In memoriam: Professor Joseph Milic-Emili

Professor Joseph Milic-Emili was a very prominent figure in the respiratory community for many years. He was made an honorary member of the European Respiratory Society in 2012, by the then President Professor Francesco Blasi, in recognition of his contributions. Here, Ahmet Baydur, Thomas Similowski, Basil Petrof and David Eidelman share a statement to mark the passing of a highly regarded scientist, teacher and colleague.

Scientist, physiologist, teacher, mentor, chef, opera lover and raconteur Dr. Joseph Milic-Emili passed away on January 8, 2022. “Milic”, as he was known to all, mentored and collaborated with hundreds of fellows and colleagues throughout the world, many of whom established their own units in respiratory medicine and physiology and in turn trained and taught the next generation of researchers and clinicians in the field.

After obtaining his medical degree in 1955 at the University of Milan, Italy (where, during his studies, he served many times as an extra during countless representations at “La Scala”, some of which featured Maria Callas, about whom Milic could talk for hours) he joined the Department of Physiology directed by Professor Rodolfo Margaria, a prominent researcher in exercise physiology. His first assigned project was to assess the relationship between ventilation and tidal volume during recovery after exercise in normal subjects and athletes. Despite challenges in the pursuit of the experiment, Milic persevered, with presentation of his first abstract at a meeting. Most important, Margaria taught him to present results in a clear and concise fashion [1].

His next project was to refine the esophageal balloon technique by making balloons from scratch as they were not available in Margaria’s laboratory. Working with a new arrival in the lab, Jean-Marie Petit, he made balloons from mini condoms manufactured by the Pirelli tire company. The result was the best esophageal balloons made until then.  Milic and Petit measured the static elastance of the esophagus using balloons of different diameter and length, positioned at different levels of the esophagus [2]. The study led to the determination of the “optimal” dimensions of the balloon and the error introduced by esophageal elastance in recording of pleural pressure. This experience taught Milic to improvise, using simple and inexpensive methods and materials which stood him in good stead for the rest of his career. Later, he and Petit developed a means to measure electrical activity of the diaphragm using electrodes mounted to a catheter and introduced through the esophagus to the level of the cardia.

At the request of his wife Ann, a Londoner who wished to move to a large English-speaking city, Milic moved to Boston in the early 1960s. Through a fortuitous coincidence, Jere Mead had been one of the two reviewers of the 1958 article, and he promptly invited Milic to join him at Harvard. With Dr. Mead and his group, the measurement of esophageal pressure was further refined [2].

After his move from Boston to McGill in Montreal, Milic and colleagues embarked on studying one of the cardinal physiologic principles in respiratory medicine: ventilation and perfusion distribution and relationships throughout the lung. Using radioisotope techniques, he and colleagues showed how, in an upright individual, both blood flow and ventilation increased from apex to base, with blood flow increasing more, resulting in a progressive decrease in the ventilation-perfusion ratio from top to bottom [3]. This concept helped explain many phenomena, such as why reactivation tuberculosis occurs at the apices (and how prolonged bed rest cured many people with this disease), why panlobular emphysema starts at the bases in alpha-1 antitrypsin deficiency and how proning helps to improve gas exchange in severe acute respiratory distress syndrome.

Milic and colleagues [4, 5] showed that airway occlusion pressure (measured at 0.1 sec after onset of inspiratory effort, P0.1 or P100) provided a valuable index of the inspiratory pressure available to produce breathing movements. It was an indirect measure of central drive. The advantage of P0.1 was that it incorporated pressure losses due to the intrinsic properties of the respiratory muscles (force-length and force-velocity properties) and distortion of the respiratory system. Later Milic regarded breathing pattern in a new way, namely as a consequence of the mechanical properties of the respiratory system. He recognized that analysis of breathing movements needed to go beyond measurement of just tidal volume and respiratory frequency. Following the pioneering work of Clark and von Euler [6] he proceeded to define a new analysis in terms of driving pressure (Vt/Ti) and a timing mechanism (Ti/Ttot or duty cycle, where Vt is tidal volume, Ti is inspiratory time and Ttot the duration of the respiratory cycle) [7]. In performing experiments, he considered the shape of both the inspirogram and the expirogram [8]. Elucidation of these concepts led to a subsequent explosion of clinical studies of control of ventilation in patients with obstructive and restrictive respiratory disorders. One of them was the demonstration that hypercarbia developing during administration of high flow oxygen in patients with exacerbation of COPD, was mainly due to increase in dead space breathing from ventilation-perfusion mismatching, with suppression of the hypoxic drive being only a minor factor [8]. In fact, P0.1 is little reduced or even higher than in normal individuals during oxygen administration.

