Historical Review
HISTORY OF DLOODGAS ANALYSIS. I. THE
DEVELOPMENTOF ELECTROCHEMISTRY
John W. Severinghaus, MD,*
and Poul B. Astrup, Dr med]"
EDITOR'SNOTE. One of the most significant advances in the field
of monitoring has been the development of techniques for
measuring "blood gases." The impact of these measurements
has reached many areas of medicine. Certainly respiratory
therapy, the intensive care unit, the prolonged management of
mechanically ventilated patients, and much of the advanced
anesthetic management of difficult surgery in difficult patients
owe their existence to blood gas analysis.
As with so many other advances, the introduction of blood
gas analysis is not the contribution of one man, or even one
laboratory or one country. Nor is it the result of a decade or
generation of targeted research. Rather, the foundation for our
facile use of blood gases today was laid for three centuries in
Europe and the United States. Its fascinating story is the story
of the physical sciences, of the men and the ideas that affected
scientific investigation for generations. It is the story of life
itself--of the passing of ideas from one mind to the next. The
stories of these men and their ideas have been told before.
They have never before been focused on blood gas analysis.
A major contributor in this field has been John Severing-
haus, who developed the electrode for measuring CO_~ ill
blood. Highly respected in physiology and medicine, as well
as in his own field of anesthesia, Dr Severinghaus provides an
insight into the scientific background and thus an understand-
ing of the gradual and continual development of ideas. More
important, he is excited and intrigued by the process o f
scientific investigation and discovery. Still more important, hc
possesses a sense of history and a compassion for people. Few
writers have combined expertise, understanding, historical
sense, and compassion. In recent history, Sir Winston Chur-
chill and Samuel Eliot Morrison come to mind. The latter, all
Admiral in the United States Navy and a professor of history
at Harvard, wrote the definitive naval history of the Second
World War. In medicine, the names o f Julius Comroe and
Lewis Thomas come to the front.
It is therefore an exceptional pleasure to introduce a series of
essays designed to educate and to engross. These essays will
cover the history of blood gas analysis from the initial perti-
nent ideas to its final realization as an invaluable resource for
all of medicine. The first essay explores the evolution of elec-
trochemistry from its early days through the development of
the glass pH electrode. Follow with fascination the thread of
discovery. We hope that you enjoy this essay and that you
look forward to the next ones as much as we do.
N. Ty Smith, MD
From the *Department of Anesthesia and the Anesthesia Research
Center, University of California Medical Center, San Francisco, CA,
and the tDepartment of Clinical Chemistry, Rigshospital, University
of Copenhagen, Copenhagen, Denmark.
Received February 26, 1985, and in revised form March 8. Accepted
for publication Mar 11, 1985.
Address correspondence to Dr Severinghaus, Anesthesia Research
Center, 1386 HSE, University of California Medical Center, San
Francisco, CA 94143.
180
Severinghaus JW, Astrup PB: History of blood gas analysis. I. The
development of electrochcnfistry.
J Clin Monit 1985;1: 180-192
ABSTRACT. In 1982 Poul Astrup, in writing a history of acid
base balance and blood gases, invited me to contribute a chap-
ter about the modern period, from 1950 to tile present. As-
trup's book is scheduled for publication at the end of 1985 by
Radiometer Company of Copenhagen; it will be distributed
by Munksgaard (Blackwell). The story of blood gas analysis
since 1950 is vast: there are some 420 references to methodol-
ogy and closely related physiology. This "moder,l" history
will appear in the Journal of Clinical Monitoring as a series of
essays. This first essay centers on electrochemistry, the basis
of modern blood gas analysis, and accordingly examines its
roots in more detail.
The 17th and 18th century exploration of electricity and gas
laws led to the development of thermodynamic electrochemis-
try in 1887 through the collaborative efforts of van't Hoff,
Arrhenius, Ostwald, and Nernst. The importance of the hy-
drogen ion in biology and ill the body's buffcring mechanisms
was worked out by Henderson, Van Slyke, Barcroft, and
many others in the first quarter of this century. Tile glass
electrode became available after 1925, but practical blood pH
measurement was introduced in the 1950s by Astrup and Sig-
gaard Andersen. Succeeding essays will concern micro pH
methods and base excess analysis, the discoveries of Stow's
CO2 electrode and Clark's 02 electrode, the development of
oximetry, and related physiology.
KEY WORDS. Acid-base equilibrium: pH methods; Measure-
ment techniques: electrodes, pH, carbon dioxide, oxygen
M o d e r n blood gas analysis depends on three electrodes:
1. T h e glass p H electrode was discovered in 1909 by
Cremer, w h o first noted that a thin glass m e m b r a n e
behaves as if it were permeable to h y d r o g e n ions.
2. T h e P c o 2 electrode, invented by Richard S t o w in
1954, is a p H electrode covered by a thin electrolyte
layer separated f r o m the sample by an insulating
C O 2 permeable m e m b r a n e , usually made o f Teflon.
3. T h e 0 2 electrode, invented by Leland Clark between
1954 and 1956, consists o f a negatively charged
platinum cathode and reference electrode behind an
insulating 0 2 permeable m e m b r a n e , usually made o f
p o l y p r o p y l e n e . T h e cathode donates electrons to 0 2
molecules diffusing t h r o u g h the m e m b r a n e .
