The purpose of this report is to describe the milestones of medical history within the area of hydrogen ion balance, and to discuss the validity of essential clinical variables for the interpretation of acid-base disorders and their application to high altitude.
MILESTONES OF MEDICAL HISTORY: THE EVOLUTION OF THE SIGGAARD-ANDERSEN DIAGRAM
In 1909 SPL Sorensen (1868-1939) introduced the "pH" concept. He wrote in German: "das ich den Namen "Wasserstoffionenexponent" und die Bezeichnung pH für den numerischen Wert des exponenten dieser Potenz benütze". In his 173 pages long, excellent thesis (1) Sorensen used for the first time the buffer concept ("Puffer" - "welche im lebenden Organismus als natürliche Schutzwehr gegen zu schroffe Änderungen des Wasserstoffionenkoncentration dienen") and measured hydrogen ion concentration ([H+]) with "die genaue, aber umständliche, elektrometrische Methode". Sorensen (1) also used the acid/base concept, but Bronsted, first, in 1923 focused on the hydrogen ion in the definition of acids and bases.
Bronsted (1879-1947) defined an acid as a substance able to give off a hydrogen
ion at a given pH, and a base as a substance that could bind a hydrogen ion
). These definitions led to the concept of conjugate acid-base
pairs. An ideal buffer pair ("Puffer") is a weak acid in equilibrium with its
corresponding weak base.
The law of mass action, related equations (Eq) and reactions (Re).
is unchanged in acute, respiratory acid-base disturbances. **[ ] denotes
Henderson (1878-1942) used the law of mass action for the dissociation of a
weak acid and the salt formed with a strong base (Table 1, Eq 2
expressed the dissociation constant as a negative logarithm, which in 1917 allowed
Hasselbalch (2) to convert Henderson´s equation to a logarithmic scale (Table
1, Eq 3
Van Slyke (1883-1971) introduced several gasometric methods, and is well known
for the Van Slyke apparatus and a brilliant textbook written together with JP
Peters (3). His equipment was mainly used to measure the total carbon dioxide
concentration in blood [total CO2
], and sometimes
the pH with an electrometer. [Total CO2
currently given in mM/L or mM. The partial pressure of CO2
) is proportional to [dissolved CO2
From the [total CO2
] and pH we can calculate
the 2 unknown variables [dissolved CO2
] or PCO2
and [bicarbonate] with the use of equations 5 and 6 (Table 1
). Van Slyke
used these quantities (pH if available, PCO2
and [total CO2
], the case history, and common
sense to diagnose acid-base disturbances.
In 1952-1953 the polio epidemic in Denmark increased dramatically the need for artificial ventilation and a reliable diagnosis of acid-base disturbances. Patients died in respiratory paresis with a high [bicarbonate] in their blood. The condition was interpreted as "alkalosis" with the laboratory terms used at that time. Bjorn Ibsen and Poul Astrup proved the "alkalosis" hypothesis to be a misinterpretation. Through the help of electrometric pH determinations the condition was shown to be carbon dioxide retention with massive respiratory acidosis. The patients were given artificial ventilation and survived. Before this insight was obtained, the high actual bicarbonate concentration was obviously misleading, since it was the consequence rather than the cause.
Poul Astrup´s group of scientists therefore developed methods to distinguish
respiratory from non-respiratory acid-base disturbances (4, 5, 6). Siggaard-Andersen
had joined the group and in 1960 they produced a micro method for the determination
of pH, carbon dioxide tension, and base excess (BE) in capillary blood (7).
