John Tyndall (1820–1893) Professor of Natural Philosophy at the Royal Institution, was the first to discover and report that CO₂ gas absorbs infra red light [3]. He built a device to measure this absorption. August Pfund (1879–1949) developed an analyser in 1939, to measure concentrations of carbon dioxide and carbon monoxide [4]. Radiation from a heated nickel chrome wire was directed through a sample cell into a detector cell containing a 3% carbon dioxide mixture, where the temperature was measured. The presence of carbon dioxide in the sample cell caused less radiation to reach the detector cell resulting in a smaller rise in temperature.

Karl Luft (1909–1999) deserves the credit for developing the modern infrared capnograph. Working with the German BASF company in 1937, he invented a clever principle to detect the infra-red (IR) light passing through an unknown gas sample [5]. His “Luft cell” incorporated two IR light sources, one beam directed through a reference cell, the other through a sample cell filled with a stream of the unknown gas (Fig. 55.2). The IR light beams then entered a two-chambered detector cell, each containing 3% CO₂. The relative heating induced by the incoming IR light beams moved a membrane separating the two chambers. An electrical capacitance sensor detected the membrane motion. The IR beams were “chopped” by a rotating shutter, providing an AC signal proportional to the decrease in IR light entering the detector on the sample side.

Shortage of components before and during World War II limited the manufacture of Luft cells to several hundred. Some were used for environmental monitoring in submarines. Others, stored in salt mines, were confiscated and removed to the US and England after the war. The Germans also telescopically tracked their buzz-bombs by the CO₂ absorption of IR light from the exhaust of the bomb.

In the 1950s, an infra-red respiratory CO₂ analyzer was designed by Max Liston (1924–2004) using German patents confiscated at the end of WWII. He was guided and encouraged by James Elam (1918–1995) and associates to apply it to operating room monitoring [6]. The Beckman Co. marketed the capnograph. Like the ECG bullet, its cast aluminum “head” near the airway was pressurized. The unpressurized capnograph amplifier control was supposed to be mounted at least 6 ft above the OR floor, a rule that assumed leaking explosive agents were heavier than air thus settling at a lower level.

The device was widely used for research but little used for patient safety monitoring. In the 1960s, the Beckman LB-1 capnometer was modified to analyze N₂O, ether, halothane or other anesthetics, for research (only one gas per instrument) [7].

Francis Aston (1877–1945), a student of Joseph (JJ) Thomson (1856–1940) at the Cavendish Laboratory at Cambridge, devised the first mass spectrometer to separate isotopes of elements in 1919. Aston was awarded the Nobel Prize in Chemistry in 1922 for his discovery. A mass spectrometer ionized substances (in a vacuum) and accelerated a beam of charged particles (elements or compounds). The beam passed through a magnetic field to bend and separate heavier from lighter particles, each weight being collected in separate metal cups from which the ion current was measured. For respiratory gas studies, an extremely small leak continuously admitted a stream of sample gas into the ionizer, providing continuous concentration information.

In the late 1950s, in order to continuously monitor many artificially ventilated ICU patients (particularly polio victims suffering from long term paralysis), several institutions used a single centrally located respiratory mass spectrometer connected through long sampling catheters to the airways to provide sequential and frequent analysis of inspired and end tidal PCO₂ [8]. The data were typically displayed on the central nursing desk. N Davies and D Denison [9] investigated the performance of long sampling catheters, and concluded that they introduced no important errors.

Mass spectrometers could also analyze inhalational anesthetics, but were too expensive and too difficult to maintain for continuous use in each operating room. However, the monitoring cost per patient could be reduced significantly by using one mass spectrometer for many patients, as in the ICU systems. In the mid 1970s at UCSF, Gerald Ozanne (1941-), Bill Young (1954-) and I installed a single mass spectrometer to sequentially sample airway gases from each patient in the 10 room OR suite of Moffitt Hospital [10]. Long nylon catheters were installed thru the OR ceilings. Young, a recent Oberlin college graduate with talents in both physical chemistry and computer programming, enthusiastically took on the design and programming tasks. We found that patient airway gases could be continuously and slowly sampled from each patient through 30 m long catheters, accurately storing in the catheters about 20 sec of data. When a catheter was switched to the mass spectrometer inlet, gas stored in the catheter was drawn into the mass spectrometer within 6 sec by a lower pressure. The inspired and end tidal concentrations of respiratory gases and the anesthetic vapor were reported on a display in each OR about once per minute (Fig. 55.3). In each OR, by default, the display was a time plot of 30 min of end tidal PCO₂ and halothane %, and a table of current values of all sampled end-tidal gases. The mass spectrometer terminal in each operating room became a communication system before the Web. It permitted Bill Young to monitor each operating room after he moved to New York. He called me one day, worried about operating room 5. I called the attending anesthesiologist and said, “New York wants to know why your patient in room 5 has a PCO₂ of 80.”