A student o f electrochemistry soon discovers that its
roots lie in the physical chemistry o f gases, beginning
with Boyle, as well as in electricity and its behavior in
solutions. This essay is the story o f the union o f physics
and chemistry in Leipzig in 1887, with a focus on Walter
Nernst, f r o m w h o s e research were developed the pH,
Pco2, Po2, and reference electrodes.
 Historical Review: Severinghaus and Astrup: Electrochemistry
FROM GILBERTTO FARADAY:OF BATTERIES
AND BALLOONS
The terms electron and electrics were coined in 1600 by
William Gilbert (1540-1603), the court physician to
Queen Elizabeth, using the Greek word elektron for
amber. Otto von Guericke (1602-1686), the mayor of
Magdeburg, was the first scientist to study both elec-
tricity and gas behavior. Not only did he invent the air
pump and demonstrate the power of a vacuum with his
Magdeburg hemispheres, but he also constructed the
first machine to generate electricity, a rotating ball of
amber. These two quite different avenues of investiga-
tion were to continue largely apart until 1887.
Balloons and batterics were part of the forefront of
scientific excitement in the 17th and 18th centuries. Sir
Robert Boyle (1627-1691) studied static electricity and
sparks and also demonstrated that gases are nearly per-
fectly elastic: pressure = k/volume. The constant, k,
was later shown to be n R T , where n = number of
moles, R = gas constant, and T = absolute tempera-
ture. This is the story of how k became part of the
Nernst equation describing single electrode potentials.
In 1678 the English microscopist and physicist Robert
Hooke (1635-1703), who started as Boyle's assistant at
Oxford, suggested that gases consist of molecules in
motion, the foundation of the ionic as well as the kinetic
theory. Hooke was highly skilled in mechanics, or was,
as we might say, a gadgeteer. He actually built, at
Boyle's request, the first modern air pump, from which
Boyle derived his law. Hooke also was the first to claim
that respiration was similar to combustion, a conclusion
he drew from pumping air into a dog's lungs and allow-
ing it to escape through lung pin holes in the open chest
without movement of the lungs, thus dispelling the idea
that the pumping of the lungs by the diaphragm was
important [1].
Hot air ballooning in France was a sport that caught
the fascination of scientists and helped penetrate the
secrets of the atmosphere. Jacques Alexandre C~sar
Charles (1746-1823), born in Beaugency, Loiret,
France, was the first to use hydrogen in ballooning. In
1787 he described the proportional expansion of gases
with heat, V = k T, a beginning in understanding hot
air ballooning. This work was the basis of the second
law of thermodynamics, as well as the concept of abso-
lute temperature derived later from extrapolation to
zero volume of the relationship between gas volume and
temperature observed by Charles and Gay-Lussac.
Charles's work was chiefly mathematical. Professor of
physics at the Conservatoire des Arts et M~tiers, he
invented a hydrometer and a goniometer and improved
Fahrenheit's aerometer.
181
John Dalton (1766-1844), a Quaker English chemist
and physicist in Manchester, proposed the law of partial
pressures in 1801 [2], a concept transferred from the gas
laws by Nernst, who saw ion activity as a sort of partial
pressure. Dalton also originated the atomic theory in
1808 and described his own color blindness, sometimes
called daltonism. Dalton's close friend and neighbor,
William Henry (1774-1836), thought he saw error in
one of Dalton's papers. To disprove it, he experimented
with the solubility of various gases in water and found
in all cases that the amount dissolved was proportional
to the partial pressure (Henry's law [1802]) [3]. Henry's
son William wrote the first biography of Dalton.
Another balloonist was Joseph Louis Gay-Lussac
(1778-1850). He became professor of physics and
chemistry in Paris after a daring balloon ascent in 1804
to test the effect of altitude on the composition of air and
on the earth's magnetic field. Claude Louis Berthollet
(1748-1822), his mentor in Paris, who wrote a treatise
on gas analysis, told him, "Young man, your destiny is
to make discoveries," a challenge that must have driven
his highly productive life. He extended the observation
of Charles on the role of temperature on gas volume,
proving that the volume of a gas is proportional to the
"absolute" temperature. Gay-Lussac established and
published in 1808 the law of combining volumes, ex-
plored almost every branch of chemistry and physics,
and edited Annales de Chimie et de Physique for many
years. Arrhenius [4] gives Gay-Lussac credit for the idea
of ionization of salts in water in 1839, 45 years before
Arrhenius "discovered" ionization.
In 1811, AmadeO Avagadro (1776-1856), a physicist
at the University of Turin, put forward his hypothesis,
an intelligent guess based on the law of combining
volumes and which required half a century to prove:
that equal volumes of all gases under the same condi-
tions of temperature and pressure contain equal num-
bers of molecules. The number of molecules in a mole,
Avagadro's number, was first given a reasonable mea-
sured value at about the turn of the century, and is now
taken to be 6.022 • 10~.
The concept and determination of absolute zero was
formalized in London in 1848 by the Scot William
Thomson, (Baron) Lord Kelvin (1824-1907), making
possible the precise measurement of the universal gas
constant, R, in the following equation, which he ob-
tained by combining the laws of Boyle, Charles, and
Gay-Lussac:
PV = nRT.
Kelvin is generally regarded as the founder of British
physics. He constructed a highly sensitive galvanometer
182 Journal of Clinical Monitoring Vol I No 3 July 1985

