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Departments of Anaesthesia and Physiology, University of Toronto, Toronto, Ontario
Submitted 30 May 2005 ; accepted in final form 10 August 2005
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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computer modeling
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Modelers of the chemoreflex control of breathing usually express the chemoreceptor stimuli in terms of PCO2 and PO2 and the resultant response in terms of pulmonary ventilation (6, 15, 27, 33, 53, 61, 64), although some early modelers used pH as the stimulus (31, 38). However, the latter modelers did not consider acid-base disturbances or any detailed models of the relation between pH and PCO2.
Currently, breathing is assumed to be the sum of three components: central and peripheral chemoreflex drives to breathe and a ventilatory drive dependent on state, an approach introduced by Lloyd and Cunningham (32) that has come to be known as the "Oxford" model. The model uses linear relations between ventilation and PCO2 above a threshold and a rectangular hyperbolic relation to describe the modulation of peripheral chemoreflex sensitivity to PCO2 by PO2. The effect of behavioral state (45, 55) is modeled as the addition of a "wakefulness drive" to breathe (34), a concept introduced by Fink (12) because the drive disappears during sleep.
Many laboratories have measured the ventilatory responses to carbon dioxide and hypoxia to establish parameters for the Oxford model, using a variety of methods. Early estimates used steady-state methods (32), and with the introduction of a convenient hyperoxic rebreathing technique by Read (49) many investigators have determined the central chemoreflex sensitivity to PCO2, the peripheral chemoreflex presumed silenced by the hyperoxia (e.g., Ref. 37). However, neither of these methods measures the wakefulness ventilation drive or the ventilatory recruitment threshold of the response to PCO2; the latter corresponds to the apneic threshold in sleep (36). Usually the ventilatory recruitment threshold has been taken as the extrapolation of the response to the PCO2 axis, but this intersection point varies with the slope or sensitivity of the response as well as the strength of the wakefulness drive, unlike the actual threshold.
In 1987, I introduced a modified version of Read's rebreathing method that allowed direct determination of the ventilatory recruitment threshold. In addition, the method measures the ventilatory response to PCO2 at a chosen isoxic PO2 tension and the subthreshold ventilation, which is taken as a measure of the wakefulness or basal drive to breathe (2, 8). A number of studies using this method (e.g., Ref. 39) accumulated sufficient data on a large number for subjects to develop a model of the respiratory chemoreflexes (9). One major change of concept in this model is the rejection of hypoxia as an independent stimulus; hypoxia only acts to sensitize the peripheral response to carbon dioxide. This point is illustrated in Ref. 39, where the effects of hypoxia on the response to carbon dioxide clearly do not affect the subthreshold ventilation, and it was directly demonstrated in Ref. 48, where the response to hypoxia below the threshold was measured. These results clearly disagree with the classical view of hypoxia as an independent stimulus to breathe, as illustrated in Ref. 43, and argue against viewing PO2 as the primary stimulus to the peripheral chemoreceptors (e.g., Ref. 63). In the present model, PO2 only modulates the sensitivity of the peripheral chemoreceptor response to PCO2.
In recent studies of the changes in the chemoreflexes induced by exposure to patterns of hypoxia (7), including altitude hypoxia (57), it became apparent that consideration must also be given to acid-base changes. These may alter the relationship between the actual stimulus to the chemoreceptors, [H+], and the measured stimulus, PCO2, and so necessitated the development of a model of the respiratory chemoreflex control of breathing in terms of the actual stimulus [H+] rather than the measured stimulus PCO2. This paper presents such a model, and it is used to illustrate how changes in acid-base variables affect the regulation of breathing. Although the predictions are based on a quantitative model, comparisons with experimental data are of necessity qualitative, because measures of the requisite acid-base variables in humans are lacking. The presentation of the model is therefore essentially as a "proof of concept," and my aim is to stimulate debate about traditional approaches to the control of breathing and acid-base balance.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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The model consists of mathematical relations between chemoreflex stimuli, PCO2 and PO2, and the resultant ventilation. As Dejours originally suggested (4), these relations describe chemoreflexes, with a reflex arc from the chemoreceptors to the outcome ventilation. The model presented here was developed from a previous model (9) that described the chemoreflex responses to hypoxia and carbon dioxide in terms of both tidal volume and breathing frequency. The model developed here expresses the response as ventilation only and was derived from the previous model by making the assumption that breathing frequency was constant at 12 breaths/min. The central and peripheral chemoreflex drives to breathe are assumed to be additive but do not actually affect pulmonary ventilation until a drive threshold is exceeded. They then add to the wakefulness drive to breathe. The following sections detail these relations in turn, presenting them in both graphical and algebraic forms (APPENDIX A).
