7.00
7.22
4.7
6.9
9.0
104
7.0
7.5
9.2
7.2
9.2
11.4
010
0.10
0.18
0.18
0.10
0.10
0.20
0.33
0.26
0.24
7.28
7.33
7.39
7.37
7.41
7.37
7.30
7.37
7.30
7.42
0.17
0.32
0.34
0.25
0.39
0.39
0.35
0.11
0.30
0.20
C. T. Kappagoda, R. J. Linden and H . M. Snow
178
to titrate the pH at a Pa,CO, of 40 mmHg back to the normal range is 1-2 (SD 0.4) times the
equivalent amount of acid required to produce the acidosis. At the infusion rate of 0-3 mEq
kg- min- the amount of bicarbonate required is 2.5 (SD 0.4) times the equivalent amounts
'
'
"F
60
/
I
0.1
I
02
I
0.3
I
0.4
Rate of infusion of NaHCO,
(mEq kg-'rnin-')
FIG.6. Relationship between rate of infusion of bicarbonate and the amount of bicarbonate/kg
required to produce a unit change in non-respiratorypH (pH at a Pa,CO, of 40 mmHg).
of acid. Therefore, regardless of whether the degree of non-respiratory acidosis is expressed
in terms of pH at a Pa,C02 of 40 mmHg or the amount of acid infused, the amount of bicarbonate required to titrate the pH to within the normal range is dependent upon the rate of
infusion.
The larger amount of bicarbonate required at a higher rate of infusion indicates its removal
or its apparent removal from plasma by mechanisms other than the buffering action. Some
bicarbonate is excreted in the urine and this excretion is dependent either upon the plasma
bicarbonate level exceeding the renal threshold (Pitts & Lotspeich, 1946) or on the dilution of
plasma solids (Matthews & O'Connor, 1968).
In five dogs the bicarbonate appeared in the urine when the plasma level exceeded 27 mEq/l
(range 22-33 mEq/l). During the infusion of bicarbonate at 0.1 mEq kg-' min-', plasma
concentrations of bicarbonate above 29 mEq/l were not observed. At rates higher than 0.1
mEq kg- min- the plasma level was as high as 38 mEq/l. This evidence suggests that at rates
not exceeding 0.1 mEq kg-' min-' the loss in urine would be minimal. No attempt was made
to calculate the amounts of bicarbonate lost in the urine.
During the infusion of bicarbonate the occurrence of atrial extrasystoles was noted in three
dogs but no conclusions could be drawn regarding the relationship between their occurrence
and the rate of infusion of bicarbonate.
DISCUSSION
Use of titration curves
It was stated in the introduction that the in vivo titration curves merely indicate how the
whole animal behaves at any particular state of non-respiratory acidosis when it is assaulted
Acid-base balance
179
with CO,. It must be emphasized that the changes considered are acute ones uncomplicated
by any significant secondary or compensatory changes. The titration curves can be used to
ascertain how the arterial pH of blood in the animal changes when a respiratory disturbance is
superimposed on an acute non-respiratory one, and therefore enable an estimate to be made of
the non-respiratory component of a mixed disturbance. For example, if an animal has an
arterial pH of 7-06 and a Pa,CO, of 70 mmHg its acid-base status can be analysed as follows.
The pH and Pa,CO, are plotted on the diagram in Fig. 3, defining a point on titration curve 3.
The animal is then assumed to be ventilated until its Pa,CO, is 40 mmHg and the arterial blood
would then have a pH of 7-2. The difference between this ‘non-respiratory pH’ and the normal
pH is an index of the severity of the non-respiratory component of this mixed disturbance. If
bicarbonate is to be administered it should be related to this value. Thus starting with the initial
measurement of the pH and Pa,CO, one could determine the contributions made respectively
by the respiratory and non-respiratory components to the final acid-base picture. It is equally
applicable to situations where the Pa,CO, is high as in a primary respiratory disturbance, or
low where the Pa,CO, could have dropped following hyperventilation in a primary nonrespiratory disturbance. In each case one has to plot the point (pH, Pa,C02) on the diagram
(Fig. 3) and then proceed to draw the titration curve through that point by approximation with
the known lines. The pH value at a Pa,C02 of 40 mmHg will give the non-respiratory pH which
will require correction with bicarbonate.