to receive messages from the first transatlantic cable,

which had too much resistance to drive the existing
receivers when it was tested. He was knighted for sav-
ing it from uselessness.
Returning to electricity, the other genetic root of elec-
trochemistry, following the friction experiments of
Otto von Guericke and Robert Boyle, Sir Isaac Newton
built a glass friction machine and studied static clectric-
ity in 1675. The first to notice that water promotes con-
ductivity in nonmetallic substances, such as thread, was
C. F. de Cisternay Du Fay, in 1732. He was able to
distinguish "resinous" charges, which collected on am-
ber, from "vitreous" electricity on glass surfaces. Benja-
min Franklin (1706-1790) unfortunately guessed wrong
about these, leaving us with "negative" to describe the
resinous charge, which we now know has the excess of
electrons. Franklin not only identified lightning with
frictional electricity with his famous kite, but also
studied the then recently discovered Leyden jar, show-
ing that its electric charge was on the glass, not on the
metal surfaces.
Electrochemistry began about 1786, when the Italian
physiologist Luigi Galvani (1737-1798), tcaching
anatomy in Bologna, noticed that a frog's legs twitched,
as if the frog were alive, when a nearby static electricity
machine was turning. He then found a similar response
to touching part of the frog with a copper wire con-
nected to an iron railing on which the frog was impaled.
Alessandro Volta (1745-1827), a physicist at Como and
later director of the faculty at the University of Padua,
then observed that such effects were very marked if the
metals were different, but did not occur at all if Fig 1. Michael Faraday (1791-1867).
the metals were the same. In 1796 Volta constructed the
first battery, or voltaic pile, from alternate sheets of
silver and zinc separated by wet cloth. Testing various tity, which we now measure in coulombs, was not
metals led him to arrange them in an electromotive clearly differentiated from the energy, which also in-
series. In 1800 William Nicholson (1753-1815) and An- cludes voltage. The faraday relates electric current to
thony Carlisle (1768-1840) used Volta's pile to dis- matter: 96,485 coulombs is one gram equivalent. It is
sociate water into hydrogen and oxygen gas. the product of Avagadro's number and the charge of an
electron in coulombs, both fundamental constants.
FARADAY:ELECTROCHEMISTRY Studies o f Volta's pile, later called Galvani's cell, or
the galvanic cell, early made it clear that some event
Michael Faraday (1791-1867) (Fig 1), brilliant appren- happens at the metallic surface, while the solution is
tice of H u m p h r e y Davy (1778-1823), attracted tremen- unaltered. An explanation that satisfied the scientific
dous public attention by demonstrations and popular world for most of the 19th century was published in
books at the Royal Institution in London in the first half 1805 by (Baron) Theodore Freiherr yon Grothuss
o f the 19th century. In 1833 Faraday established the (1785-1822). He suggested that the salts in solution,
quantitative laws of electrolysis that bear his name and which were known to be composed of two parts, such
coined many terms still in use, such as ion (from the as sodium and chlorine, could swap partners in the solu-
Greek word for wanderer), anion, cation, anode, and tion, and did so when electric current was passed
cathode. He wrote, "The chemical power of a current of through the metal electrode into or out of the solution.
electricity is in direct proportion to the absolute quan- According to this idea, ionization, as Arrhenius later
tity of electricity which passes." At that time the quan- described it, existed only while current was flowing.

Fie 2. Josiah Willard Gibbs (1839-1903).
The Grothuss theory could not account for the diffcr-
cnt mobilitics or conductivitics of various salts, a defcct
first noted by Wilhclm Hittorf (1824-1914), professor
of physics and chemistry at the Univcrsity of Mfinstcr.
From 1853 to 1859, from studies ofthc conductivity of
various salts, hc generated a table of "transport num-
bers" for thc migration of thc particlcs (ions) in clcc-
trolysis. Rudolph Julius Emnaanucl Clausius (1822-
1888), professor of physics (primarily a mathcmatical
physicist) in Zurich theorized in 1857 that "currcnt does
not decompose the molecules but only guides those that
are momentarily frec."
THERMODYNAMICS
Coincident with the growth of the knowlcdge of chemi-
cal reactivity from the standpoint of kinetics, the science
of thermodynamics developed. In 1824 Nicolas Leonard
8adi Carnot (1796-1832), a French army officer, studied
the extent to which heat could be transformed into use-
Historical Review: Severinghaus and Astrup: Electrochemistry 183
Fig 3. Hem'i Louis Le Chatelier (1850-1936).
ful work. This led in 1842 to the first law of thermody-
namics (conservation of energy). In the same year
Clausius and William Thomson deduced the second
law. In 1857 Clausius concluded, as had Gay-Lussac,
that ions already existed in solutions, rather than being
caused by passing electric current through the solution.
The idea was ignored until Arrhenius quoted Clausius
in his 1884 thesis.
Josiah Willard Gibbs (1839-1903) (Fig 2), professor of
mathematical physics at Yale and the most distinguished
American mathematical physicist of his day, is best
known for the phase rule, which he published in 1876. It
was his insight into thermodynamic events at metallic
surfaces that led to the quantitative relationship between
the free energy of a reaction, its temperature coefficient,
and the electromotive force of a reversible half cell reac-
tion. The Nernst equation derives in part from the
Gibbs-Helmholtz equation
E = - A H / n F + T(dE/dT),
184 Journal of Clinical Moniloring Vol 1 No 3 July 1985

