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Concept of Acid-Base Balance in Medicine

	Abstract

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 
This paper attempts to illustrate historically how important developments in the comparatively new field of physical chemistry during the second half of the 19th century made possible the understanding of ions and acid-base phenomena in clinical and laboratory medicine. Primarily based upon the revolutionary concept of ionization by Svante Arrhenius , it was the studies of two Americans, Lawrence Joseph Henderson and Donald Dexter van Slyke, during the first two decades of the 20th century that resulted in the elucidation and clinical laboratory evaluation of two major diseases, diabetes and nephritis, and the resulting recognition of the phenomena of acidosis and alkalosis.

	Introduction

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 
In science it is sometimes impossible to solve particular problems at a specific time until new knowledge, techniques, or instrumentation in collateral fields have evolved to make further progress on these problems feasible. This paper will present an example of this fact by a discussion of how discoveries in physical chemistry during the 19th century led to the elucidation of the nature of coma in two common diseases, diabetes and nephritis. In these conditions, understanding their terminal phases had remained mysterious; gross anatomical findings at autopsy could not explain them.

William Osler (1849–1919) [1] speculated about these problems in his textbook of medicine by writing with regard to diabetes: "There has been much dispute as to the nature of these symptoms (ie, coma with Kussmaul’s "air hunger"), but our knowledge of the disease is not yet sufficiently advanced to give us rational explanation. The character of the attack and the similarity, in many instances to uremia, would indicate that it depended upon some toxic agent in the blood. The theory most commonly held, that this material is acetone, is supported by the presence of the acetone reaction in the urine and its odor on the breath. Ernst Stadelmann believes the condition is not acetonemia but that the poisonous agent is an intermediate product between the sugar and the acetone, an oxybutyric acid."

Regarding uremia, Osler wrote:

"Two opposite views are held with reference to the production of uremia (coma):

(a) that it is due to the accumulation in the body of excrementitious body poisons which should be thrown off by the kidneys.

(b) Traube suggested that the chief symptoms of uremia, particularly the coma and convulsions, were due to localized edema of the brain."

Experiments carried out in Europe did throw some light on the problem of coma in diabetes. Friedrich Walter [2] gave rabbits large amounts of hydrochloric acid by stomach tube and found that he could reduce the amount of carbon dioxide in the animal’s blood from a level of 27 vol% to <3 vol%, at which time the rabbits developed hyperpnea, but they could be restored to normal with iv injections of sodium bicarbonate.

E. Stadelmann (1853–1941) [3] recognized that Walter’s rabbits showed the same type of breathing as in Kussmaul’s comatose diabetic patients. He attempted unsuccessfully to isolate the acid, which he assumed was the toxic agent that produced the coma. Oscar Minkowski (1858–1931) [4] working in Bernhard Naunyn’s laboratory found an acid that he identified as 3-hydroxybutyric acid, but in addition, using the same type of pump as Walter, he confirmed that the amount of carbon dioxide in the blood of comatose diabetic patients was much less than normal. Consistent with Walter’s finding in rabbits, he showed that such patients could be clinically improved by parenteral administration of sodium bicarbonate solution. He thus came to the conclusion that diabetic coma was produced by a generalized acidosis, rather than a direct toxic effect by an abnormal acid, such as beta-hydroxybutyric acid, but the nature of the acidosis remained obscure.

	Claude Bernard (1813–1878)

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 
The terminal stages of diabetes would ultimately be explained by studies of the chemical composition and nature of the "milieu interieur," a concept that Claude Bernard evolved over his many years as a physiologist. It was described in a posthumous publication [5] as follows:

"I think I was the first to urge the belief that animals have two environments: a milieu exterieur in which the organism is situated and a mileu interieur ...which is formed by the circulating organic fluid which surrounds and bathes all of the tissue elements; this is the lymph or plasma which in higher animals is the basis of all local nutrition and the common factor of all elementary exchanges ...Stability of environment implies an organism so perfect that it can continually compensate for and counterbalance external variations ...that their equilibrium is the result of compensation established as continually and as exactly as if by a very sensitive balance."

Regarding this concept, the 20th century physiologist, Homer W. Smith (1895–1962) [6] quoted John Scott Haldane as stating: "no more pregnant (idea) was ever framed by a physiologist." In 1878, the molecular nature of the "milieu interieur" was beginning to be elucidated. It took the work of many researchers through much of the following century before it was possible to explain all of its aberrations, not only in diabetes and nephritis, but in many other clinical conditions that would be included in a field called "acid-base balance." Three individuals were the leaders in this quest.

