The primary reason for increased ventilation during dynamic exercise is to raise alveolar ventilation in proportion to O2 consumption and CO2 production and to regulate acid-base balance. The matching of ventilation to metabolism is accomplished with remarkable precision, emphasizing a highly ordered structure and control system. In the healthy human, arterial blood gas homeostasis is maintained from rest to maximal exercise (although the endurance-trained athlete may be an exception). This is impressive considering the additional demands of heavy exercise during which mixed venous blood becomes markedly hypercapnic and hypoxemic. It is also necessary to maintain a low pulmonary vascular resistance in the face of increased pulmonary blood flow. To generate the appropriate level of ventilation during exercise the respiratory muscles must generate substantial pressures without incurring fatigue or requiring disproportionate blood flow or energy utilization. With the above in mind we have chosen to highlight Canadian contributions in specific areas of study: (1) control of ventilation, (2) gas exchange and blood flow, (3) lung mechanics and (4) high altitude. Synthesizing the many contributions of Canadian researchers to the field pulmonary exercise physiology is a formidable task. It is likely we have missed the contributions of some investigators and any omission is unintentional on our part.
Control of Ventilation
The largest ventilatory adjustment made by humans is in response to dynamic exercise where ventilation increases in direct proportion to the increase in metabolic rate. The control of ventilation is of fundamental biological importance yet our understanding of the controlling mechanisms is incomplete. Despite this, important advances have been made and Canadian researchers have made significant contributions to our understanding of exercise hyperpnea. The respiratory control system can be simplified into two general categories: feed-forward and feed-back influences. Much of the evidence for a feed-forward or central neural command of ventilation comes from animal models. However, Dr. James Duffin (University of Toronto) has pursued this hypothesis in healthy humans performing dynamic exercise. Using creative experimental approaches, he and his trainees have provided important advances to our understanding of the neural drive to ventilation during exercise (Duffin, 2014). Importantly, by using integrative models he has also shed light on the concept that the drive to breathe can be modulated by afferent feedback from the exercising muscles.
The candidates for feed-back influences on ventilation are numerous and generally relate to exercise-induced changes to the blood. One hypothesis for the control of exercise hyperpnea relates to the metabolically-induced rise in CO2 that accompanies exercise; the so-called ‘CO2 flow hypothesis’. It has long been known that CO2 output (V. co2) closely tracks ventilation during exercise, thereby preventing CO2 and H+ from increasing in arterial blood. In an important study for the field, researchers from the University of Toronto (Phillipson et al., 1981) used an extracorporeal gas exchanger to remove CO2 from the peripheral venous blood of exercising sheep at a rate equal to its metabolic production with corresponding changes to ventilation. These finds provided in vivo evidence for the coupling of V. co2 and ventilation under physiologically relevant conditions.
Dr. Jerome Dempsey, a native Canadian who received his training at the Universities of Western Ontario, Alberta and Wisconsin, has made a number of fundamental findings that have shaped current thinking on ventilatory control during exercise and hypoxia. Providing an exhaustive summary is beyond the scope of this review but the interested reader is directed to a recent authoritative review (Forster et al., 2012). As one example of his many contributions was resolving the role of cerebrospinal fluid H+ under conditions of sustained hyperventilation in chronic hypoxia. These studies were important, as, at the time, there was significant scientific debate as to the underlying mechanisms. The group from McMaster University (Kieran Killian, Norman Jones, Moran Campbell) made a great number of contributions to our understanding of ventilatory control, among others. The collective works of George Heigenhauser and Mike Lindinger has advanced our appreciation of the complex interplay between ventilation and acid-base balance.
Beyond the typical exercise physiology study that uses ‘college age’ males as research participants a number of outstanding contributions have come from Canadian researchers that have addressed ventilatory control in other populations. For example, the question of how healthy aging alters peripheral chemoreflex sensitivity was addressed in an excellent series of studies from researchers and their students at the University of Western Ontario (David Cunningham, Donald Patterson, John Kowalchuk, Mark Poulin, Claudette St. Croix). The physiological changes that accompany pregnancy are complex and include alterations to ventilatory control. The group from Queen’s University (Larry Wolfe, Denis Jensen, Denis O’Donnell) have made important contributions to the field by advancing our understanding pregnancy-induced changes to the drives to breathe (Jensen et al., 2008) and how this may modulate sensations of breathlessness/dyspnea (Jensen et al., 2009).
Gas Exchange and Blood Flow
In any article that examines the influence of Canadian expertise in exercise physiology a good place to start is with the contributions of Dr. Roy Shephard (University of Toronto). With over 1000 publications in the medicine and science of sport, physical activity and exercise there is no area that he has not touched. His leadership in this field is reflected not only in the literature, but also by the number of scientists he has mentored and the guidance that he has given to National and International organizations. A series of original papers by Dr. Shephard examined respiratory and hematological adaptations in patients with congenital heart disease. This work was done as part of his doctoral thesis at the University of London over 60 years ago. Much of his early work was relevant to clinical populations but Roy also helped in evaluating measurement tools of pulmonary function such as the Douglas bag and a portable apparatus for field-testing pulmonary diffusion. His productivity has not changed and he recently has published a historical review of the Douglas bag and chemical analyzers (Shephard, 2017).