where E = cell electromotive forcc, H = enthalpy, n =

valence, F = faraday, and T = temperature. Gibbs's
paper was unnoticed for several years, but was later
taken up in A m s t e r d a m by the theoretical chenlists
Hendrik Willem Bakhuis R o o z e b o o m (1854-1907) and
Jacobus Hendricus van't Hoff. In 1901 the Copley
Medal o f the Royal Society was awarded to Gibbs for
being the first to apply the second law o f t h e r m o d y n a m -
ics in relating chemical, electrical, and thermal energy
and capacity for external work.
The next step in the synthesis o f gas and electrochem-
ical cell theory came in the 1884 principle o f van't H o f f
and Le Chatelier. Henri-Louis Le Chatelier (1850-1936)
(Fig 3) was professor o f general chemistry at the Sor-
bonne. He found that if one perturbs an equilibrium
chemical system by changing temperature, prcssure, or
concentration, the equilibrium shifts to "nullify," or
counteract, the effect and reach a new equilibrium. This
is the crucial relationship (used by Nernst) between the
equilibrium constant, K, and temperature, T:

In K = C - AH/RT.

VAN'T HOFF, ARRHENIUS,AND OSTWALD:GASES,

OSMOTIC PRESSUREAND IONS.

In 1887 scientific electrochemistry was born when van't

Hoff, Arrhenius, and Ostwald almost simultaneously
realized that the thermodynamics o f Gibbs and Le
Chatelier could be used to " m a r r y " the gas laws and
ionic behavior.
Fig 4. Jacobus Hendricus van't Ho[f (1852-1911).

Jacobus Hendricus van't H o f f ( 1 8 5 2 - 1 9 1 1 )

The Dutch genius Jacobus Hendricus van't Hoff (Fig 4), was
born in 1852 in Rotterdam, studied with A. F. Kekule in
Bonn, taught chemistry at Utrecht, and became professor of
chemistry, mineralogy, and geology in Amsterdam in 1878.
His nomination to the Royal Netherlands Academy of Sci-
ences was rejected in 1880 due to lack of acceptance of his ideas
in his own country, but was approved five years later. His
pressure laws were given general validity by the electrolytic
dissociation theory of Arrhenius, the first foreigner to come to
work in his laboratory. In 1901 van't Hoff received the first
Nobel prize in chemistry for his pioneering work on chemical
dynamics and osmotic pressure in solutions, proving that os-
motic pressure and gas pressure are identical. From his insight
that the bonds of carbon were in the shape ofa tctrahedron he
deduced that optical rotation required asymmetry, the basis
for all stereochemistry. Overwhelmed by the burdens of
teaching and examination in Amsterdam, he accepted appoint-
ment as Honorary Professor in Berlin in 1896, where he
studied the origin of oceanic deposits. Van't Hoff valued the
power of imagination in science and championed the concept
of a "special class" of scientists, to be relieved of administra-
tive and teaching responsibilities and protected and nourished
by society. An admirer of Byron, a naturc lover, and an en-
thusiastic traveler, he died in Steglitz on March 1, 1911.
Influenced by Raoult's 1881 paper showing that molal
concentration determines freezing point, boiling point,
and vapor pressure, van't H o f f was able in 1885 to
mathematically relate thesc three properties to the os-
motic pressure. He showed that the osmotic pressure o f
a given solution was equal to the pressure the same
quantity o f the substance would exert as a gas at the
same temperature. There was, however, a problem
with electrolytes, which, o f course, was caused by the
increase in the n u m b e r o f particles with ionization. In
his Nobel lecture, van't H o f f w r o t e , "1 should not have
had the pleasure o f giving this lecture if Professor Ar-
ri-..enius had not succeeded in demonstrating the cause o f
these exceptions." He deduced that an equation similar
to the gas laws equation, P V = iRT, would apply to
osmotic pressure in a solution, where i was related to
the io'.lization. By analogy, solution ion theory could be
 Historical Review: Severinghaus and Astmp: Electrochemistry 185

derived from gas theory, each property depending on

the n u m b e r o f particles o f a substance per unit volume.
With this insight van't H o f f provided the needed
theoretic link between the more advanced science o f
gases and the newer studies o f electrochemistry with
which we are here concerned.
In his most important paper, published in 1887 in the
first volume o f Zeitschrifi fib" physikalische Chemie [5],
van't Hoff, often called the father o f physical chemistry,
established the mathematic basis o f the relationship o f
heat o f reaction to the equilibrimn constant, in an equa-
tion called the van't H o f f isochore. He also d e m o n -
strated that the m a x i m u m external w o r k obtainable
from a chemical reaction m a y be taken as a quantitative
measure o f chemical affinity. During the years follow-
ing Arrhenius's publication o f the theory o f ionization,
van't H o f f further developed the relations o f ionization
to his gas analogy. At the same time, in Stockhohn,
Svante August Arrhenius was beginning his thesis stud-
ies o f the conductivity o f solutions.