Administration of bicarbonate
Mellemgaard & Astrup (1960) postulated that the dose of sodium bicarbonate required to
correct a non-respiratory acidosis in man could be calculated in terms of the following
formula :
Dose of sodium bicarbonate (mEq) =
0.3 x body weight (kg) x base deficit in mEq/l of blood
However, in assessing the amount of bicarbonate required retrospectively either in terms of the
ratio bicarbonate given/acid infused or in terms of bicarbonate required to produce a unit
change in the non-respiratory pH it is seen that the rate of infusion has to be considered. Our
results in dogs show that there is a relationship between the rate of infusion and the efficiency
of the bicarbonate infusion as judged by the criteria laid down earlier. In view of this finding
an ideal regime for correcting a non-respiratory acidosis within our experimental conditions
would be as follows. The infusion should be started at a rate of 0.1 mEq kg-’ min-’ and the
non-respiratory pH assessed every 5 min. These results are then plotted as in Fig. 4. From the
rate of increase of the non-respiratory pH a reasonable estimate of the time required for the
pH at a Pa,C02 of 40 mmHg to return to normal could be made. In the final analysis this
gradient is an index of the rate at which the bicarbonate stores are repleted and gives an idea
as to the time at which the next pH estimation should be made.
These results emphasize the difficulties encountered in attempting to predict the amounts of
bicarbonate required to correct a non-respiratory acidosis without reference to the rate of
infusion of sodium bicarbonate. The dose required will depend on the extent to which bicarbonate ‘stores’ in the body have been depleted and the information currently available does not
permit either an accurate assessment of the stores already present or the extent to which they
have been depleted.
180
C. T. Kappagoda, R. J. Linden and H . M . Snow
During the infusion of sodium bicarbonate it was found that an effort had to be made to keep
the Pa,CO, at 40 mmHg by altering the ventilation volume. However, at the higher rates of
infusion it was increasingly difficult to maintain the Pa,COz at 40 mmHg and in some cases an
increase occurred.
For these reasons the rate of infusion should not be overlooked in considering possible
application of these techniques to clinical problems in man.
General discussion
i t will be appreciated at this stage that no reference has been made in this analysis to the
haemoglobin and the plasma protein concentration in the blood. Although these two factors
are most important when the in vitro CO, titration curves of blood are considered they have
much less influence when the whole animal is titrated with CO, ; the haemoglobin and plasma
proteins are in effect ‘diluted’ by the whole extravascular fluid volume. The buffering power of
the whole body is thus relatively less than that of blood as expressed by the COz titration
curves in vivo and in vitro.
The use of arterial blood in monitoring acid-base changes affecting the whole animal has
been questioned. i t has been suggested that acid-base changes in mixed venous blood may
better reflect the changes in the tissues (Roos & Thomas, 1967; Michel, 1968). The main reason
for this assertion appears to be the fact that the lungs merely act as tonometer and blood passing through the lungs behaves according to an in vitro titration curve whereas blood passing
through the tissues behaves according to an in vivo titration curve. Thus it has been pointed
out that in response to changes in blood flow through the tissues, the samples of arterial blood
will not indicate the same changes as samples of mixed venous blood (Roos & Thomas, 1967;
Michel, 1968). However the differences are small e.g. with the doubling of oxygen extraction
in the tissues to maximum extraction resulting from halving of the tissue blood flow, there
would be only a small difference of about 1 mEq/l between the two estimations of the bicarbonate concentration. Until more data are available on the simultaneous changes in mixed
venous and arterial blood during acid base disturbances and following alterations in cardiac
output, it is not possible to be certain of the magnitude of the error which may result from the
use of data obtained from arterial blood alone. At present however, there seems to be no
practical advantage in sampling mixed venous blood for routine purposes instead of arterial
blood, especially as in practice it is necessary to have information about the respiratory component of an acid-base disturbance which is obtained from the arterial sample.
This study has been conducted in dogs and although there is some evidence to the effect that
the in vivo acute CO, titration curve for the dog is not significantly different from that in man
(Cohen et al., 1964; Brackett et al., 1965) no definite conclusion can be drawn about the value
of this approach in man until C 0 2 titration curves are obtained at different values of nonrespiratory pH.
i t is intended to study the CO, titration curves in man in various states of acute non-respiratory acidosis and to ascertain whether the dose of bicarbonate required to correct a nonrespiratory acidosis is rate dependent in man as has been shown in the dog.
ACKNOWLEDGMENTS
The authors are indebted to Mr G . Wade and Mr D. Pamphilon for technical assistance and
Acid-base balance
181
are grateful for support from the British Heart Foundation, the Medical Research Council and
the Wellcome Trust. H. M. Snow is a Beit Memorial Research Fellow.
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