Here, BE different from zero in whole blood was proposed as an index of metabolic
acid-base disturbances. Two years later Siggaard-Andersen published his work
on experimental acid-base disturbances in dogs (8), his alignment nomogram (9)
followed and then his dissertation describing the acid-base status of blood
and of the whole organism (10). However, he had already considered the importance
of standard base excess (SBE) in the extended extracellular fluid volume (eECF),
and he also introduced the term 'concentration of titratable hydrogen ion' as
an alternative to SBE. The SBE is equal to the actual BB minus normal BB (Table
). The 'titratable hydrogen ion concentration difference' can be shortened:
'Titratable Hydrogen Ion Difference' or THID, which is equal to SBE but with
The variables used in that dissertation were accepted as a rational choice, but the concept of 'base excess in whole blood' was criticized. In their criticism Schwartz and Relman (11) concluded "that the traditional measurements of pH, PCO2 and plasma bicarbonate continue to be the most reliable biochemical guides in the analysis of acid-base disturbances" - and - "allow rational evaluation of even the most complicated acid-base disorders." Let us see whether these statements hold true.
In reality, SBE and THID represent the same concentration difference from normal in mM but with opposite signs. Hence, from now on THID is used instead of SBE. This value in normal subjects is equal to 0, positive in primary (bicarbonate treatable) metabolic acidosis and negative in primary metabolic alkalosis. SBE is discharged, since the essential variable is not a base and in reality is not always an excess (ie, excess or deficit).
Hydrogen ion balance
The body tends to maintain a pH of around 7.40 in the extracellular fluid volume
by respiratory excretion of carbon dioxide and renal excretion of non-carbonic
(non-volatile) acid or base. During light activity the oxidative metabolism
produces up to 1 M of CO2
per hour that is eliminated
by the lungs at the same rate. Hereby, the alveolar fraction and tension of
is maintained at around 5.33 kPa (40 mmHg)
at sea level.
Hepatic production of hydrogen ions depends upon its daily amino acid load from
intestinal absorption. Persons on a normal mixed diet produce up to 100 mM of
daily in the liver by oxidation of sulphydryl
groups in amino acids and hydrolysis of phosphate esters from lipids. Of these
100 mM H+
daily, 70 mM are typically excreted
in 24 h urine. The remaining 30 mM of metabolic H+
is eliminated by oxidation of 30 mM organic bases from the gut (RCOO-
Amino acids are oxidized into CO2
The amino nitrogen is liberated as ammonia (NH3
One ammonia molecule combines in the liver with 2 carbon dioxide molecules to
form one urea molecule via the Krebs urea cycle, so normally the hepatic ammonia
production eliminates itself. One mol of nitrogen daily can produce 500 mM of
urea, which is equal to the typical urinary urea excretion. Alkalosis stimulates
urea production. The daily urea filtration flux is 900 mM (5 mM x 180 L of plasma
each day). The degree of reabsorption of the water-soluble urea depends upon
the tubular flow rate.
In the kidneys, there is ammonia production from glutamine, a non-toxic ammonia
store. One molecule of NH4+ is produced by deamination of one glutamine molecule
by the enzyme glutaminase, and a second by oxidative deamination of glutamic
acid forming alpha
-ketoglutarate that is metabolized.
proximal tubule cells is in equilibrium with minimal amounts of NH3
at the relatively low pH. The NH4+
secretion into the tubular fluid makes use of the Na+
antiporter, where NH4+
. The NH4+
passes with the tubular fluid to the thick ascending limb of the Henle loop,
where a major portion is reabsorbed and accumulated in the interstitial fluid.
Ammonia diffuses easily into the urine and binds to a hydrogen ion to form NH4+
About 30 mM of NH4+
is excreted in the normal daily urine, but the excretion is controlled during
acid-base disorders. During acidosis, the high [H+
stimulates hepatic glutamate and renal NH4+
production, and the renal NH4+
excretion increases towards 400 mM daily. During alkalosis, the urea production
accounts for the nitrogen elimination and only negligible amounts of NH4+
Normally, the daily filtration flux of bicarbonate amounts to 4500 mM (ie, filtration
of 180 L of plasma with a mean concentration of 25 mM). Most of the filtered
bicarbonate flux is reabsorbed already in the proximal tubules, where the luminal
membrane contains a Na+
The bicarbonate reabsorption is accomplished by means of H+
Most of the H+
secreted in the proximal tubules
is derived from the Na+
-H+ exchange through the
antiporter. When the tubular fluid reaches the collecting ducts an important
secretion is mediated by a proton-K+
ATPase in the intercalated cells.