Svante August Arrhenius (1859-1927)

Svante August Arrhenius (Fig 5) was born in Vik, Sweden, on

February 19, 1859, where his father was a surveyor and estate
manager. After attending Uppsala's cathedral school, he
studied physics, mathematics, and chemistry at Uppsala Uni-
versity. In pursuit of his doctorate he moved to Stockholm.
He wrote later [4], "The opportunities for working it out in
nay home university, Uppsala, were not favorable, therefore l
went to Stockholm. Thereby l came under the influence of the
great electrician, Edlund, who had very great diversity of in-
terests . . . He did not encourage me very much to continue
with chemical ideas, because he did not understand them very
well. He was a pure physicist, but l had some ideas of nay
own." At that time physics and chemistry were completely
unrelated fields, and Cleve, Arrhenius's chemistry professor in
Uppsala, was equally lost in physics. A genial, nature-loving
man who made friends wherever he went, Arrhenit, s turned
Iris interests to immunology, geology, and cosmology in later
years, speculating on the spread of bacterial life through the
universe by light pressure. He died in Stockholm on October
2, 1927.
T h r o u g h a fortunate choice o f studying very dilute
salt solutions, whereas previous workers had used con-
centrated solutions, Arrhenius was able to separate the
surface potentials from the conductivity changes and
was working at levels where salts are indeed more
nearly completely ionized. Arrhenius was thereby suc-
cessful in correlating the chemistry o f the colligative
properties o f solutions o f acids, bases, and salts with the
physics o f their electrochemical properties. This was the
fundamental accomplishment o f his theory o f elec-
trolytic dissociation, sometimes called the classical
theory o f ionization, the e m b r y o form o f which was
Fig 5. Svante August.Ardlenius (1859-1927).
contained in the thesis he defended in May o f 1884. His
studies o f the conductivity o f dilute solutions suggested
to him that the dissolved salts were completely sepa-
rated into the two components, a metal and a gas or
other molecule. This was radical thinking, since at that
time it was assumed that the metal should then behave
like a metal, sodium, for example, and react violently
with water. Arrhenius recalled the Aha! reaction he had
on reading Clausius and Berthollet during his research:
" T h e active molecules in regard to electricity are also
active in regard to chemical properties, and that was the
great s t e p . . . I got that idea on the night o f l 7 t h o f May
in the year 1883, and I could not sleep that night until I
had worked through the whole p r o b l e m . "
T o describe these separate components o f the salts,
which he believed to be dissociated from each other,
Arrhenius reintroduced the terms o f Faraday, cation,
anion, and ion, and rather timidly prepared his thesis.
Years later, in 1911, Arrhenius told the audience for
his Gibbs lecture at the American Chemical Society, "I
186 Journal of Clinical Monitoring Vol 1 No 3 Jul), 1985

knew m y professors in Uppsala too well and found that

it would be impossible to get them to believe that [all
the molecules o f salt were dissociated]. Therefore, if I
had made such a statement in m y doctor's thesis, it
would not have been approved, so that I would have
had to work on a new thesis before I could be
nominated doctor." His thesis, the first clear link o f
chemistry to physics, was given the lowcst possible
passing mark at Uppsala. Arrhenius sent copies to Ost-
wald, Clausius, and Lord Kelvin. Ostwald, highly im-
pressed, came to Uppsala to visit him and tried to per-
suade the authorities o f the importance o f Arrhcnius's
work, despite the obvious skepticism o f Professor
Cleve, who taunted Ostwald, "And you also arc a be-
liever in these little sodium atoms swimming around?"
Nonetheless, Ostwald's support got Arrhenius a Privat-
dozent nomination in physical chemistry. T w o years
later Arrhenius went to Riga and spent most o f the year
with Ostwald exploring the details o f his ionization
theory.

Wilhelm Ostwald ( 1 8 5 3 - 1 9 3 2 )

Wilhelm Ostwald (Fig 6) studied chemistry at Dorpat Univer-

sity in Estonia, where he was born, and held university posts
under two important scientists there, Arthur yon Octtingen
and Carl Schmidt, to whom he attributed his scientific train-
ing. In 1887 he accepted a position as professor of physical
chemistry in Leipzig, estab]ishiug the world's first laboratory
of physical chemistry. His teaching attracted students from all
over the world, including the chemist William Ramsay from
London, Harvard chemist Theodore William Richards, Ar-
thur Ames Noyes from Massachusetts Institute of Technol-
ogy, and Arrhcnius. Ostwald's studies of ionization of electro-
lytes, stimulated by Arrhenius and followed by work on
catalysis, chemical equilibria, and reaction velocities, led to the
Nobel prize in chemistry in 1909. In association with van't
Hoff, Ostwald founded and edited Zeitschrift fiir physikalisdw
Chemie in 1887. Ostwald discovered that ammonia could be
oxidized with platinum catalysts, the crucial method that per-
mitted tile Germans to make explosives during the World War
I blockade. In 1906, at age 53, he retired to Saxony, but re-
mained vigorously active in the middle class pacifist move-
ment, educational reforms, and monism, opposing thc estab-
lished Church's claims to power in natural sciences. He
published several books on natural philosophy and founded
and edited Annalen der Naturphilosophie and Klassiker der ex-
akten Wissenscha.fien (1889), of which more than 250 volumes
have been published. He maintained an interest in color per-
ception and standardization until his death, near Leipzig, on
April 4, 1932.
T o w a r d the end o f their year together in Riga, when
Ostwald was preparing for his move to Leipzig in 1887,
Arrhenius went to study in Wfirzburg with Kohlrausch,
where he learned o f van't H o f f s memoire on osmotic
pressure. Arrhenius experienced another sudden in-
F(~, 6. Wilhehn Osewald (I853-1932).
sight, realizing that each molecule o f salt produces two
"molecules" (ions) affecting conductivity and osmotic
pressure. He immediately wrote to van't Hoff, who is-
sued a highly enthusiastic invitation to his laboratory in
Amsterdam for joint work, beginning a long and deep
friendship between the two foremost physical chemists
o f the age.
Later in 1887, Arrhenius rejoined Ostwald in Leipzig.
He published his n o w polished and revised dissociation
theory in the first volume o f Ostwald's Zeitschrifi fiir
physikalische Chemie [6]. This same first issue also con-
tained van't Hoff's most important paper, described
above, quantitatively relating the behavior o f gases and
solutes. This publication, but even more important, the
persistence o f Ostwald and van't H o f f i n persuading the
Uppsala faculty o f the importance of28-year-old Svante
Arrhenius, finally won him acclaim and a lectureship at
Uppsala. After declining a chair in Giessen, he went to
the S'ockholm Royal Institute o f Technology as lec-
 Historical Review: Severinghaus and Astrup: Electrochemistry 187