Jerry Dempsey has been mentor to several Canadian scientists who travelled to Wisconsin to examine the interaction between physical activity and the pulmonary system. Drs. Norm Gledhill, Mike Sharratt and Jim Thoden all studied with Dr. Dempsey. The seminal study by Dempsey, Hanson and Henderson (1984) and the 1985 ACSM Wolfe Lecture (Dempsey 1986) opened the door to discussion and debate on the role of the respiratory system and limitations to performance. The lack of adaptation of the pulmonary system to physical training and the mechanisms responsible for exercise-induced arterial hypoxemia (EIAH) captured the attention of many Canadian scientists. Relative hypoventilation was proposed as a mechanism by Dempsey, and he also hypothesized that transit time through the pulmonary capillary bed might not be sufficient to allow equilibrium. Dr. Susan Hopkins, a Canadian who studied at UBC, and now a Professor at UCSD, hypothesized that the hypoxic drive to breathe (HVR) might explain the failure to hyperventilate and the development of EIAH. In well-trained subjects there was no relationship between minute ventilation, arterial desaturation and HVR, nor was it related to maximal aerobic capacity (Hopkins and McKenzie 1989; Sheel et al., 2006). Sue also examined transit time and measured VA/Q inequality, which was responsible for >60% of the variation of paO2 with heavy work (Hopkins et al., 1996). Her recent pulmonary research is focused on advanced imaging of the lung. Other Canadians have continued to examine the mechanisms underlying EIAH. Dr. Michael Stickland (University of Alberta) has postulated that interpulmonary shunts were partially responsible for the hypoxemia observed in healthy, athletes (Stickland and Lovering 2006). Drs. Alastair Hodges (University of the Fraser Valley), Jordan Guenette (UBC), Meaghan MacNutt (Quest University, Squamish), Jane LaBreche (OTP) and Don McKenzie (UBC) have used CT and MR imaging to investigate the possibility of transient pulmonary interstitial edema as a contributor to EIAH. While transient edema may occur in some individuals it does not appear to be a major contributor to abnormal pulmonary gas exchange during exercise at sea level.
Bill Sheel (UBC) and his students have examined sex-differences in the pulmonary system. They have demonstrated that women have smaller conducting airways than men, even when matched for lung size. This has a significant influence on airflow particularly during strenuous exercise with high ventilation rates. Women are more likely to experience expiratory flow limitation and exercise-induced arterial hypoxaemia and have a higher metabolic cost of breathing for a given ventilation. They also have shown that the female diaphragm is more resistant to fatigue, relative to their male counterparts (Guenette et al., 2010). Michael Stickland’s group has recently shown that, during exercise, women have a lower DLCO, Vc and Dm compared to height-matched men, although these differences are not significant after correction for lung size (Bouwsema et al., 2017).
Dr. Sheel’s lab has also been instrumental in examining the complex relationship between the respiratory work of breathing and locomotor limb blood flow-the metaboreflex, both at rest and during exercise (Dominelli et al., 2017). Dr. Michael Koehle (UBC) has examined the effect of different intermittent hypoxic exposures on measures of chemosensitivity and also has supervised clinical studies examining the effects of air pollution on the pulmonary response to physical activity (Giles and Koehle 2014).
Respiratory Muscles and Lunch Mechanics
Dr. Roy Shephard (University of Toronto) has many important contributions to the field of exercise physiology including some seminal works on the pulmonary system. As mentioned, several early works (1950’s and 1960’s) represented important methodological advances for the field. The respiratory musculature must contract in order to generate inspiratory and expiratory flow. A long-standing question was how costly is the hyperpnea of exercise? This question was addressed in 1966 in a carefully conducted study (Shephard, 1966) and the results have stood the test of time and showed that the muscles of breathing command a significant fraction of O2 uptake. Building on these results and those of others Dr. Jerry Dempsey found that work of breathing also has a significant effect on the distribution of cardiac output. In a series of highly invasive experiments (femoral artery & vein catheterization; Swann-Ganz catheter in the pulmonary artery) it was shown that experimentally reducing or increasing the work of breathing during heavy exercise up to 14-16% of cardiac output is directed to the respiratory muscles. These studies were made possible by the creative creation of a proportional assist ventilator by Dr. Magdy Younes (University of Manitoba).
