| |
|
There are three fundamentally important compounds
for the occurrence of life on our planet: water, oxygen and carbon
dioxide, and they are all involved in the metabolism of hydrogen
ions. Water is necessary for the appearance of hydrogen ions;
oxygen is necessary for the maintenance of the internal fire in
the animal kingdom by the continuous burning of nutrients, leading
to the formation of hydrogen ions from volatile and non-volatile
acids, which are excreted as soon as possible through lungs, gills,
kidneys, etc. They are continuously reused in the building up
of the vegetable kingdom by the photosynthetic process. Without
hydrogen ions life on hearth would not have developed in the way
it did. In my speech today I shall concentrate on a few important
steps in the development of our knowledge to the hydrogen ions
- from the early days of physics, chemistry, physiology, and medicine
to our days' complicated instrumentalization of clinical care.
According to a Chinese report, strong acids were
known in India in the seventh century A. D. It was described as
a wondrous liquid, sometimes cold, sometimes hot, it could dissolve
wood, herbs, gold and iron, and if one held it in one's hand,
the hand would waste away. From India the skill of making mineral
acids was handed down to the Arabs and reached Europe in the thirteenth
century.
The strong bases are mentioned in Hindu literature
from the eight century. They were made from the ash of burned
wood, by the Arabs called "al quali", or by burning
lime.
Acids and bases were very important for the development
of chemistry from the praxis of gold-making into a scientific
discipline. There were various ways of explaining their actions,
but an all-important change in the conceptions was introduced
with the theory of electrolytic dissociation enunciated in 1887
by Svante Arrhenius in Sweden. Nobody in Sweden, however, believed
in his ideas, but Jacobus van't Hoff in Amsterdam and Wilhelm
Ostwald in Riga did, and now the Swedes acknowledged the ideas
and awarded Arrhenius the Nobel Prize in 1903.
Strong acids had, since Volta in 1800 discovered how to make an electrical current, been used for this purpose in European physical laboratories, leading to the construction of the so-called "gas cells". They consisted of platinized platinium electrodes in glass tubes in contact with oxygen and hydrogen respectively, and immersed in dilute sulphuric acid. Wilhem Ostwald discovered that the decisive factor for the generation of the current was the concentration of hydrogen ions and hydroxide ions formed by the two gasses. This led him to employ hydrogen electrodes to determine the dissociation constant of water, a factor of primary concern in physical chemistry.
Ostwald was very proud of this achievement and reported
it at a meeting of the Royal Saxonian Scientific Society on 9
January 1893.
His work was of the greatest importance for the development
of not only physics and chemistry, but particularly of the biological
and medical sciences, with Lawrence Henderson, professor of physiology
at Harvard, and S.P. L. Sørensen, professor at the Carlsberg
Laboratories in Copenhagen, as the pioneers. The life work of
Henderson concentrated on giving a description of the many variables
influencing the neutrality of blood, since its most significant
and most conspicuous property was its ability to neutralise large
amounts of acids or bases without losing its neutral reaction.
Sørensen in Copenhagen worked with the enzymatic break
down of proteins and demonstrated the vital importance of pH control
to the enzymatic process. He introduced the concept of "buffer"
and further the term "hydrogen ion exponent" which he
symbolised by "pH". Both concepts were immediately accepted
by the scientific world.
One of Sørensen's pupils was the young Danish
physiologist K. A. Hasselbalch, who in 1917 by using a hydrogen
electrode was the first to measure correct pH values of blood
at 37 degrees centigrade. He became interested in medical acid/bases
disorders and was the first to distinguish between metabolic and
respiratory disturbances, which could be compensated or uncompensated
according to the measured blood pH value. His name is used in
the well-known Henderson-Hasselbalch equation, expressing the
buffering action of bicarbonate/carbonic acid in blood.
However, measuring of blood pH values at 37 degrees
centigrade with a hydrogen electrode was far too difficult for
hospitals in the first half of this century - and still is! Before
1920 only a few of the more advanced university hospitals had
small research laboratories belonging to the medical departments,
and laboratory analyses to support the routine clinical examinations
were few. However, the introduction of insulin for treating diabetes
created a need for blood sugar analyses and for diagnosing diabetic
acidosis. Now small clinical laboratories began to appear. Donald
D. van Slyke's methods for determining the total amount of carbon
dioxide in serum were chosen as the most reliable ones for diagnosing
acidosis, and in the 1930'ies and 1940'ies his gasometric measuring
instruments were found in most of the clinical laboratories. The
name alkali reserve or bicarbonate were used to characterise a
measured result: low values signified a metabolic acidosis, high
values a metabolic alkalisis. The metabolic disturbances were
considered as the most important to diagnose, since a correct
treatment could be lifesaving. The respiratory acid/base disorders
were relatively rare, caused usually only minor changes in the
alkali reserve values, and treatment dealt with changes of the
alveolar ventilation. Therefore it was often soon forgotten in
clinical departments that the total content of CO2
in serum, as measured by the van Slyke equipment, was not synonymous
with the alkali reserve, but was dependent also on the actual
carbon dioxide tension.
At least it was so at the fever hospital in Copenhagen,
where a severe polio epidemic began in August 1952. The incidence
of respiratory paralysis was unusually high, and after the first
couple of weeks 27 of 31 patients treated in respirators had died.
The situation was desperate, and the epidemic was still in its
beginning. At that time I was, as head of the laboratory of the
hospital, summoned from my summer holidays in order to attend
a conference with the anæsthesiologist Bjørn Ibsen
and the hospital's clinicians to discuss the causes of the deaths.
The patients were well oxygenated by the time of death, and the
only objective indication was a high level of "bicarbonate"
in blood as measured in a van Slyke apparatus. The clinicians
believed that the patients had a metabolic alkalosis of mysterious
origin. Ibsen promptly dismissed this suggestion and argued that
it could just as well be caused by carbon dioxide retention. Quickly
executed determinations of blood pH at 37 degrees centigrade soon
proved him right, and on the following day a patient was tracheotomized
and given manual positive pressure ventilation which immediately
caused the "alkalosis" to disappear. Subsequently, this
treatment was used on all patients having respiratory paralyses.
This outright misinterpretation of a high CO2
content of serum as alkalosis in patients with respiratory insufficiency
made a deep impression on me as a laboratory doctor, and lead
to new ideas of how to measure on blood for obtaining acid/base
parameters which were correct in chemical and physical aspects
and easy to understand and use by the clinicians in their daily
work.
After some years of work at my department in Copenhagen
we ended up first with a macro method using 2-3 mL of blood and
later with a micromethod requiring as little as 50-75 microlitres
of blood, which in a couple of minutes could give all the relevant
values for expressing an acid/base status of the blood.
We had constructed the whole equipment, except the
pH-meter, in my department at the University Hospital in Copenhagen,
and now offered it to Radiometer. However, the directors here
had become tired of physicians' and hospitals' continuous claim
for service, so they were not interested in manufacturing it.
However, a brother of one of the directors was a strong believer
in the revolutionary power of ideas, so at Radiometer it constructed
a piece of equipment in secret. It was looking and functioning
so well that the directors finally decided to manufacture it.
The success was obvious.
Before I finish I should like to add that another
polio epidemic, in USA in 1954, led Richard Stow at the Ohio State
University in Columbus to the construction of a pCO2
electrode. Leland Clark in USA, working in a team using cardiopulmonary
bypass, discovered in 1953 that membrane covered oxygen electrodes
did not suffer from oxygen poisoning, and this led to the construction
of the oxygen electrodes which we use in our hospitals today.