	Svante August Arrhenius (1859–1927)

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 
By 1878, most of the organic components of the "milieu interieur" had been qualitatively identified in blood as belonging to 1 of 3 major groups: proteins, lipids, and carbohydrates. Some smaller molecules, eg, urea, uric acid, creatinine, bile pigments and hemoglobin, had been isolated from blood and had been measured semiquantitatively in various physiological and pathological conditions. It was known that blood glucose was elevated in diabetes, urea in uremia, uric acid in gout, bile pigments in liver disease, and that blood hemoglobin was decreased in anemias.

With regard to inorganic components, an early physiological chemist, Johann F. Simon (1807–1843) in his Animal Chemistry [7] stated:

"In the present state of our chemical knowledge, it is impossible to assign with certainty any definite function to the large quantity of salts which enter the blood but is not transferred to any of the solid textures of the body."

In 1878, Charles T. Kingzett (1852–1935) [8] wrote that the function of the salts in blood was still unknown and they were still quantitatively measured in terms such as potash, soda, lime, magnesia, chlorine, and phosphoric acid, with the assumption that they existed as such in the blood in the normal state.

Coincidentally, in the same year, a young Swedish graduate student, Svante Arrhenius, who was a candidate for a degree in chemistry and mathematics at the University of Upsala, in an attempt to explain certain paradoxes in chemistry, developed a revolutionary theory that not only had great repercussions in chemistry, but also in biology and medicine, ie, the theory of ionization [9].

Although Michael Faraday (1791–1867) had experimented during the years 1833–1834 with the conduction of electricity through solutions of salts, weak acids, or alkalies, and introduced the terms electrolyte, ions, anion, and cation, he believed that the charges on the particles were produced by the electric current of a battery [10]. However, this concept generated the following questions that Faraday could not answer:

1. Why are distilled water or solid sodium chloride unable to conduct electricity from a battery while a solution of that salt in water is an excellent conductor?

2. Why are water solutions of all salts, acids and bases good electrical conductors while a solution of sugar is not?

3. Why are some acids such as hydrochloric acid, nitric or sulphuric acid, good conductors while weaker acids are not, although the weaker acids can neutralize the same amount of base such as sodium hydroxide?

These were the questions that Arrhenius attempted to answer for his doctoral thesis. Building on a suggestion of Rudolf Clausius (1822–1888) in 1857 that a small part of dissolved salt might dissociate into individual particles, Arrhenius developed the theory of ionization, which assumes that when an electrolyte like sodium chloride dissolves in water, it tends to dissociate into ions or particles that have electrical charges. These ions wander randomly until passage of an electrical current draws each to an electrode bearing a charge opposite to its own. He noted that the strong acids were better conductors than weak ones and he concluded that this difference was based upon the degree of dissociation of the acids. In all cases the concentrations of ions obeyed the Law of Mass Action developed by the Norwegians, Cato M. Guldberg (1836–1902) and Peter Waage (1833–1900) [11].

When Arrhenius presented his thesis in 1884, it was not well received by the Swedish academics, since it proposed separate particles in solution such as sodium and chloride that could not be visualized or reconciled with the nature of these elements. Logically, it would be expected that sodium atoms would react violently with water, and chloride atoms would combine to produce a yellowish green poisonous gas. Therefore, Arrhenius received only a provisional acceptance of his thesis. He found allies in Wilhelm Ostwald (1853–1932), professor of chemistry in Riga, and Jacobus Henricus van’t Hoff, (1852–1911), professor of chemistry in Amsterdam, who successively invited Arrhenius to work in their laboratories. Van’t Hoff had already presented to the Swedish Academy of Sciences experiments on chemical equilibria, but he had found discrepancies he was unable to explain: specifically why some solutions of salts, acids, or bases have higher vapor pressures, greater osmotic pressures, and greater depression of the freezing points of water than were predicted from his calculations. These discrepancies could be explained if he used Arrhenius’s electrolyte dissociation data. The two men collaborated with Ostwald to perform osmotic pressure experiments that resulted in the modern theory of ions in dilute solutions. Their results were consistent with the concepts of earlier chemists regarding atoms and molecules.