Acidosis, which involves the intracellular space and stimulates production of
ATPase, also favors H+
secretion. Hereby, bicarbonate reabsorption is stimulated, whereas alkalosis
inhibits bicarbonate reabsorption by the opposite mechanisms.
THE VALIDITY OF ESSENTIAL CLINICAL VARIABLES
This section describes both the Acid-Base Chart and the Strong Ion Difference.
The acid-base chart
In 1971 Siggaard-Andersen published his widely used acid-base chart (12). Blood
plus interstitial fluid function as one compartment (eECF). Carbon dioxide diffuses
easily through the red cell membrane, so eECF functions as the primary distribution
volume for H+
changes. In his latest publication
(13) the BE scale has been altered to a titratable hydrogen ion concentration
The eECF is important, because the whole purpose for our homeostatic acid-base
balance is to protect the cellular content against consequential alterations
derived from the extracellular environment.
The titratable hydrogen ion concentration or BE of this eECF is shown in the
chart (Fig. 1
The Acid-base Chart was copied with permission from Radiometer Copenhagen
The three variables in Eq. 5, Table 1
, are easy to handle. Rearrangement
of Eq. 5
with constant [bicarbonate] results in the following equation:
log PCO2 = - pH + k (or y = - x + k) Eq
where k stands for three constants (6.1 + log [constant bicarbonate] - log 0.03).
Thus, y is a linear function of x, and the slope of the line is -1 (- 45°). This is called an iso-bicarbonate line, and the slope reflects the buffer capacity (rise in carbonic acid per pH unit) of the bicarbonate buffer in plasma-water. Iso-bicarbonate lines are indicated with small -1 divisions on an abscissa axis located at 5.3 kPa (40 mmHg) on the ordinate at sea level.
By analogy, the slanting lines on the Chart we would call iso-THID lines. They project to the scale on the upper left corner. These iso-lines are steeper than -1, illustrating the expected larger buffer capacity of the eECF compared to bicarbonate buffer only. The slope depends mainly of the hemoglobin concentration, which in the eECF is 3 mM (9.18/3) at sea level. It is noteworthy that each point on the chart can be reached in several ways. The case history, not the acid-base variables, is the only source to the actual sequence of events.
Before and after Siggaard-Andersen´s dissertation, other coordinate systems
have been introduced. Early on, Van Slyke proposed the use of the pH bicarbonate
system, which was adapted by Davenport in his widely used textbook (14). The
Davenport diagram depicts pH as the abscissa and bicarbonate concentration as
the ordinate. In this diagram, the iso-PCO2
are exponential curves. Others (15) have constructed standard log bicarbonate
(ordinate) - pH nomogram, where the iso-PCO2
lines obtained are straight (a modification of Eq 7, Table 1
, where y
is equal to or approximately equal to x + k).
In Europe, none of the many coordinate systems proposed are as widely used as
the acid-base chart (Fig. 1
) along with its related computer strategies.
The titratable hydrogen ion concentration difference (THID) is ideally determined
by titration to a pH of 7.40 at a PCO2
kPa (40 mmHg) at sea level, oxygen saturated and at a blood temperature of 37°C
A useful model of the eECF is an arterial blood sample diluted threefold in
its own plasma (16). In practice, the THID in the eECF is calculated from the
Van Slyke equation based on the measurements of pH and PCO2
It calculates the change in buffer anion concentration from the value at pH
= 7.4, PaCO2
= 40 mmHg and body temperature
at sea level. The equation reads as follows:
THID = - 0.93 x (
+ 14.6 x (pH-7.40)),
= [actual bicarbonate] - 24.5 mM, for a hemoglobin concentration of 3 mM in
eECF. The factors 0.93 and 14.6 depend upon the hemoglobin concentration (12).
The THID in vivo
is independent of PaCO2
since any change in PaCO2
implies opposite molar
changes of the bicarbonate and the non-carbonic buffer concentrations. Hereby,
there is no change in THID so the value is constant (normally equal to zero)
during acute changes in PaCO2
by hyper- or hypoventilation.
