Frontiers reviewLactic acid buffering, nonmetabolic CO2 and exercise hyperventilation: A critical reappraisal
Introduction
This report re-examines a comprehensive model of acid–base balance and hyperventilation in response to exercise (Wasserman, 1982), which has been widely accepted and which is a central tenet in the interpretation of clinical exercise testing of patients with cardiopulmonary diseases (Wasserman, 1986b, Wasserman, 1988, Wasserman, 1997, Wasserman, 2002b, Casaburi et al., 1987, Casaburi et al., 1989, Casaburi et al., 1991, Wasserman and Sietsema, 1988, Patessio et al., 1992, Patessio and Donner, 1994, Johnson et al., 2003, Wasserman et al., 2005). This model is as follows (Fig. 1). Bicarbonate is the main buffer in the muscle, and the disproportionate increase in at the mouth above the ventilatory threshold (VTH) reflects the production of extra CO2 due to lactic acid buffering by plasma bicarbonate entering the cell in exchange with lactate. Plasma standard bicarbonate concentration decreases in an almost 1:1 ratio with the increase in plasma lactate concentration. For each mmol of lactic acid buffered in the muscle, 1 mmol (22.3 mL) of extra CO2 is generated above that produced by aerobic metabolism. According to the model, this extra CO2 also called “buffer” CO2 (Wasserman, 1994, Zhang et al., 1994) or “nonmetabolic” CO2 (Anderson and Rhodes, 1991, Patessio et al., 1992, Roecker et al., 2000) is in turn considered to be partly responsible for hyperventilation above VTH because the resulting increase in CO2 flow to the lungs is thought to stimulate pulmonary ventilation () (Wasserman et al., 1977a, Wasserman et al., 1977b, Wasserman et al., 1980, Wasserman et al., 1986b).
The main experimental arguments offered in support of this model are the reportedly close inverse relationship between changes in plasma lactate and bicarbonate concentrations, and the close relationship between at the mouth and in a wide variety of situations. These arguments are presented in the original paper in which the model has been suggested (Wasserman, 1982) as well as in several subsequent reviews (Wasserman, 1984a, Wasserman, 1984b, Wasserman, 1986a, Wasserman, 1986b, Wasserman, 1987, Wasserman, 1988, Wasserman, 2002a, Wasserman et al., 1986a, Wasserman et al., 1986b, Wasserman et al., 1990, Wasserman et al., 1994, Wasserman and Casaburi, 1991, Whipp and Ward, 1991), and in a book (Wasserman et al., 2005). However, as explained in the present report and in contrast to the assertions of the model, experimental data show that: (1) bicarbonate is not the main buffer in the muscle; (2) the decrease in plasma standard bicarbonate concentration during exercise is not the mirror image of the increase in plasma lactate concentration; (3) H+ buffering by bicarbonate does not increase CO2 production in the muscle over what is produced by aerobic metabolism (in other words, no nonmetabolic CO2 is produced in the muscle); (4) the CO2 flow to the lungs (which is confused with at the mouth in the model) does not increase with workload at a faster rate above than below VTH; (5) the increase in above VTH is not due to the increase in at the mouth; (6) on the contrary, and as suggested before 1982 (Hill et al., 1924, Naimark et al., 1964, Wasserman and McIlroy, 1964), the disproportionate increase in at the mouth above VTH is due both to the increase in and the ensuing reduction in , and to the reduction in arterial pH.