Central chemoreflex. Figure 2A shows the central chemoreflex alone as a linear relation between central PCO2 input and the central chemoreflex drive to breathe output, and it assumes an aggregate response of all central chemoreceptors. The drive to breathe can be thought of as the signal transmitted from the central chemoreceptors to the medullary respiratory neurons measured in terms of pulmonary ventilation, with the slope of the response indicating the sensitivity of the chemoreflex. In addition, there is a central chemoreceptor threshold: the PCO2 above which the central chemoreceptors generate a drive signal. The response to carbon dioxide is therefore determined by both sensitivity and threshold parameters according to Eq. A1.
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Central and peripheral chemoreflex drives sum. Currently the prevailing view is that the central and peripheral drive signals sum centrally to produce an overall drive to breathe without a more complex interaction (28). However, the summed signals must increase beyond a drive threshold before pulmonary ventilation is affected, as illustrated in Fig. 3. In other words, even though the central and peripheral chemoreceptors are generating signals, ventilation is unaffected until their summed signal strength is large enough to exceed the drive threshold of 18.5 l/min and produce an increase in pulmonary ventilation. As a result, when measuring the central chemoreflex ventilation response to carbon dioxide, there is another threshold created: the ventilatory recruitment threshold is the PCO2 below which ventilation is unaffected by carbon dioxide and above which the response is linearly related to PCO2. This ventilatory recruitment threshold is equivalent to the apneic threshold when the wakefulness drive is absent during sleep (36).
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A complete graphical picture of the control of breathing in a resting individual may be developed by assuming a difference between central and arterial PCO2 of 6 Torr. This value was chosen partly as a compromise between the measured differences between cerebrospinal fluid (CSF) and arterial PCO2 of 
10 Torr and suggestions that the actual medullary PCO2 in the region of the central chemoreceptors may be only a few Torr above arterial due to their differential perfusion (23). An estimate can also be made from the differences steady-state and rebreathing ventilatory responses to carbon dioxide. The steady-state responses are plotted against end-tidal estimates of arterial PCO2, whereas the rebreathing responses are plotted against end-tidal estimates of central PCO2. In our laboratory's previous study comparing steady-state and rebreathing responses (40) they were parallel and separated by a mean of 7 Torr PCO2.
This assumption has the effect of displacing the central chemoreceptor threshold downward by that amount, because central PCO2 is assumed to be 6 Torr above arterial. It therefore affects the model predictions quantitatively but not qualitatively. Then, adding the chemoreflex and wakefulness drives to breathe produces a graph of the dependence of ventilation on PCO2 shown in Fig. 4.
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Modeling Acid-Base Relations
Traditional model.
The traditional model of acid-base describes the equilibrium reaction of carbon dioxide and water expressed by the Henderson-Hasselbach equation, which defines pH. This approach leads to a simplistic understanding of acid-base balance, especially easy to understand when the linear form of the equation (44) is used:
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An increase in PCO2 due to decreased pulmonary ventilation, or a reduction in [HCO3–] due to a presumed increase in kidney excretion, will cause an increase in [H+], and the inverse changes will cause a decrease in [H+].
However, phosphate and proteins that contain histidine residues, like hemoglobin, also act as buffers within the body, so Siggaard-Andersen (56), recognizing the importance of these noncarbonic buffers, introduced the concept of "base excess," the amount of bicarbonate required to return plasma pH to 7.4 under standard conditions in vitro. Other modifications such as the concept of "anion gap" followed. This empirical approach provides insight into the classification, magnitude, and the nature of clinical acid-base disturbances, but the model breaks down at physiological extremes (10, 11). Furthermore, it uses transformed variables like pH and artificial concepts like base excess and anion gap, and it fails to identify the dependent and independent variables.