Anesthetists at UCSF became dependent on (addicted to) this device. So did researchers. A couple of things flowed from this dependence. One was a demand for such analysis by other institutions. At one point, several hundred of these multiplexed multi-OR systems were in use at institutions, mostly in the U.S. The second was that the device needed competent technician care and was susceptible to occasional breakdown, affecting all the operating rooms. Not good for anesthetists addicted to minute by minute analyses of anesthetic concentrations. This stimulated various manufacturers to develop cheaper stand-alone respiratory gas monitors, using the infrared principle already described.

The absorption spectrum of each anesthetic vapor is unique, especially in the far IR band from 8–9 µm wavelength. The technology for inhaled anesthetic analysis was slowly improved, primarily by the Datex Co, until mixtures of several halogenated vapor anesthetics, CO₂ and N₂O could be successfully analyzed with a single Luft type IR detector cell, including correcting for overlap of the IR absorption peaks [11]. With the addition of an internal polarographic O₂ electrode, end-tidal gas monitoring in every operating room became widely employed. These monitors were less expensive to maintain than the mass spectrometer systems, a failing unit could rapidly be replaced, and only affected one OR. By 1995, multiplexed mass spectrometers had been replaced by stand-alone infra-red gas analyzers [12].

I was invited by Bjørn Ibsen (1915–2007; Fig. 55.4) to dine in his apartment with his wife, shortly after arrival for my first sabbatical in Copenhagen, in 1964–5. I was there to study the possible active transport of something, presumably HCO₃ ⁻, across the blood brain barrier to account for the rapid reduction in CSF HCO₃ ⁻ and relatively constant, slightly increased pH found during altitude acclimatization. I had met Poul Astrup (1915–2000; Fig. 55.5) in London in December, 1958, at the Ciba Symposium on blood gas analysis organized by John Nunn (1923-). I collaborated with Astrup and Ole Siggaard Andersen (1932-) on acid base problems, and taught 3^rd world WHO anesthesia students in an ongoing program, mostly taught by well trained Danish anesthesiologists (Fig. 55.6).

A vicious polio epidemic struck Copenhagen in 1952–3. Hundreds of people, especially the young, were sent for isolation to the communicable disease Blegdams hospital just across Tagensvej from Rigshospitalet. The director, Professor HCA Lassen, was overwhelmed. He and his associate Mogens Bjørneboe had not understood the cause of many deaths. High CO₂ concentrations in blood samples led him to assume that the patients were somehow developing a metabolic alkalosis.

After a suggestion from Bjørneboe, Lassen asked Ibsen, a young anesthesiologist (who had trained at the Massachusetts General Hospital) at Rigshospitalet to help. Ibsen, looking at the blood studies, that did not include pH, realized that the diagnosis was not metabolic alkalosis but hypoventilation, with CO₂ retention and resulting severe hypoxia [31]. Blegdam hospital had only one iron lung and some almost useless cuirass ventilators. Ibsen initiated ventilation in a 12-year-old girl (Fig. 55.7), at first by an anesthesia bag and mask, then later ventilation powered by hand via a tracheotomy. She survived.

Ibsen was not sure how much ventilation the patients needed. He asked Poul Astrup for help by determining what the arterial PCO₂ was in some of the patients in order to guide adjustments needed to maintain PCO₂ at the normal level of 5% (or 40 mm Hg). Astrup was a young clinical chemist in charge of the laboratory at Rigshospitalet. He had no routine way of measuring PCO₂ but knew the method: Measure arterial pH, and measure plasma or serum CO₂ content using a Van Slyke manometric analyser. Compute PCO₂ by the Henderson-Hasselbalch equation, formalized in Copenhagen 35 years earlier by Hasselbalch.

Astrup knew that the pH of blood must be measured at body temperature. No temperature controlled pH meters were available so Astrup took his lab pH meter into his 37°C culture room, and waited while the meter and the blood sample warmed. He soon became involved in speeding up the analysis of large numbers of samples, doing arterial punctures, transporting the warm blood, in a syringe wrapped in a blanket, to his culture room, computing PCO₂ and sending the result to help the student adjust the ventilation toward a more normal level.