The concept of ions remained a difficult one for the chemistry community to accept until it was explained during the first decades of the 20th century by the studies of Joseph J. Thomson (1856–1940), Ernest Rutherford (1871–1937), Gilbert N. Lewis (1875–1946), and Niels Bohr (1885–1962). They reached the conclusion that all atoms consist of nuclei with orbital electrons. Thus, in the case of sodium chloride in solution the sodium atom transferred its single electron in its outer orbit to a chlorine atom which was missing a single electron in its outer orbit. The results were a positive sodium ion and a negative chloride ion.

	Ionization Theory

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 
It was several years before the biology and medical community recognized the import of Arrhenius’s electrolyte theory to explain biological phenomena. As monumental as Arrhenius’s studies had been since 1884, there were no references to "ions" or "electrolytes" in the 1893 Textbook of Physiological Chemistry by Olof Hammersten (1842–1932) [12] or the 1895 Textbook of Physiology [13] by Michael Foster (1836–1907). This was the case despite the fact that Arrhenius’s ideas could easily explain the well known observation that urine, which normally had an acid reaction with litmus paper, varied in its titratable acidity when the urine contained various concentrations and types of salts. Not until Arrhenius received the Nobel Prize for his electrolyte work in 1903, did discussions of ions begin to appear in standard texts on physiological chemistry or physiology. Theoretical inorganic chemists were also slow in recognizing the significance of the work of Arrhenius. Thus, Ida Freund’s monumental "The Study of Chemical Composition," written in 1904, makes no mention of Arrhenius’s discoveries [14]. Although Arrhenius’s theory was later modified to account for the behavior of electrolytes in very high concentration, at the low concentrations of ions in body fluids, the theory proposed by Arrhenius remains valid.

Although the United States had contributed few original physiological and chemical discoveries during most of the 19th century, in comparison to Europe, the United States began to take the leadership in medical research during the first decades of the 20th century. This was primarily due to the financial support of research by the philanthropic activities of John D. Rockefeller, Andrew Carnegie, and others who made donations to medical schools and research institutions.

With regard to the study of acid-base balance, two major centers evolved in the United States: the laboratories of Lawrence Joseph Henderson at Harvard in Boston and of Donald Dexter van Slyke at the Rockefeller Institute in New York.

	Lawrence Joseph Henderson (1878–1942) [15]

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 
In 1894, at age 16, Lawrence Joseph Henderson, enrolled at Harvard College, where he majored in physical chemistry. During this time he wrote an essay on Arrhenius’s ionization theory. After receiving a bachelor’s degree, he entered Harvard Medical School and although he never was interested in practicing medicine, he acquired an appreciation and knowledge of human physiology and pathology that was difficult to obtain elsewhere.

Because the emphasis in regard to chemistry at the medical school consisted primarily of learning the various diagnostic tests on body fluids, Henderson, still impressed by his essay on Arrhenius, decided, after medical school, to study in Strasbourg in the laboratory of Franz Hofmeister (1850–1922). Since 1887, this German biochemist had been studying the effect of various salts on protein solutions in regard to viscosity, precipitation, and osmotic pressure. Henderson did not perform any notable experiments in Hofmeister’s laboratory, but he spent much time conversing and theorizing on the experimental data of the senior chemists there. After two years, Henderson joined the faculty of the chemistry department at Harvard. During the years 1904–1909 he performed research on electrolytes in blood, culminating in his classic paper, "The Theory of Neutrality Regulation in the Animal Organism" [16], in which he used the concepts of Arrhenius and van’t Hoff to explain much of Bernard’s "milieu interieur."

Henderson’s major conclusions, based upon dissociation and equilibrium reactions, were that the first defense of the body fluid neutrality is the physicochemical mechanism of the presence of weak acids and their salts, which react with strongly dissociated acids to form a neutral salt and a slightly dissociated weak acid, thus minimizing changes in hydrogen ion concentration. These systems are principally bicarbonates, secondarily phosphates, and to a lesser extent proteins, and they function according to circumstances as either donors or acceptors of hydrogen ions. These, in turn, are secondarily controlled by the kidney and lungs, the organs leading to Bernard’s "milieu exterieur."

By this time, leaders of the medical community had recognized that the phenonoma of generalized acidosis was probably the cause of coma in diabetes, rather than a direct poisonous effect of ketones or acidic substances such as 3-hydroxybutyric and other ketone bodies. However explaining and proving such a concept was difficult since there were no simple tests to determine the danger to the patient because the hydrogen ion concentration would barely shift at a time when the neutrality system of the blood was already greatly compromised.

