Being John’s Fellow
As John’s fellow, I quickly learned a few things about him. First, John Severinghaus was creative. He demonstrated that with his elegant simple experiment measuring the uptake of nitrous oxide,1 and with his development of blood-gas electrode systems. I had watched him do part of that development while he and I were residents at Iowa. Second, John knew more about uptake and distribution than anyone else. Third, he could make any electronic gadget work, exposing me to the workings of infrared analyzers2 and other devices. Finally, I had wrongly assumed that John was as fascinated with uptake and distribution as I was. Not so. John’s passion was understanding respiratory physiology, particularly the control of breathing. To get him to teach me about uptake and distribution, I (and fate) would have to supply the stimulus. John was the brilliant sparkler, shedding light everywhere. But for John, his nitrous oxide experiment was a wonderful one-off. He had moved on. Fortunately, something beyond his control brought John back to uptake and distribution. I was in the right place at the right time (Figure 6.1). More about that in a moment.
Being John’s fellow was like living in a grownup version of the Hyde Park School for Little Children. Every Monday morning John held the fellow’s meeting. Show and Tell! Admission to the Bookhouse! I learned what everyone was doing and told the group what I’d done the previous week and would do the next week. I loved it. As I grew academically, my love of it increased. I pushed John to continue his fellow’s meetings long after the time he felt they were no longer necessary. Later, when I had fellows, I held my own Monday Lab Meeting.
By the late 1960s, I went my own way in the world of research, focusing on quantitating the effects of inhaled anesthetics and defining the factors that governed inhaled anesthetic pharmacokinetics. I went on to explore the mechanisms by which inhaled anesthetics act. My formal fellowship with John ended.
Nevertheless, in my mind, I was, and always remained, a Severinghaus fellow.
How Fast Does CO2 Increase in an Apneic Patient?
When I’d settled in, John gave me the first of several assignments in respiratory physiology research: measure the rate at which arterial PCO2 (PaCO2) increases when a patient stops breathing (apnea), an increase that stimulates breathing and thus determines how quickly a patient might breathe after anesthesia.3 In part, the change simply reflects the rate at which the body makes CO2. It also reflects the body’s capacity to store the CO2 that it makes. That is, it reflects the solubility and buffering of CO2 in tissues. Aha! An uptake problem! Being in John’s lab, I knew that the end-tidal PCO2 (PACO2) approximately equaled the arterial PCO2 (PaCO2). So, I just had to measure the end-tidal CO2 in an apneic subject. This seemed like a contradiction, how can an apneic patient have an end-tidal anything? We approximated that by having patients rebreathe from a small (400 mL) bag loaded with air containing their initial CO2 concentration,3 finding that CO2 in the small bag increased at a steady-state rate of 2 to 4 mm Hg/min. It increased faster in the first minute as the lungs went from equilibrating with the arterial CO2 to equilibrating with the greater CO2 in venous blood, perhaps 8 to 10 mm Hg greater. Hypothermia slowed the rate of rise, partly because metabolism decreased and partly because the solubility of CO2 increased.
John supported my fascination with inhaled anesthetic kinetics and dynamics but never pursued them as I did. He took me and other fellows to work in the high-altitude laboratory on White Mountain at 12,000 ft. I remember falling asleep in the communal dormitory, listening to the breathing around me, breathing stimulated by the diminished oxygen partial pressure at high altitude. One individual exhibited a particularly interesting breathing pattern, a Cheyne-Stokes pattern in which his breathing increased and then faded away and stopped. I suddenly awoke from my reverie, terrified at the realization that I had stopped breathing.
John took a sabbatical in 1966 just as I was finishing the research on carbon dioxide pharmacology. Fearing I would be at loose ends, John set me a task with the ever-delightful Ralph Kellogg and others, including Allan Mines. We tested the thesis that a sustained (8-hour) decrease in PACO2 would shift the resting PACO2 versus ventilation curve to the left and that the shift would be larger if hypoxia accompanied the sustained decrease. As our report noted,4 during the 8-hour period of acclimatization, the subject “was allowed to read, watch television (I Love Lucy was a favorite), or do nothing; at no time was he allowed to sleep.” We did many things to keep each subject awake, the most effective being a blast of air in his ear. The experiment included studies of the effect of administering several combinations of oxygen and carbon dioxide for 8 hours (only one combination for a given 8-hour period). The combination of decreased oxygen and increased carbon dioxide was particularly unpleasant. The resulting stimulation of breathing and a sense of claustrophobia kept subjects awake without the blast of air in the ear. I couldn’t deal with the claustrophobia and declined to be a subject! The results confirmed the above thesis.