Astrup sought a better method of measuring PCO₂. His solution became known as the “equilibration method”. He modified one of Hasselbalch’s ideas: Measuring “reduced pH” after equilibration of a blood sample to 40 mm Hg PCO₂. Astrup modified Van Slyke’s graph showing the linear relationship of log PCO₂ to pH after equilibration of blood with differing PCO₂ gases [32]. Displacement of this straight line by added acid or base permitted Astrup, and his student and associate Ole Siggaard Andersen (1932-), to estimate not only PCO₂ but also the acid-base abnormality of the blood, later named base excess.

Astrup and Svend Schroeder of the Radiometer Co. designed and built an apparatus to measure pH at 37°C before and after equilibration with gases of known CO₂ content. Over the next decade, it was modified by Siggaard Andersen [33], improved, marketed by Radiometer, and widely used as the “Astrup Apparatus” (Fig. 55.8). The Stow-Severinghaus PCO₂ electrode gradually made it obsolete.

The term base excess (BE) was originally introduced to define blood metabolic (non-respiratory) acid base balance [34]. Some clinicians rejected BE because it changed with altered PCO₂ as plasma bicarbonate equilibrated readily with all the body’s extracellular fluid (ECF), about 3 times the blood volume. To obtain an index independent of acute changes in PCO₂, in 1966, Siggaard Andersen introduced a modified index termed Standard Base Excess (SBE) and published a modified Van Slyke equation to compute SBE now used in most blood gas analyzers [35]. SBE is nearly independent of acute changes in PCO₂, and applies to the ECF of the entire body by assuming a total ECF hemoglobin concentration of 5 g/dl.

A CO₂ electrode was first described by physiologists Robert Gesell (1886–1954) and Daniel McGinty at the University of Michigan in 1926, for use in expired air, but not in blood [36]. It used the effect of CO₂ on the pH of a film of peritoneal membrane, wet with a salt solution, and wrapped over an antimony pH electrode.

In Columbus, Ohio, a physical chemist, Richard Stow (1916-), in the department of Physical Medicine, Ohio State University, (Fig. 55.9), needed to measure blood PCO₂ to guide the setting of mechanical ventilators in the care of polio patients in 1951–3. In the library, he found several Macy reports about ion-specific electrodes. They triggered an idea. He knew that carbon dioxide permeated rubber freely and that it acidified water. He conceived of an electrode for measuring PCO₂ using a latex film to separate a blood sample from a glass pH electrode wet with distilled water. Being an expert glass blower, he constructed his own combined glass pH and reference electrode (Fig. 55.10). He immediately confirmed that the pH electrode potential increased in response to increasing PCO₂ in either gas or liquid. As he expected, pH was a logarithmic function of PCO₂.

In August 1954, Stow reported his design at the fall meeting of the American Physiologic Society in Madison, Wisconsin [37]. He had been unable to prevent significant drift, and therefore concluded that his electrode probably could not be useful. During the question period after his talk, I asked Stow whether he had considered adding bicarbonate to the distilled water electrolyte. He said he had assumed that bicarbonate was a buffer that would prevent any change of pH when PCO₂ varied. I realized that, despite his doctorate in physical chemistry, Stow clearly did not grasp the differences between fixed and volatile buffering systems. We agreed that I would construct and investigate a CO₂ electrode with a bicarbonate electrolyte [38].

A few days later, using a Stow type pH and reference electrode, I found that a 25 mM sodium bicarbonate electrolyte solution stabilized the pH signal and doubled the PCO₂ sensitivity such that a 10 fold change in PCO₂ altered pH by almost 1 pH unit. A spacer of cellophane was needed to hold a wet film between the non-conductive rubber membrane, and the pH glass surface (Fig. 55.11). In 1959, Forrest Bird (1921-), inventor of a popular ventilator, arranged for his firm, the National Welding Co, to make my CO₂ electrodes commercially available. The unpatented design concept was soon copied and marketed by Beckman, Radiometer, Instrumentation Labs and several other firms in the US, Europe and Japan.

The method now called polarography originated in Nernst’s laboratory in Göttingen, Germany. Nernst suggested to his assistant Heinrich Danneel (1867–1942), that he investigate the properties of single noble metal electrodes (gold, platinum) in solutions, by using large and non-polarizable reference electrodes to maintain a constant and known solution potential. Danneel soon noted that oxygen in the solution interfered with measurements whenever the test metal was cathodic (negative). In studying this, he showed that the reaction of oxygen with a negatively charged metal (cathode) was approximately a linear function of the oxygen pressure in the solution [39]. Danneel’s work was soon forgotten because the noble metal surface was easily contaminated or ‘poisoned’ by organic substances but his work had identified the basis of the polarographic oxygen electrode.