Henderson’s equations, published in the physiological journals [17,18] were mathematically difficult not only for clinicians to understand but also for physiologists who were just beginning to appreciate the concept of ionization. Two major factors occurred following Henderson’s papers that clarified his concepts. The first was a publication of Soren P. L. Sørensen (1868–1939) [19] in Denmark who, studying the effects of acid and salts on the stability of enzymes, developed the concept of "buffer" systems (Sørensen likened them to shock absorbers on trains), which described Henderson’s "neutrality systems" in that they resisted moderate production of acids with little change in hydrogen ion concentration. In addition, Sørensen proposed the use of the term "pH," which is the negative log of the hydrogen ion concentration, instead of the traditional use of "normality." Thus, the acidity of normal blood would be designated pH 7.4 instead writing 4 x 10^-8 N or the unwieldy 0.00000004 N. The second factor occurred when Karl A. Hasselbalch (1874–1962) [20] in Germany, using Sørensen’s nomenclature for hydrogen ion concentration and the equilibrium constant expressed Henderson’s equation of:

where Ka is the dissociation constant for HA, a weak acid, and square brackets enclose the concentrations of undissociated acid and the salt of that acid.

Thus the famous Henderson-Hasselbalch equation was born that resulted in the names of these investigators becoming immortal.

In regard to Henderson’s work on the carbonates in blood, the equation then becomes:

It may be mentioned that Henderson, working in the chemistry department at Harvard College, had hoped to become chair of the new Physiological Chemistry Department for Harvard Medical School in 1909. Otto Folin (1867–1934) [21] was appointed instead, primarily because he had been involved in developing accurate colorimetric quantitative assays for important metabolites on small amounts of body fluid for use in clinical diagnosis and prognosis.

By 1919, when Henderson’s work was recognized as ground breaking and he was being courted by Johns Hopkins University, the dean of Harvard Medical School agreed to create a Physical Chemistry Department for Henderson, with no other responsibilities than research. There Henderson continued his studies with a research staff, becoming more "a master strategist rather than an expert in tactics," as described by his friend and colleague, Walter B. Cannon. Henderson developed an interest in sociology, and the major advances in acid-base balance shifted to New York, where Donald Dexter van Slyke was making significant progress in this field.

	Donald Dexter van Slyke (1883–1971) [3,22]

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 
Although Henderson’s studies had emphasized the importance of electrolytes in health and disease, one of the major problems of clinicians was not having simple methods for diagnosing and evaluating abnormal electrolyte problems. It was in this area that Donald van Slyke showed his genius. As an organic and analytical chemist who had studied with Hermann Emil Fischer (1852–1919) in Germany and whose major interest during the years 1907–1914 had been analyzing protein, it was fortuitous that van Slyke was asked by the director of the new Rockefeller Hospital to become the chief chemist to aid young clinicians who were coming to this institution to study various diseases. Not being a physician and having great reservations about this new assignment, van Slyke nevertheless diligently studied physiology texts. He found out as much as he could about the biochemistry of diabetes and the mystery of why it produced coma. Knowing of Henderson’s studies on bicarbonate, and with the aid of Walter W. Palmer and Reginald Fitz, former associates of Henderson, van Slyke deduced that if diabetic coma were due to accumulation of aceto-acetic and 3-hydroxybutyric acids these metabolites would react and lower the concentration of bicarbonate. Using his experience developing a gasometric method for determining the amount of ammonia and carbon dioxide released by the action of urease on urea, he thought this technique could be used to measure the amount of bicarbonate in small amounts of blood during diabetic acidosis. In 1917, he developed a glass instrument, known as the "van Slyke apparatus," that was used in almost every clinical laboratory for the following 50 years as the only practical method for determining metabolic acidosis. Initially, this invention made it possible to administer a proper amount of bicarbonate solution to patients in diabetic coma. After Banting’s discovery of insulin in 1921, the apparatus was useful to monitor insulin therapy of diabetes.

Van Slyke also aided in recognizing other electrolyte dysfunctions, such as alkalosis, and their causes, both metabolic and respiratory, in which the amounts and the relative ratios of bicarbonate and carbonic acid varied [23]. Fig. 1 from his 1921 paper [23], which was reproduced in many medical, physiology and biochemistry texts during the next half century, shows that blood pH is a function of the ratio of the bicarbonate concentration to the carbonic acid concentration. Fig. 1 thus illustrates that, for example, when the blood bicarbonate is high, low, or normal, the blood pH could be high, low, or normal, depending on the relative concentration of carbonic acid. The diagram delineates 9 areas with only one, area 5, reflecting a normal acid-base balance.