The buffer capacity of the carbon dioxide - bicarbonate buffer is high, since
respiratory elimination of CO2
excretion by the kidneys rapidly maintains PaCO2
Strong ion difference
Even before Bronsted defined acids and bases in 1923, these concepts were used in technical and biological sciences and their rational use has continued ever since. However, a drawback occurred in 1948, when Singer and Hastings (17) reintroduced the old Chinese definitions of acids and bases. They consequently defined the buffer base concentration in plasma as the sum of strong non-buffer cations ('bases') minus the sum of non-buffer anions ('acids'). Such definitions were widely accepted in the medical world.
Schwartz and Relman (11) recommended already in 1963 the use of the actual plasma
bicarbonate concentration in the evaluation of acid-base disorders. A change
in the bicarbonate concentration does not reflect the total alteration of non-volatile
acid or base, and the bicarbonate concentration depends upon the PCO2
The actual bicarbonate concentration thus disqualifies as an essential variable.
According to the law of mass action the dissociation constant for water (K'w)
is defined by: K'w = [H+
The dissociation constant is temperature-dependent and of the order of 10-14
M/kg - as measured long ago (1; p. 302). The molality for water is high (1000/18
= 55.56 M/kg) and its size essentially unaffected by the small dissociation,
so (K'w x [H2
O]) is equal to a new constant,
K'w. Since pure water is electrically neutral, the [H+
] and [H+
= K'w; the hydrogen ion activity equals the square root of the new constant
in pure water.
Sound considerations like these lead to the application of a similar line of reasoning and algebra to strong ion solutions and to complex body fluids (18). In complex body fluids SID was defined as the sum of all strong cation concentrations ('bases') minus the sum of all strong anion concentrations ('acids'), just like the definition of buffer base (17). However, SID does not measure the essential variable, THID, and thereby disqualifies.
Stewart´s SID approximation (18) was reintroduced (19). Soon after, the misleading
use of the SID concept was pointed out (16, 20). An analysis of the Stewart
model (21) concludes that SID offers no quantitative advantage over BE in whole
blood. However, the analysis overlooks the advantages of THID - not in blood
- but in the eECF. THID in eECF is independent of PaCO2
and independent of the hemoglobin concentration within normal
limits. It provides enough information to calculate directly the need for immediate
treatment of metabolic acidosis. The amount of bicarbonate in mM given intravenously
can sometimes be calculated by multiplying the THID (in mM) times 20% of the
body weight in kg or liters. THID in eECF remains equal to zero during acute
alterations of PaCO2
, such that these are purely
of respiratory origin. THID in eECF, together with the case details, tells the
total metabolic story, and not part of it as most of the older concepts do.
All that makes THID the diagnostic choice.
ACID-BASE BALANCE AT HIGH ALTITUDE
Humans can suffer from four acid-base disorders: respiratory acidosis, respiratory
alkalosis, metabolic acidosis, and metabolic alkalosis. The four primary or
acute acid-base disturbances, and their four compensated or chronic types, constitute,
together with the normal condition, the nine van Slyke conditions. Plotting
the measured pH and PCO2
in the acid-base chart
allows estimation of the BE or THID, and combined with the case history, as
an absolute requisite, the correct diagnosis can be reached (Fig.1
Acidosis is defined as a disorder with pH in the arterial blood (pHa) less than
7.38, and alkalosis as a condition with a pHa larger than 7.44 for females (7.37-
7.43 for males).
Respiratory acid-base disorders cause primarily acute changes of PCO2
leading to acute changes of pH, whereas THID in eECF is maintained around zero.
Secondarily, the acute changes are more or less compensated by altered renal
excretion of acid or base in a matter of days, so pH tends to be normalized.
Metabolic acid-base disorders cause primary changes in BE or THID in eECF. Secondarily,
these changes are partially compensated by the lungs in a matter of hours. The
final correction of metabolic disorders is typically renal and takes days.