turer. Within 5 years Arrhenius, throughout his life a

delightful, witty, and gracious man, became professor,
then rector. He was o f e r e d the most prestigious chair in
chemistry at Berlin, but declined it when the Nobel
Institute o f Physical C h e m i s t r y was created to keep him
in Stockholm, a clear indication that not all Swedes
shared Cleve's skepticism o f s w i m m i n g sodium atoms.
Arrhenius received the Nobel prize in 1903. The
Nobel committee had the wit to require Cleve to make
the award spcech at the ceremony. Arrhcnius recalled
from his early research days [4]: "I came to m y profes-
sor, Cleve, w h o m I admire very much, and I said: 'I
have a new theory o f electrical conductivity as a causc o f
chemical reactions.' He said: 'That is very interesting,'
and then said, ' G o o d b y e . ' He explained to me later,
when hc had to pronounce the reason for m y receiving
the Nobel prize for that work, that hc kncw very well
that there are so m a n y diffcrent theories formcd, and
that they are all almost certain to be wrong, for after a
short time they disappear; and thereforc, by using the
statistical manner o f forming his ideas, he concluded
that m y theory also would not exist very long."
Taken together, Arrhenius's ionic theory and van't
H o f f ' s linkage o f ions with gases made it clear that ions
behave like gases, exhibiting activity comparable to par-
tial pressure, but observed as voltage.

NERNST:SINGLEELECTRODETHEORY

Fig 7. Walther Hermama Nernst (1864-1941).

Wahher Hermann Nernst ( ! 8 6 4 - 1 9 4 1 )

Walther Hermann Nernst (Fig 7) was born in Briesen, West

Prussia, in 1864. He was educated at the universities of Zurich
and Graz and received his doctorate in physics at Wfirzburg in
1887. Nernst came to Leipzig in 1887 as Ostwald's assistant
and found himself fascinated by the new field of physical
chemistry. He was appointed to the physics departnaent at
G6ttingen in 1890, where he spent 15 years before becoming
professor of physical chemistry ill Berlin. In 1924 he was ap-
pointed director of the Institute for Experimental Physics in
Berlin, where he remained until retirement in 1933. Although
the Nobel prize was awarded to Nernst in 1920 primarily in
recognition for the development of the third law of thermody-
namics, the heat theorem, it was his early study of single
electrode potentials that led directly to our modern elec-
trochemical analytic methods, and, curiously, it was about
electrochemistry that he chose to lecture for the Nobel award,
believing this to have been his most important work. He also
made fundamental contributions to theory of solutions, ther-
modynamics, solid state chemistry, and photochemistry. Me-
chanically minded, Nernst was interested in applications of
science in industry. He invented a better electric light and an
amplifier for the piano, and in later years wrote on astrophys-
ics. He had five children, and his only two sons were killed in
World War I. He died November 18, 1941, in Muskau.
Ostwald, as editor o f Zeitschrift fiir physikalische
Chemie, immediately recognized the significance and the
research possibilities provided by the Arrhenius and
van't H o f f papers and put Nernst to w o r k on them.
During the next t w o years in Leipzig, Nernst worked
out the mathematic relationships between van't H o f f ' s
gas-solution analogy and Arrhenius's ionic theory, de-
riving, in 1889, the theory o f galvanic cells by assuming
an electrolytic pressure o f dissolution, which forced ions
from the electrode into solution, and which was op-
posed by an osmotic pressure o f the dissolved charged
ions. The investigation led Nernst to the equation that
bears his name [7]:
E = E ~ + [RT/nF]log(a/a~
The change o f voltage, E, from E ~ proved to be pro-
portional to the logarithm o f the change o f activity, a,
from the initial value, a ~ multiplied by the constant
188 Journal of Clinical Monitoring Vol 1 No 3 July 1985

[RT/nF], which Nernst showed could be given in volts.

Its value is 59.5 mV at 25~ 61.5 mV at 37~ It incor-
porates the universal gas constant, R (from Boyle's law,
as modified by Charles and Gay-Lussac and formalized
by Kelvin), absolute temperature, T (which also was
computed from gas behavior), the valence, n, and the
Faraday constant. Nernst's equation brings together the
understanding o f gases, thermodynamics, ionization
theory, and electrochemistry. It underlies all three o f the
modern blood gas electrodes, and a fourth, the reference
electrode, which is used in all three.
It was also Nernst who first realized in 1889 that the
liquid junction potential developed between differing
solutions resulted from the differing mobilities o f the
cations and anions, leading to different rates o f their
diffusions across the junction. He proposed the selection
o f salts with as nearly equal diffusion o f charges as pos-
sible, and is thus responsible for the almost universal usc
o f potassium chloride to connect an unknown solution
to a reference electrode. This suggestion was taken up
by Niels Bjerrum (1879-1958) [8] in the development o f
the salt bridge in 1905.
In the fourth essay we shall return to Nernst's labora-
tory, where Danneel discovered the polarographic re-
duction o f oxygen, the beginning o f the development o f
the oxygen electrode.