Dr. Dempsey and his trainees (including Canadian Dr. Mark Babcock) made many other contributions including a key study examining exercise-induced fatigue of the diaphragm (Johnson et al., 1993). This was an important finding as it showed that under physiologically relevant conditions (i.e., exercise) that the human diaphragm could indeed fatigue. To further emphasize the ‘Canadian connection’ it should be noted that several aspects of the phrenic nerve stimulation methodology were acquired while he was on sabbatical at McGill University. Dr. Mike Sharratt (University of Waterloo) while on sabbatical at `the University of Wisconsin – Madison conducted a number of studies that have added to our understanding of how lung volume is regulated and how diaphragmatic length is optimized.
The mechanics of breathing can be altered by the inclusion of occupational breathing devices. In a series of investigations, researchers from the University of Alberta (Neil Eves, Richard Jones, Stuart Petersen, Scott Butcher) demonstrated the work of breathing is significantly higher when using a self-contained breathing apparatus (SCBA) used by firefighters, and other working in dangerous environments (Eves et al., 2003; Eves et al., 2005; Butcher et al., 2006). The contemporary breathing apparatus worn by firefighters decreases maximal O2 uptake and peak power output owing to a ventilator limitation imposed by the added expiratory resistance. They further demonstrated that the additional respiratory work could be reduced by breathing a less dense gas (i.e., helium and oxygen mixture). The reduction in respiratory muscle work was associated with a lowering of blood lactate and ratings of perceived exertion, which may have occupational relevance.
Any discussion regarding high altitude medicine and physiology research involving Canada must begin with Dr. John Sutton. An Australian by birth, John spent 17 years at McMaster University as an exercise scientist and internal medicine specialist. He had a wide range of research interests but his love of research was expressed best at, or studying high altitude. He was active as a mountaineer as well as a clinician and scientist. John was the driving force behind the Operation Everest II study that followed the original study on Mt. Everest, but conducted as a 40-day simulated ascent of Mt. Everest in a decompression chamber (Sutton et al., 1988). The massive amount of data collected in this study provided new information on human adaptation under conditions of severe hypoxia. Under conditions of profound hypoxemia and hypocapnia a fourfold increase in alveolar ventilation from baseline was reported but no change in O2 diffusion from the alveolus to end-capillary blood. Diffusion from the capillary to the muscle mitochondria was increased at altitude and an abnormally high muscle diffusing capacity, related to increased muscle capillary density, appears to be the major attribute that allowed Habeler and Messner to ascent Everest in 1978 without oxygen (Wagner, 2017).
Canada is well-represented in High Altitude research. John had a strong interest in acute mountain sickness, and other severe medical conditions associated with hypoxia. He collaborated with and Drs. Howard Green and Rich Hughson from the University of Waterloo as well as Drs. Duncan MacDougal, Norman Jones, Digby Sale and Geoff Coates at McMaster in a wide-range of experiments from muscle metabolism, pulmonary gas exchange to hormonal responses to exercise and hypoxia. Dr. Jim Thoden (University of Ottawa) worked with Jerry Dempsey and others on the effects of acute vs. life-long exposure to hypoxia on pulmonary gas exchange during exercise (Dempsey et al., 1971). They reported that the highlander avoided the increased work of breathing experienced by the lowlander exposed to moderate altitude and yet maintained systemic O2 delivery via increased pulmonary diffusion and high O2 carrying capacity. More recently scientists at UBC Okanagan (Phil Ainslie and Ali McManus) have examined the responses to hypoxia in girls and women and reported similar changes in respiratory parameters (Morris et al., 2017).
In terms of cellular respiration, Drs. Peter Hochachka, Bill Milsom and David Jones and colleagues from UBC have made enormous contributions to the study of adaptation to a hypoxic environment in human and animal populations. (Hochachka et al., 2002)
Canadian Sport and Exercise Conferences
In addition to the number of contributions listed above, we would be remiss to not emphasize that over the years a number of Canadian and International researchers have presented provocative symposia and lectures at CASS or CSEP meetings. Outstanding published symposia reports relating the pulmonary system during exercise appear in the Society’s journals. The reader with an eye towards understanding the historical basis for contemporary thinking is directed to following symposia: (i) The Respiratory System as a Limiting Factor in Prolonged Effort (Canadian Journal of Sport Sciences, vol. 12, suppl. 1, 1987), (ii) Respiratory Control During Exercise (Canadian Journal of Applied Physiology, vol. 19, no. 3, 1994) and (iii) The John Sutton Lecture: Pulmonary System Limitations to Exercise in Health, Canadian Journal of Applied Physiology, vol. 28, suppl. 2003).
Dr. John Sutton was instrumental, with G. Coates and C. Houston, in establishing the International Hypoxia Symposium, a bi-annual Conference in Lake Louise and Banff, originated in 1979, which brings the world leaders in altitude research and hypoxia to Canada on the first full moon in February! These Proceedings are published and represent a wealth of knowledge by world-class scientists and clinicians.
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