This work segued into investigation of the active impedance of the respiratory system. In contrast to the passive volume-elastic and flow-resistive impedances of the lungs, airways and chest wall, when inspiratory muscles contract agonistically, their active force-length and force-velocity properties add to the volume-elastic impedance (elastance) and the force-resistive impedance (flow resistance), respectively [9-11]. Pressure losses due to thoracic distortion from its relaxed (passive) configuration contribute to the difference between active and passive respiratory impedance [12, 13]. In other words, during inspiration, the respiratory system “stiffens”, a useful mechanism by which passive loads can be compensated. Such properties help explain how individuals with advanced respiratory disorders can maintain ventilation despite disadvantageous mechanics.

Shortly thereafter, during the 1980s and 1990s, Milic and colleagues further explored the dynamic forces that developed in opposition to the driving pressures determined by mechanical properties of both lung and chest wall. Their studies built on earlier work by Mead and Agostoni [14] and Rodarte and Rehder [15]. Milic helped revive the interrupter technique to measure and partition respiratory resistance and elastance into its lung and chest wall components. These studies confirmed that viscoelastic properties determine the frequency dependence of these components [16]. Viscoelastic behavior also determined the time course of volume during passive expiration and that expiratory flows are markedly dependent on previous volume history of the lung.

Such factors produce inaccuracies in the determination of expiratory flow limitation (EFL) during conventional spirometry and why body plethysmography has been advocated as the preferred technique (although, it too has its inherent flaws). The FEV1 is a poor predictor of EFL during quiet breathing, which is closely associated with dyspnea at rest and minimal exercise. As a consequence, Milic sought a more reliable method to detect EFL in individuals with lung disease. He designed the negative expiratory pressure (NEP) technique which consists of applying a gentle negative pressure at the mouth during tidal expiration (about –5 cm H2O) and comparing the ensuing expiratory flow-volume curve with that of the preceding control tidal expiration [17]. The application of a NEP at the airway opening increases the expiratory driving pressure and should increase expiratory flow if the individual is not flow-limited (FL). In contrast, if FL is present, expiratory flow should not change with application of NEP. The technique has been shown to be more reliable than spirometry and plethysmography and has been validated by concomitant determination of isovolume flow-pressure relationships. This concept in turn led to a plethora of studies of EFL in both spontaneously breathing and ventilated patients [18].

Willingness to laugh and work closely with young fellows as well as seasoned clinicians was a characteristic Milic maintained throughout his career. Possessed also of a sharp, biting sense of humor (and sometimes irony), Milic enabled one to perceive certain realities in a different perspective, which was entertaining in many respects. He would take the time to explain complex concepts in understandable terms (“keep it simple”). He could also be hilarious, recounting many instances of his travel adventures and jokes originating from the many countries he visited.

One series of encounters during which everyone was intrigued and challenged at the same time was the informal seminars held weekly at the Meakins-Christie. Regardless of whether the speaker was a fellow or a prominent guest speaker, they would always be subject to piercing questions from Milic regarding their research and suggestions to interpret the results of a particular investigation in a different light. Sometimes he would interrogate the speaker even before they began their talk. Some of the guest speakers who came to speak at the seminars included Sol Permutt, Charles Irvin, Magdy Younes, Ludwig Engel, Dudley Rochester and John Faulkner, all experts in respiratory muscles and control of breathing and some who themselves had spent time previously at Meakins-Christie. All participated in lively discussions with Milic.

Milic was many things: teacher, mentor, friend and confidante; fierce competitor and taskmaster; cheerleader and career promoter; critic and antagonistic prosecutor (getting past the first slide was murder – hence the famous advice that puzzled so many of his research fellows: “never ever start with slide one”); historian and philosopher; master of ceremonies and stand-up comedian. He was an enormously talented and complex man.  Throughout it all, he always had that little twinkle in his eyes, and he embraced life.  He was one of a kind, and there will never be another like him. The giant is gone, but many will continue to stand on his shoulders.

When Milic’s passing was announced, a torrent of testimonies flowed through several strings of emails. Dozens of people who had worked with Milic expressed how he had been important to them, professionally and personally, attesting to Milic’s prolific capacity to attract people to him, something he did relentlessly throughout his career. Scientific anecdotes were told. Jokes were remembered. This was deeply moving. But something very peculiar also happened; people who had not been recruited, trained, supervised, promoted, advised or helped by Milic joined in. People who had not worked with him but who had been influenced by him. Remarkably enough, Milic’s influence went way beyond “his people” and extended, to quote Martin Tobin, who did not work directly with Milic, “on researchers who never met him and subsequently on their trainees, like the ripples generated by dropping a stone into a pond”. This is a very rare achievement for a scientist.

