You cannot understand history without having lived through history yourself.


The Copenhagen (København) Poliomyelitis Epidemic

The 1952 Copenhagen epidemic affected about 3,000 people and, despite heroic efforts to provide manual ventilation, about 345 died (Berend 2018). Most of the 3,000 patients were admitted to the Blegdam Hospital, an infectious-disease hospital. Although it seems hard to believe, the timing might have been even worse. Bjørn Ibsen, an anesthesiologist, had worked at the Massachusetts General Hospital. He knew that a child there had been treated with curare to control tetanus and had then been successfully ventilated manually through a tracheostomy.

Accordingly he proceeded to manually ventilate a cyanotic girl with limb paralysis via a cuffed endotracheal tube in a tracheostomy. His insight was the basis for recruiting 1,500 medical and dental students to provide 165,000 hours of ventilatory support. Initially, there was no way of measuring the PCO2. Accordingly the high bicarbonate values were thought to indicate an alkalosis of unknown origin rather than a respiratory acidosis. Ibsen is generally credited with creating the concept of critical care medicine.

Subsequent Events

Patient Selection for Manual Ventilation: It was also Ibsen who realized that the high PCO2 levels combined with water to produce carbonic acid and hence also high bicarbonate values; these values were not indicating an alkalosis of unknown origin. PCO2 measurement was achieved by interpolation on an acid-base nomogram employing measurements of pH and bicarbonate at known PCO2 levels. With this new understanding, patients were selected largely based on the measurement of their Blood PCO2 levels.

Measurement of the Metabolic Component came later. Reliable measurement was neither a priority in the poliomyelitis patients nor was it then feasible. In 1960 Siggaard-Andersen introduced Base Excess based on titrating whole blood back to a normal pH under a standard temperature (37o) and normal PCO2. In 1963, Schwarts and Relman criticized this measurement. They pointed out that in the laboratory the buffering by hemoglobin only dealt with the plasma. In the body this buffering dealt with the entire extracellular fluid.

Standard Base Excess was devised by Siggaard-Andersen and colleagues in response. The laboratory calculation was performed using a hemoglobin concentration of 5 g/dL (3 mmol/L), which approximates the in-vivo situation. This satisfactory measure of the Metabolic Component remains the standard today.

Growth of Knowledge

Our understanding of acid-base balance depends on numerous underlying inventions, discoveries and theories. Blood gas analysis is used frequently partly because it is now convenient, and partly because of the growth in our knowledge and understanding of acid base physiology.

Interest in acid base balance stems from its physiologic importance, from fascination in a subject which has exercised and challenged scientific interest during the last century and, regrettably, from the requirement to set and pass examinations

The history has been presented as a book, The History of Blood Gases and Bases by Poul Astrup and John Severinghaus, and as Six History Articles in the Journal of Clinical Monitoring (1985 and 1986): 123456. and also reviewed by Kenrick Berend (2018)

The critical events and participants are summarized in the Acid-Base Event List below which emphasizes several points:

  • The time taken for ideas and equipment to penetrate.
  • The names of the prominent investigators.
  • The approaches to measuring metabolic disturbances.
  • The controversy surrounding the introduction of “base excess”.

Personal Contributions

See the separate page About the Author.