SgRENSEN,HENDERSONAND HASSELBALCH:pH

From the studies o f single electrode potentials in

Nernst's laboratory, there developcd at the turn o f the
century a widespread use o f the hydrogen gas platinum
electrode as the standard zero potential for all other elec-
trodes. Platinum potential is zero when the acid o f the
solution is 1 molar and the partial pressure o f H2 gas is at
1 atmosphere. The potential falls 59.5 mV per decade
reduction in hydrogen ion concentration (at 25~ per-
mitting measurement o f H + activity. Biologists found
themselves measuring the reaction, or hydrogen ion
concentration, at 0.00000005 molar, or 50 x 10 -'j.
S~ren Peter Lauritz Sorensen (1868-1939) (Fig 8), in his
research on acidity, developed the hydrogen electrode
for biologic use and suggested the pH nomenclature to
more conveniently express this number as the negative
logarithm o f H + concentration, in this case 7.3 [9]. Af-
ter his thesis at Copenhagen University, he succeeded
Johan Gustav Christoffer Kjeldahl (1849-1900) as direc-
tor o f the chemical section o f the Carlsberg Laboratory,
where he gradually redirected his own interests from
analytic inorganic chemistry to biochemistry. He is still
best known as "the father o f p H . "
F(e. 8. S,,re, Peter Lauritz Sorensen (I868-1939).
La u, rence Joseph Hen derson ( 1 8 7 8 - 1 9 4 2 )
Lawrence Joseph Henderson (Fig 9) studied physical chemis-
try at Harvard because no biochemistry courses were avail-
able. His interest was captured by acid-base equilibria, leading
to an essay he wrote on Arrhenius's dissociation theory in
competition for a Bowdoin Prize. After completing medical
school (with no intention of practicing medicine) and a two-
year stay in Strassburg with Hofineister, hc joined the Har-
vard Medical School as a lecturer in biological chemistry. He
remained at Harvard the rest of his life. He founded the Labo-
ratory of Physical Chemistry, the Fatigue Laboratory, which
was directed by Bruce Dill (curiously in the school of Business
Administration), and the Society of Fellows at Harvard. Hen-
derson's diverse interests led him to study and write in
oceanography, formation of the earth, the telcologic appear-
al~:e of nature, and philosophy; he even attcmpted to apply
Gibbs's equations and concepts to the sociologic theory of
organization of society and many aspects of biochemistry and
general physiology. He died unexpectedly of a postoperative
pulmonary embolus on Febrt, ary 10, 1942.
 Historical Review: Severinghaus and Astrup: Electrochemistry 189
Fig 9. LawrenceJos~Th Henderson (1878-1942).
In 1908 Henderson discovered thc remarkable capac-
ity o f carbonic acid to prcscrvc ncutrality in an aqueous
solution containing bicarbonate. In the coursc o f his
studies o f blood as a physicochcmical system, he rcad
Gibbs's " O n thc equilibrium o f hctcrogcncous sub-
stance," which hc characterized as "the greatest effort at
sustained abstract thinking in the history o f Amcrica."
Hc synthcsizcd the insights o f Gibbs with the h o m o -
graphic method o f d ' O c a g n e to represent mathemat-
ically the acid-base system o f blood. From thc law of
mass action, publishcd in 1867 by the Norwegians Cato
Maximilian Guldbcrg (1836-1902) and Pctcr Waagc
(1833-1900), Henderson derived the equation following
[10]:
K = l H+ IIHC03-lilaC021,
where de02 (dissolved CO2) includes both the CO2 gas
and H2CO3.
Fig 10. Karl Albert Hasselbalch 1874-1962).
All biologic liquids contain C O , and 0 2. The hydro-
gen electrode must be operated at zero 0 2 pressure, and
it is also difficult to keep Pc02 constant; thus, p H mea-
surements are rather impractical with the He electrodes.
Actually, Hasselbalch, about 1910, worked out a way of
repeatedly flushing a new plasma sample into a sealed
H2 bubble until Pc02 was equilibrated to measure pH.
Karl Albert Hasselbalch (1874-1962)
Karl Albert Hasselbalch (Fig 10) was born in 1874 in Hjorring,
Denmark, educatcd in the Soro Academy, and studied
medicine at Copenhagen University. He assisted Bohr and
Krogh in the discovery of the "Bohr effect" of CO2 on hemo-
globin oxygen reactions. He became director of the laboratory
at thc Finsen Institute in Copenhagen, where ultraviolet light
was first used to treat lupus vulgaris. Hassclbalch obtained a
master's degree in agriculture and left the Finsen Institute in
1917, devoting himself to scientific agriculture and making the
world's first soil pH measurements. He died on his farm in
northern Sjaelland in 1962.
190 Journal of Clinical Monitoring Vol 1 No 3 July 1985
Influenced by Sorensen's pH nomenclature, Hassel-
balch adopted the Henderson equation and rearranged it
into the now familiar Henderson-Hasselbalch equation
[111:
pH = pK + log{[HCO3-]/[dC02]}.
The equation was written to permit the calculation of
pH from the measurable total CO2 after equilibration
with known Pco> calculating [HCO3-] as total CO2
minus dissolved CO_,. In blood, pH was not readily
measurable.
Eric Johan Warburg (1892-1969) was professor of
medicine in Copenhagen from 1931 to 1962. He for-
malized the ideas, gradually developing since Gilbert
Lewis introduced the concept of activity in 1908, that
pH must represent hydrogen ion activity, not concen-