View larger version (141K): [in this window] [in a new window]   Fig. 1. Van Slyke’s diagram of normal and abnormal variations of the bicarbonate ions and pH in serum or oxalated plasma. The arterial conditions are indicated by solid lines; the venous by broken lines [24]. The diagram’s 9 areas were interpreted as follows: Area Concentrations Ratio pH Possible mechanisms BHCO3 H2CO3 BHCO3/H2CO3 1. Uncompensated alkali excess N NaHCO3 overdose 2. Uncompensated H2CO3 deficit N Hyperpnea 3. Partial compensation of H2CO3 deficit Increase in urinary BHCO3 and titratable acids 4. Compensated BHCO3 or compensated H2CO3 excess N N Emphysema and retarded CO2 from lungs and BHCO3 decreased excretion 5. Normal (N) N N N N Normal 6. Further compensated BHCO3 or H2CO3 deficit N N Diabetes and nephritis improvement 7 and 8. Uncompensated H2CO3 excess Morphine narcosis, pneumonia 9. Uncompensated BHCO3 deficit N Premortal diabetes/nephritis

	Practical Applications

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 
By the 1920’s, the study of acid-base balance in normal and abnormal conditions had made significant progress. The basic categories of acidosis, both metabolic and respiratory, and alkalosis, both metabolic and respiratory, are still discussed in much the same terms as in the 1920’s, but now there are many subcategories based upon precise determinations of all of the ions in the various body fluids and compartments. The latter advances are due to the development of the flame photometer following WWII, which enabled precise determinations of the sodium and potassium in minute amounts of body fluids. Additionally, there were new automated methods to determine not only bicarbonate and chloride, but also pH. These technical advances resulted in detailed descriptions of electrolyte balance and renal physiology in all the parts of the nephron, with the development of nephrology as a specialty of internal medicine.

In regard to the questions posed by Osler at the beginning of this paper, by the end of the first quarter of the 20th century, it was possible to say that the comatose condition of patients with advanced diabetes or nephritis was almost always due to a generalized acidosis, and not to a specific metabolic poison produced by each disease. The development of the van Slyke apparatus made the indirect but accurate quantitative evaluation of blood bicarbonate possible. It took several more years to delineate that diabetic acidosis was due to production of abnormal quantities of ketone metabolites from deficient oxidation of carbohydrates and lipids, while the acidosis of nephritis was caused by retention of phosphate and sulfate ions in addition to the excretion of bicarbonate.

There were many clinical scientists who had either been trained or inspired by Henderson and van Slyke. The passage of their knowledge has extended into several generations of teachers and clinicians who have become experts on acid-base or electrolyte balance, particularly those in the field of nephrology.

	Summary

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 
The theory of ionization as proposed by the physical chemist, Svante Arrhenius, made possible the understanding of acid-base balance primarily by the studies of Lawrence Joseph Henderson and Donald Dexter van Slyke during the first quarter of the 20th century. These studies answered the questions posed by Osler regarding coma in diabetes and nephritis, and made possible great advances in medical therapy in diverse clinical conditions, while revolutionizing the understanding of physiology and biochemistry. Despite the fact that inorganic constituents, mostly in the form of salts, make up only 1% of the human body, after being ingested and then absorbed into the blood as ions, they act in dynamic but specific ways, as functions of their individual properties and electrical charges. These ions are distributed in water, a compound that, while comprising 70% of the body weight, also dissociates at an extremely low level into two of the most important ions, H⁺ and OH^-. These ions, interacting with those contributed by ingested salts, determine the body’s pH, which in turn explains the signs and symptoms of various disease states in the absence of early morphological changes. Importantly, the understanding of ions acting in conjunction with various organic compounds, eg, proteins, carbohydrates, and lipids, has made possible an understanding of Bernard’s "milieu interieur," proposed >150 yr ago.

	References

Top Abstract Introduction Claude Bernard (1813-1878) Svante August Arrhenius (1859... Ionization Theory Lawrence Joseph Henderson (1878... Donald Dexter van Slyke... Practical Applications Summary References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Malkin, H. M. Search for Related Content PubMed PubMed Citation Articles by Malkin, H. M.