Respiratory alkalosis is caused by ventilation that is disproportionately high
compared to CO2
production, whereby PaCO2
falls and pH increases (acute hypocapnia, in Fig. 1
). As the PIO2
falls with increasing altitude in normal subjects, PaO2
eventually falls below the ventilation threshold 55 mmHg, which stimulates the
chemoreceptors to induce hyperventilation (CO2
washout). Hyperventilation is a typical reaction to high altitude.
It is estimated that over 110 million people live at altitudes above 2500 m,
around the world (Table 2
). Tourism and mountain sports are on the rise,
thereby extending this number by several million per year. Intensive care units
are increasing in numbers as the population growth demands. It is essential
that the attending physicians have precise guidelines for treatment of acid-base
disorders at high altitude. This critical life-saving procedure has up to now
Altitudes and populations of different cities and towns around the world.
Acute respiratory alkalosis is compensated by increased renal excretion of bicarbonate,
which is the result of decreased tubular H+
This is because the low PaCO2
reduces the tubular
secretion, and alkalosis inhibits formation
and secretion of NH4+
After a few days, renal compensation of the respiratory alkalosis is complete,
and pH is back to normal. This is called totally compensated respiratory alkalosis
or chronic hypocapnia (Fig.1
). If for example, Siggaard-Andersen's Acid-Base
chart is used at the altitude of La Paz, where PaCO2
normally is 30 mmHg, the correction of metabolic acidosis is made to sea level
values. Yet they should, in reality, be made to a +5 mM in SBE or -5 mM as THID.
This applies both to permanent residents and to newcomers.
Results from high altitude
Statistical analysis was performed on arterial blood samples from 1865 persons,
breathing ambient air analyzed at the High Altitude Pathology Institute in La
Paz at 3510 m with a Radiometer pHMK2. These included ambulant and hospital
patients, both male and female, of all ages. The mean PaCO2
was 29.4 ±0.16 mmHg, which, presumably due to inclusion of hyperventilating
sea level newcomers, was slightly below the normal value of 30 mmHg in La Paz.
The mean pH was 7.4 ±0.005, which is identical to the normal value at any altitude.
From these two values, THID (or SBE) in the eECF was calculated by means of
the Van Slyke sea level equation to be -5 (or 5 mM). The normal area, therefore,
for an average of 3600 m (ie, La Paz and Lhasa) on the sea level Siggaard-Andersen
Chart is shifted down into the chronic hypocapnia zone. From the high altitude
point of view this is not chronic hypocapnia but rather normal values (22),
so all the 9 Van Slyke conditions have to migrate with the normal area. Consequently,
acid-base charts have been developed for three different altitudes to aid clinicians
at the sites of high altitude residence, exemplified in Table 2
Although altitude shifts within the same city give rise to significant acid-base
changes, as for example in La Paz (23), the average altitudes were given for
each city in Table 2
. Furthermore, there is a considerable variation
in normal values found at similar altitudes around the world in different populations,
so in order to simplify the charts an acceptable range (shaded area) is included
for each altitude, calculated from the bibliographic data (21, 24, 25).
Several linear formulas for the calculation of PaCO2
at different altitude, were proposed, but according to the authors of this article,
the following formula fits the known data quite well up to 5000 m: PaCO2
in mmHg = (38.3 - 2.5 x altitude in km), although it seems that an exponential
equation would be more adequate like the one for the barometric pressure (PB
The calculated mean PaCO2
values for the chosen
altitudes (2500 m, 3500 m, and 4500 m) are 32.5 mmHg, 29.5 mmHg, and 27.5 mmHg,
respectively. The BE or THID scale on the top left also moves down with the
new values, so that a correction for acid-base disorders to a THID of 0 is performed.