tration. Warburg's thesis at Copenhagen University
[12] was the first major theoretical study of the Hender-
son-Hasselbalch equation.
The Arrhenius theory of electrolytic dissociation as-
cribed the aciditic properties to H + ions, the basic to
O H - ions. The problem arose in biologic solutions of
multiple weak acids and bases, whose ionization was
altered by pH changes. The difference between actual
acidity and titratable acidity was first noted by S~rensen
in 1909. In 1923 the Danish chemist Johannes Nicolaus
Br~nsted (1879-1947) [13] suggested the concept that an
acid is a proton donor, a base a proton acceptor. An acid
is a base plus a proton, forming a "conjugate pair." In
the same year Gilbert Newton Lewis (1875-1946) pro-
posed his electronic theory of acids and bases, a more
general but not contradictory approach, in which a base
can furnish an electron pair and an acid can accept an
electron pair to form a coordinate covalent bond, which
may then ionize. The Bronsted concept, now widely
accepted, was quite the opposite of that held by the Van
Slyke school, where sodium was considered a base (see
discussion in [14]).
THE GLASSELECTRODE
The glass pH electrode did not come into use in biology
until about 1925, but the discovery that a thin glass
membrane develops a potential depending on the pH
difference across it was made in 1906 by a biologist,
Max Cremer (1865-1935) [15]. Fritz Haber (1868-1934)
and Zygmunt Klemensiewicz (1866-1963) studied this
effect in 1909 [16], and W. S. Hughes put the glass
electrode on a rather firmer scientific basis in 1922 [17],
but the first glass electrode used for blood work was
constructed by Phyllis Tookey Kerridge in London in
1925 [18]. Her electrode (Fig 11) was a glass bottle with
/ Said. Kd,
, / salt bridges
Unknown 'I-~
Fig 11. The first blood pH electrode, constructed b), Kerridge in
I925. Satd. KC1 = saturated potassium chloride.
a small concave spoon-shaped thin glass wall on one
side, into which blood could be put under oil, with a
reference electrode liquid junction dipping into the
blood through the oil.
Duncan Arthur Maclnnes (1885-1965) and Malcolm
Dole (1903-) [19] conducted detailed studies of glass pH
electrodes in 1929. They found that glass with 72%
silicone dioxide, 6% calcium oxide, and 22% disodium
oxide had the lowest melting point possible with these
three components and the lowest resistance (tenfold less
than ordinary soft glass). Their electrode was a tube of
ordinary glass with a very thin film of this pH glass
sealed across its end, and it had about 10 megohms resis-
tance. Their formula, adopted by Coming, is known as
015 pH glass.
It is a curious glass, tending to crystallize, particularly
after repeated melting. It must be hydrated in order to
work. Under a microscope, old, dried-out capillaries of
015 may be seen to have a reticulation pattern. It is
possible that the actual conductivity occurs along sub-
microscopic stress discontinuities, or cracks, extending
through the glass, in which water molecules can exist,
with which hydrogen ions as well as cations can ex-
change. The 015 glass seems to need these discon-
tinuities to work. If it is carefully annealed, its resistance
increases toward infinity and pH response disappears.
The conventional theory of function is of exchange of
H + and cation at both surfaces, with migration of cation
within the glass [20].
Stadie, O'Brien, and Laug [211 developed a 38~
thermostatted glass electrode as early as 1931, but it was
not made commercially available. David Bruce Dill
(1891-), with C. Daly and William H. Forbes (1902-)
[22], also constructed temperature-controlled pH elec-
 Historical Review: Severinghaus and Astrup: Electrochemistry
trode, the oxygen electrode story will take us back
nearly 100 years to Leipzig and G6ttingen, and to
Prague in the 1920s.
REFERENCES
Fig 12. The Machines Belcher "condenser" glass electn~defrom
1933, the first commercially produced anaerobic pH electrode us-
able for blood. P = pH electrode output; a-b = tube (pH glass);
G = electrolyte of fixed pH; C = calomel reference electrode.
trodes for accurate studies o f the carbonic acid dissocia-
tion constant, p K ' .
Maclnnes and Belcher [23] in 1933 introduced the first
practical blood electrode, using a thin-walled tube o f
glass, at first having a spiral shape, with the sample
inside and standard buffer solution outside in a sealed,
double-wall system. The electrode looked a bit like a
condenser for a still, hence it was called the condenser
electrode (Fig 12). This nonthermostatted electrode,
marketed by the C a m b r i d g e Instrument C o m p a n y with
an electrometer amplifier, was the principal p H elec-
trode available for blood analysis in America in 1950. It
was assumed that blood would be measured at r o o m
temperature and corrected to body temperature [24], or
that the user would thermostat the electrode. Additional
history o f glass electrode and p H technology may be
found in Dole [20], Maclnnes [25], and Bates [26].
While this brief review sets the stage for the develop-
ment o f p H and acid base clinical chemistry by Astrup
and his colleagues in the 1950s and for Stow's CO2 elec-
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