Milic spent most of his career in North America, where he settled and lived. He was a Canadian citizen. He held tenure at McGill University in Montreal where he chaired the Department of Physiology from 1973 to 1978 and then directed the world-famous Meakins-Christie Laboratories from 1979 to 1994. He was a Fellow of the Royal Society of Canada, and, in 1990, was inducted into the Order of Canada, the cornerstone of the Canadian honors system that recognizes outstanding achievement and service to the Canadian nation. But Milic was also quintessentially European. He was born in Sezana in 1931, then in the Kingdom of Italy in the Province of Trieste, and, from 1947, part of the Socialist Federal Republic of Yugoslavia (until the independence of Slovenia in 1991). He trained in Italy and in Belgium until 1963. Then, after having definitively opted for North America, he spent several sabbaticals in European countries, as attested to by four of his five Doctor Honoris Causa degrees (Université Catholique de Louvain, Belgium; University of Montpellier, France; Athènes, Greece; and Ljubljana, Slovenia ; the fifth one is from the University of Kunming, China) and by the immense number of research fellows whom he recruited in the Old Continent. At certain points of time, young researchers who worked with Milic at Meakins would learn Italian much faster than any other languages, so numerous were the pupils he had recruited from Italy. Visiting European cities with Milic was always a mine of cultural enrichment. Of notice, Milic authored or co-authored 29 research articles in the European Respiratory Journal, starting in 1988 (volume 1) and until 2006, after 10 articles published in the ERJ’s direct ancestors namely the Bulletin de Physio-pathologie respiratoire and the Bulletin européen de physiopathologie respiratoire (roughly 10% of his scientific production).

Milic is survived by his wife Ann and 3 children.

Milic will be missed but his life work will be remembered, honored and always applied in clinical care.

Ave atque vale.

References  

1. Joseph Milic-Emili J. A respiratory physiologist by hook or by crook. Am J Respir Crit Care Med 2003; 167, https://doi.org/10.1164/rccm.2302008
2. Milic-Emili J, Mead J, Turner JM, et al. Improved technique for estimating pleural pressure from esophageal balloons. J Appl Physiol1964 Mar; 19:207-11. doi: 10.1152/jappl.1964.19.2.207.
3. Kaneko K, J Milic-Emili J, Dolovich MB, et al. Regional distribution of ventilation and perfusion as a function of body position. J Appl Physiol 01 MAY 1966https://doi.org/10.1152/jappl.1966.21.3.767.
4. Whitelaw WA, Derenne JP, Milic-Emili J. Occlusion pressure as a measure Pengelly LD, Alderson A, Milic-Emili J. Mechanics of the diaphragm. J Appl Physiol 1971; 30:796-806. adva of respiratory center output in conscious man. Respir Physiol 1975; 23:181-199.
5. Siafakas NM, Chang HK, Bonora M, et al. Time course of phrenic activity and respiratory pressures during airway occlusion in cats. J Appl Physiol 1981; 51:99-107.
6. Clark FJ, von Euler C. On the regulation of depth and rate of breathing. J Physiol 1972; 222:267-295.
7. Milic-Emili J. Recent advances in clinical assessment of control of breathing. Lung 1982; 160:1-17.
8. Aubier M, Murciano D, Milic-Emili J, et al. Effects of the administration of oxygen therapy on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis 1980; 122:747-754.
9. Siafakas NM, Peslin R, Bonora M, et al. Phrenic activity, phrenic pressures and volume changes in cats. J Appl Physiol 1981; 51:109-121.
10. Zin WA, Pengelly LD, Milic-Emili J. Active impedance of respiratory system in anesthetized cats. J Appl Physiol 1982; 53:149-157.
11. Zin WA, Marlot D, Bonora M, et al. Active and passive respiratory mechanics and control of breathing in kittens. J Appl Physiol 1983; 55:183-190.
12. Pengelly LD, Alderson A, Milic-Emili J. Mechanics of the diaphragm. J Appl Physiol 1971; 30:796-806.
13. Behrakis PK, Higgs BD, Baydur A, et al. Active inspiratory impedance in halothane-anesthetized humans. J Appl Physiol Respir Environ Exerc Physiol 1983 Jun;54(6):1477-81. doi: 10.1152/jappl.1983.54.6.1477.
14. Mead J, Agostoni E. Dynamics of Breathing. In Handbook of Physiology, Section 3, Respiration, vol. 1. Edited by WO Fenn and H Rahn, Washington, DC, American Physiological Society, pp. 411-427.
15. Rodarte JR, Rehder K. Dynamics of Respiration. In Handbook of Physiology, Section 3, The Respiratory System, vol. 3, Mechanics of Breathing. Edited by PT Macklem and J Mead, Washington, DC, American Physiological Society, pp. 131-144.
16. Similowski T, Levy P, Corbeil C, et al. Viscoelastic behavior of lung and chest wall in dogs determined by flow interruption. J App Physiol67:2219-2229.
17. Koulouris NG, Valta P, Lavoie A, et al. A simple method to detect expiratory flow limitation during spontaneous breathing. Eur Respir J1995; 8:306-813.
18. Eltayara L, Becklake MR, Volta CA, et al. Relationship between chronic dyspnea and expiratory flow-limitation in COPD patients. Am J Respir Crit Care Med 1996; 154:1726-1734.