A modification of the Van Slyke equation (26) is hence required:
THID in eECF = (1 - [Hb] / 43) x (
+ ßB x (pH-7.4))
Where [Hb] = Hb in mM/3 in the eECF and
= [actual HCO3-
- [Altitude HCO3-
= -1.8 x (altitude in km) + 24.32
The calculated mean altitude HCO3-
values for the chosen altitudes (2500 m, 3500 m, and 4500 m) are 19.8, 18 and
16.2 mM, respectively.
Additionally the buffering capacity of a normally increased hemoglobin concentration at high altitude must be taken into account in order to be precise. The first term in the Van Slyke equation ([Hb] factor 1) is calculated based on the data from our laboratory: [Altitude Hb] = [Hb] + 0.2 x (altitude in km), which results in 0.92, 0.91 and 0.91 at the three altitudes, respectively. The buffer value of non-bicarbonate buffers in blood (ßB) is calculated using these altitude Hb values and the formula: ßB = 2.3 x [Hb] + 7.7 mM being 15.8, 16.2, and 16.7 mM at the 3 altitudes, respectively. Furthermore, one fundamental observation that is borne from this analysis is that the much lower bicarbonate buffer concentration at high altitude minimizes its buffer capacity, whereas the non-bicarbonate buffer capacity increases somewhat.
The same calculations can be performed using the barometric pressure:
= 0.0256 x (PB in mmHg) + 5.15
[Altitude Hb] = [Hb] + (2.25 - 0.003 x (PB in mmHg)).
Barometric pressure is taken into account, since most acid-base analyzers now
have barometers included. Accordingly, the formulas for each level shown in
the graphs (Fig. 2
THID in eECF = -0.93 x (
+ 14.6 x
pH) for sea level
= [actual bicarbonate] - 24.5 mM.
THID in eECF = -0.93 x (
+ 14.9 x
pH) for 2500
= [actual bicarbonate] - 19.8 mM
THID in eECF = -0.92 x (
pH) for 3500 m
= [actual bicarbonate] - 18.0 mM.
THID in eECF = -0.91 x (
pH) for 4500 m
= [actual bicarbonate] - 16.2 mM.
Again, note that the THID is the old SBE with a reversed sign. The normal area for pH is maintained for all three altitudes at 7.4 ±0.04. This further stresses the point of view that it is not the anion or cation changes that are important, but rather the pH balance that is crucial also at high altitude. Actual on-site high altitude hydrogen ion titrations are required in the near future repeating those originally carried out by Siggaard-Andersen.
THID is transcendental and life saving for the high altitude residents and the
newcomers alike. The immediate strategy upon arrival to a given altitude is
to help the body adapt. Most problems arise within 48 h following arrival, where
the acid-base balance is changing. Therefore, when therapy is required in an
intensive care unit during this period, it should point to correcting the acid-base
imbalance of newcomers to that of a normal, well adapted resident (Fig. 2
The Siggaard-Andersen acid-base chart modified for altitudes 2000-2999,
3000-3999, and 4000-4999 m above sea level. The shadowed area provides
margins to variations in normal values at different locations around the
world. Titratable Hydrogen Ion concentration, a deviation from normal
in extended extracellular fluid volume, is abbreviated as THID.
New technology increases the need for an easy interpretation of laboratory data.
As shown above, the acid-base chart and the related computer strategies make
the diagnosis of acid-base disorders easy at a glance. Further developments
and supplements of the chart were performed with the oxygen status algorithm
(26) and recently with a new PO2
diagram (27). Such diagrams ought to be included in all medical textbooks and
in internationally standardized laboratory journals. Altitude specific charts
are included for 2500 m, 3500 m, and 4500 m and the altitude correction factors
are included in the Van Slyke equation. This is of fundamental use for ever
growing high altitude populations around the world, high altitude tourism and
mountain sports, allowing adequate and precise correction of the acid-base disorders.
The THID in the extended extracellular fluid volume is efficient and theoretically
better than any other determination of the metabolic component in acid-base
disturbances even at high altitude.
We acknowledge the assistance of Professors Gustavo Zubieta-Castillo, Joop Madsen,
Simon Rune, and Ole Siggaard-Andersen for contributions and of Kirsten McCord
with the final electronic format.
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