Acid-Base Time Line

1660: Boyle
Reported that Pressure in a gas is inversely proportional to its volume – which became known as “Boyle’s Law.” Boyle actually gave credit to for this finding to Robert Hooke. The French have a claimant, Edme Mariotte, who published work on this topic in 1676 and so the full name of this law may be: The Boyle-Marriotte Law
1749: Benjamin Franklin
Submitted a summary of his experiments in which he called “vitreous” charges “positive” which later necessitated the labeling of excess electrons with the adjective “negative”.
1801: Dalton
Proposed law of partial pressures (total pressure equals the sum of the partial pressures).
1802: Henry
“Dissolved gas proportional to partial pressure.”
1808: Gay-Lussac
1. Pressure proportional to ‘absolute’ temperature.
2. Law of combining volumes (gases react in simple whole number proportions).
1811: Avogadro
Equal volumes of all gases at the same temperature and pressure contain equal numbers of molecules
1833: Faraday
Coined terminology (ion, anion, anode, etc.) and established laws of electrolysis.
1848: Lord Kelvin
Combined known gas laws to permit calculation of the universal gas constant, R, in:
PV=nRT (P = pressure, V = volume, n = number of moles, and T = temperature).
1857: Clausius
Concluded that ions already exist in solutions.
1887: Van’t Hoff
Linked the “gas laws” to the behavior of osmotic pressure in solutions.
1887: Arrhenius
Proved that dissolved salts and acids are ionized, thus introducing the concept of the Hydrogen ion – H+.
1887: Ostwald
Made first electrical measurement of hydrogen ion concentration.
1889: Nernst
Derived equation which related change in voltage to the universal gas constant (R), the absolute temperature (T), the valence (n), the faraday (F) and the activity (a):
E = Eo + [RT/nF] log(a/ao ). (note: RT/nF = 61.5 mV at 37o C)
1889: Nernst
Also recommended selecting salts with ions having similar diffusion rates to avoid error voltages at liquid junctions.
1905: Bjerrum
Adopted Nernst’s recommendation; introduced now standard potassium chloride salt bridge.
1906: Cremer
Discovered that a difference in acidity can cause a potential difference across a glass membrane.
1908: Henderson of the “Henderson Equation
Discovered buffering power of CO2 and applied law of mass action:
K = [H+] [HCO3] / [dCO2] (where dCO2 = dissolved CO2)
Sorensen (1909)
Suggested the pH terminology. Also developed the hydrogen electrode for biologic use.
1916: Hasselbalch
Used Sorensen’s terminology for Henderson’s equation in logarithmic form:
pH = pK + log(HCO3/dCO2)
1916: Hasselbalch
Proposed measuring metabolic acidosis using “Standard pH” at 38oC with PCO2 = 40 mm Hg (analogous to the ‘standard’ bicarbonate later introduced by Jorgensen and Astrup).
1921: Van Slyke
Published acid-base diagram using, as axes, log[H+]:log(PCO2) the forerunner of the in-vivo Siggaard- Andersen diagram (1971).
1923: Brønsted and Lowry
Independently, Johannes Nicolaus Brønsted and Martin Lowry characterized acids and bases as donors or acceptors of protons (hydrogen ions). They also stated that when an acid ionizes in water, the “free” hydrogen ion is often attached to H2O to make H3O+.
1924: Van Slyke
Originated manometric Van Slyke apparatus to measure gas quantities released from blood.
1927: Eisenman
Derived pH by interpolation on a graph using log(CO2 content):log(PCO2) axes. Measurements of CO2 content were made using Van Slyke measurement at known PCO2.
1929: MacInnes and Dole
Perfected glass composition for pH electrodes (later known as 015 pH glass – Corning).
1933: MacInnes and Belcher
Designed the first commercial electrode to measure blood pH.
1952: Poul Astrup
Encountered the need to measure PCO2 in his clinical laboratory during the Copenhagen polio epidemic, and derived PCO2 by interpolation on a graph of log (PCO2): pH. Measurements of pH were made at known PCO2 levels.
1954: Stow
Covered pH and reference electrode with rubber to make a practical PCO2 electrode, later modified and improved by Severinghaus.
1956: Poul Astrup
Designed practical thermostatically controlled glass electrode for use in a CO2 equilibration chamber.
1957: Jorgensen and Astrup
Introduced “Standard Bicarbonate” (the bicarbonate level at PCO2 = 40 mmHg) as the “best available measure of non-respiratory disturbances”.
1958: Astrup and Siggard-Andersen
Introduced the capillary microelectrode and the concept “Base-Excess” as a measure of treatment required to correct metabolic disturbances. The “in-vitro” base excess was dependent on the hemoglobin level – subsequently a source of criticism and debate.
1958: Severinghaus and Bradley
Demonstrated blood-gas apparatus which contained both PCO2 and PO2 electrodes.
1960: Siggaard-Andersen and Engel
Published Acid-Base Nomogram using log(PCO2):pH axes for calculating, by interpolation, the PCO2, the bicarbonate, the standard bicarbonate and the base-excess. The technique required pH to be measured at known PCO2 levels.
1962: Siggaard-Andersen
Published Acid-Base Nomogram Revised. Available Here.
1963: Schwartz and Relman
Critically reviewed the concept “base-excess” and proposed the use of linear equations to characterize acid-base syndromes. By this means they avoided describing the adaptation to chronic hypercapnia as “metabolic alkalosis” but, rather, they regarded the patient as being compensated to chronic hypercapnia if he fitted their equation.
1966: Severinghaus
Introduced “Standard Base Excess” and developed his blood-gas slide rule.
1976: Grogono, Byles, and Hawke
Published a simple In-Vivo Diagram based on the Siggaard-Andersen nomogram but employing for the axes the two linear clinical components, metabolic acidosis and respiratory acidosis.
1983: Stewart
In his book in 1981 and paper in 1983 Stewart introduced Strong Ion Difference (SID) as an alternative technique for assessing acid-base disturbances. It has been controversial due to added complexity and limited confirmed benefit. This has prevented it from from receiving widespread acceptance.
1986: Astrup PB and Severinghaus JW.
Published their wonderful book: The History of Blood Gases, Acids, and Bases from which I have drawn much of the historical information.
1997: Sahlin et al
Described a method of measuring intracellular pH (pHi) in muscle of resting volunteers. They calculated that pHi = 7.0 +/- 0.06; and intracellular bicarbonate = 10.2 +/- 1.2 mMol/L;
1997: Schlichtig, Grogono, and Severinghaus
Reviewed the literature and devised new, accurate regressions between Standard Base Excess (SBE) and PCO2 which characterized the classical acid-base disturbances; they also introduced a revised In-vivo Acid Base Diagram. See: Human PaCO2 and Standard Base Excess Compensation., and Acid-base quantitation in Physiology and Medicine which are the sources for the regression equations and the new diagrams used in this website.
2018: Berend
Published Diagnostic Use of Base Excess in Acid-Base Disorders including a history of the Danish Poliomyelitis Epidemic.