Section snippets
Bicarbonate is not the main buffer of H+ in the muscle cell
The model in Fig. 1 is based on the hypothesis that “bicarbonate is the primary buffer for the new H+” released in the muscle cell (Wasserman et al., 2005; p. 28). It is recognized that protein and phosphate buffer systems are available and that creatine formed from the splitting of creatine phosphate might buffer the initial increase in lactic acid (Beaver et al., 1986a). However, based on changes in plasma bicarbonate and plasma lactate concentration, it was concluded that these intracellular
Standard bicarbonate is not the mirror image of lactate concentration
One of the experimental arguments in support of the model in Fig. 1 is the assertion that above VTH, the reduction in standard plasma bicarbonate concentration is almost equal to the increase in plasma lactate concentration as soon as lactate concentration increases by ∼0.5 to ∼1 mmol/L (Wasserman, 1987, Wasserman, 1988, Wasserman et al., 1990, Wasserman and Casaburi, 1991). This is offered as evidence that lactate leaving the muscle and plasma bicarbonate entering the muscle are exchanged in a
Lactic acid buffering by bicarbonate does not generate CO2 in tissues
One of the main assertions of the model in Fig. 1 is that lactic acid buffering by bicarbonate generates CO2 in the muscle in addition to the CO2 produced by aerobic metabolism, with “approximately 22.3 mL of CO2 […] produced over that from aerobic metabolism for each mmol of lactic acid buffered by HCO3−” (Wasserman et al., 2005; p. 28). This is offered as an argument to explain the “obligatory” increase in in tissues and at the mouth accompanying lactic acid production and buffering
The CO2 flow to the lungs levels off above VTH
Consistent with the hypothesis of nonmetabolic CO2 production in the muscle due to lactic acid buffering by bicarbonate, the model in Fig. 1 predicts that above VTH the CO2 flow to the lung increases. The CO2 flow to the lung, or , in L of CO2/min, is equal to , where and are, respectively, the cardiac output in L/min, and the CO2 content in mixed venous blood in mL/L. The increase in above VTH is considered to be one factor responsible for
Excess CO2 released at the mouth and nonmetabolic CO2
According to the model in Fig. 1 the excess CO2 released at the mouth is the extra nonmetabolic CO2 produced in the muscle due to lactic acid buffering by bicarbonate and is equal, mole for mole, to the amount of lactic acid produced and buffered by bicarbonate. Based on this hypothesis several studies have attempted to estimate lactic acid production from the excess CO2 released at the mouth (e.g., Ardevol et al., 1997, Roecker et al., 2000). These attempts were bound to fail because no
is not the CO2 flow to the lungs
One of the experimental arguments in support of the hypothesis that the increase in is due to an increase in the CO2 flow to the lungs, is the observation that during exercise, changes in are tightly coupled to changes in at the mouth in a wide variety of situations (Casaburi et al., 1977, Casaburi et al., 1987, Diamond et al., 1977, Wasserman et al., 1977a, Wasserman et al., 1977b, Wasserman et al., 1986b, Ward et al., 1983, Wasserman and Whipp, 1983, Whipp et al., 1984, Anderson
during ramp exercise: role of hyperventilation and low pH
A counter argument for the assertion that at the mouth determines , is the observation that actually at the mouth follows changes in , as shown in studies, where was voluntarily increased at rest (Brandi and Clode, 1969, Ward et al., 1983) or exercise (Fig. 5) (Jones and Jurkowski, 1979, Haffor et al., 1987, Ozcelik et al., 1999). The reduction of due to hyperventilation favors CO2 release at the mouth without any changes in CO2 production in tissues. This phenomenon
Conclusion
In conclusion, the model in Fig. 1 for describing H+ buffering in the muscle, acid–base balance and hyperventilation in ramp exercise does not appear to be valid. At the present time there is no comprehensive explanation for the control of ventilation in response to exercise below or above VTH (Whipp, 1983, Whipp et al., 1984, Powers and Beadle, 1985, Wasserman et al., 1986b, Paterson, 1992, Mateika and Duffin, 1995, Forster, 2000). However, as shown in Fig. 6, the mechanisms by which
Acknowledgements
F. Péronnet's work is supported by a grant from the Natural Sciences and Engineering Research Council of Canada. This report results in part from exchanges and discussions conducted in several workshops on clinical exercise testing organized by HYLAB (Grenoble, France), and sponsored by Boehringer Ingelheim, France, and Schiller France.
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