by "Grog" (Alan W. Grogono), Professor Emeritus, Tulane University Department of Anesthesiology
History of Acid-Base Balance
"You cannot understand history without having lived through history yourself." – Goethe.
The Copenhagen (København) Poliomyelitis Epidemic (Berend 2018)
The 1952 Copenhagen epidemic affected about 3,000 people and, despite heroic efforts to provide manual ventilation, about 345 died. 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.
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, summarized in their series of Review-Essays in the Journal of Clinical Monitoring (1985, 1986), and more recently reviewed by Kenrick Berend (2018) Some of the critical events and participants that they mention are summarized in the Time-Line 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".
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".
Proposed law of partial pressures (total pressure equals the sum of the partial pressures).
"Dissolved gas proportional to partial pressure."
1. Pressure proportional to 'absolute' temperature. 2. Law of combining volumes (gases react in simple whole number proportions).
Equal volumes of all gases at the same temperature and pressure contain equal numbers of molecules
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).
Concluded that ions already exist in solutions.
1887: Van't Hoff
Linked the "gas laws" to the behavior of osmotic pressure in solutions.
Proved that dissolved salts and acids are ionized, thus introducing the concept of the Hydrogen ion – H+.
Made first electrical measurement of hydrogen ion concentration.
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)
Also recommended selecting salts with ions having similar diffusion rates to avoid error voltages at liquid junctions.
Adopted Nernst's recommendation; introduced now standard potassium chloride salt bridge.
Discovered that a difference in acidity can cause a potential difference across a glass membrane.
Discovered buffering power of CO2 and applied law of mass action:
K = [H+] [HCO3-] / [dCO2] (where dCO2 = dissolved CO2)
Suggested the pH terminology. Also developed the hydrogen electrode for biologic use.
Used Sorensen's terminology for Henderson's equation in logarithmic form:
pH = pK + log(HCO3-/dCO2)
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.
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.
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.
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.
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.
Published a simple In-Vivo Diagram based on the Siggaard-Andersen nomogram but employing for the axes the two clinical components, metabolic acidosis and respiratory acidosis.
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.
Medical School: I entered The London Hospital Medical College in 1953 – one year after the Copenhagen poliomyelitis epidemic. Fear of polio was understandable: critical care and formal recovery rooms did not exist. I enjoyed medical school but was not a particularly good student – focusing principally on writing, and participating in the annual Christmas Review. Several of us managed to fail a pharmacology course several times. We created a "failed pharmacology course tie" which we wore to the professor's remedial lectures. This failure makes an interesting contrast with my career choice employing drugs with and my creation, years later, of a mobile consisting of a history lesson of anesthetic molecules. Long after I had graduated, a chance meeting with the professor occurred when my wife and I were house-hunting. He opened the door and I believe I detected long dormant pain on his expression. We made no reference to the past and didn't buy the house.
Ether: I started my first training job in anesthesiology at the The London Hospital in 1960. There were only one or two ventilators in the entire suite of operating rooms and fear of the use of curare was common: "For patients that worry you – trust ether!" At the time, anesthesia gases were casually and freely released into the room. When I administered ether, particularly when dripping it onto a gauze mask over a child's face, I inhaled it and it was absorbed into my fat. My friends could smell it on my breath for many hours. After 13 weeks I abandoned anesthesiology in favor of obstetrics – because the obstetric job was associated with directing the Christmas Review. I made this switch even though I had already designed a new ventilator.
First Ventilator: Experience with the new balanced anesthetic approach using a blend of curare, nitrous oxide and morphine very rapidly convinced us trainees that this mantra about ether was outdated. The need for more ventilators was dire – arriving late in the operating room eliminated the chance of grabbing a ventilator and manual ventilation was tedious. This manual ventilation stimulated creativity. The oxygen and nitrous oxide exiting the flow meters could surely be stored under pressure until there was enough for the next breath. My first ventilator used wood and a rubber bellows and I suggested trying it on a patient. Sadly, as I then thought, wiser heads prevented my trial. I likened the mechanism to the tank above a men's urinal. It fills until a trigger causes a flush or, in this case, a breath.
Competition: At the time I was oblivious of almost identical and independent creativity by Howells and Manley, two other anesthesiology trainees in London. They both produced excellent minute-volume divider anesthesia ventilators that were widely adopted. Howells later became a colleague and a friend when I became a consultant at the Royal Free Hospital.
Critical Care: While completing my training at King's College Hospital, I became acutely aware of the need for Critical Care. The battle to find space, staff, personnel, and other essential resources was overwhelming. It also taught me another valuable lesson: it requires dedicated medical staff as well. Completing my training and devoting "spare" time to Critical Care was imposible – my wife and I were raising four children and rebuilding an old Victorian house with our bare hands.
Second Ventilator: My fascination with anesthesia ventilators eventually resulted in a New Ventilator/Humidifier. Now the anesthesia gas accumulated in a metal container – a pressure cooker. Rising pressure tripped a mechanism that released the gas to the patient. The prototype was used for years in the animal laboratory in the Upstate Medical Center, Syracuse NY. However, it was never a commercial success due to difficulty achieving the required reliability and growing concern about releasing high flows of anesthetic gases into the operating rooms.
First Acid-Base Diagram: In 1974, Hawke, Byles and I experimented with various diagrams to represent acid-base base balance. The magnificent but intimidating Siggaard-Andersen Alignment Nomogram provided us with data which allowed every possible combination to be plotted: PCO2 against pH, pH against Bicarbonate, Standard Base Excess against pH, Hydrogen ion concentration against Standard Base Excess, etc. All of these attempts produced awkward curves or misshaped clinical zones. Imagine our excitement when we plotted PCO2 against Standard Base Excess to show the pH. Plotting the respiratory and metabolic components against each other produced straight pH lines and clinical zones which were like spokes of a wheel.
Meeting John Severinghaus: In 1984 Jack Aron made a generous endowment to honor his friends and I became the Merryl and Sam Israel Chair of the department of Anesthesiology. I was asked to invite a speaker and, to my delight, John Severinghaus accepted the invitation that formed the basis for our enduring friendship. Towards the end of his life Jack Aron developed Amyotrophic Lateral Sclerosis (Lou Gehrig's disease). He asked for my advice, which was disturbing but flattering. I would like to think I helped him decide what he should do.
More on Ventilators: Around 1988 Prof. Wilhelm Erdmann of the Erasmus University in Rotterdam visited me unexpectedly. He stimulated my interest in a new electronic anesthesia machine, and invited me to join the design team. I was excited because among its many other innovations, it minimized waste gas liberation and allowed oxygen consumption to be measured. It was never sold in the US and was acquired by DrägerⓇ who eventually allowed it to vanish. I obviously bring bad luck to ventilators!
Another Acid Base Diagram: In the late 1990s John Severinghaus introduced me to Robert Schlichtig who had compiled an extraordinary set of acid-base values from 21 published reports of patients with purely acute or chronic metabolic or respiratory acid-base problems. From this he calculated regression equations which allowed us to update the original Grogono diagram to accurately locate the Clinical Zones.
This Website: I created the first version of this website in December 1998. It was hosted on the Tulane Medical Center website and remained there until 2005 when hurricane Katrina inactivated the Tulane servers for some weeks. The website has attracted several hundred links and many kind testimonials.