Stewart model. Peter Stewart (58) suggested that a more rigorous physicochemical approach was feasible for clinical practice, because the complex equations of such an approach could easily be solved by modern computers. The Stewart approach considers PCO2 and two other variables, SID (strong ion difference; the concentration difference of strongly dissociated positive and negative ions in solution) and [Atot] (the total concentration of weakly dissociated anions in solution) to be the independent variables that determine the dependent variables [H+] and [HCO3–]. The six equations he developed are listed in APPENDIX B.
Modified Stewart model. One weakness of the Stewart model was the assumption of a single dissociation constant for all plasma proteins to determine the contribution of weakly dissociated anions. The model does not therefore readily account for changes in phosphate or albumin that are often relevant in critically ill patients, chronic renal failure, and altitude acclimatization. In a modified version of the Stewart model developed by Figge et al. (10, 11), phosphate and albumin are substituted for total protein.
These investigators showed that globulins have a negligible role in acid-base equilibrium and quantified the role of phosphate and albumin, the latter the protein of greatest significance. Subsequently, Watson (62) simplified their approach by pointing out that only the histidine component of proteins can buffer hydrogen ion in the concentration range compatible with life and that although phosphoric acid has three dissociation constants only one is within the physiological range of [H+]. The resulting modified Stewart model equations are listed in APPENDIX C.
Chemoreflex Model in Terms of [H+]
Model equations. The chemoreflex equations with PCO2 as the input variable were converted to use [H+] as an input variable. In this new model the forward part of the feedback loop remains the metabolic hyperbola but the feedback part now contains an additional function to transform PCO2 into [H+] as the block diagram in Fig. 5 illustrates. The [H+] is assumed to be that of the interstitial fluid in the vicinity of the central chemoreceptors, an extracellular stimulus. The model is therefore not valid in its present form if the actual stimulus is an intracellular one (47).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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Measurements of the ventilatory response to carbon dioxide during dietary acid-base disturbances show that the response is displaced leftward during metabolic acidosis produced by ingesting ammonium chloride and rightward during metabolic alkalosis produced by ingesting sodium bicarbonate (30, 46). These dietary inputs produce changes in SID, and in a series of investigations Jennings and colleagues (reviewed in Refs. 25, 26) examined the control of breathing in dogs using diet to control SID and therefore disturb acid-base balance. They too found that there was a change in the chemoreflex threshold for PCO2 and noted that it counterbalanced the effects of SID on [H+] such as to restore [H+] to normal.
To simulate the effects of dietary acid-base disturbances, alterations in SID were applied to the chemoreflex model, and the model equations were used to predict the resting ventilation, arterial [H+], and PCO2 from the intersection of the ventilatory response to carbon dioxide and the metabolic hyperbola, i.e., the equilibrium point. First, the changes were equally applied to both arterial and central SID, which were displaced from their normal values, 5 mM/l above and 5 mM/l below. Then, because Jennings (26) found that the dietary changes in central SID were about half those of arterial SID, changes of 10 mM/l above and below normal were applied to arterial SID while central SID varied by 5 mM/l from normal. For all these simulations it was assumed that central PCO2 was 6 Torr higher than arterial PCO2 and that this difference remained constant. In addition, a carbon dioxide production of 0.3 l/min and a wakefulness drive of 7 l/min were assumed, and PO2 remained constant at 100 Torr. The chemoreflex responses to [H+] were assumed to be unaltered throughout.
The resulting simulation equilibrium values and assumed parameters are detailed in Table 1. Figure 6 shows the resulting ventilation vs. PCO2 graphs, for the arterial and central SID changes 5 mM/l above and below normal. The changes were exaggerated when the arterial SID was varied by 10 mM/l from normal rather than 5 mM/l (shown in gray in Fig. 6). Inset: mean steady-state ventilatory responses to carbon dioxide in humans from Ref. 30 during acid-base changes induced by diet that produced base excesses of –7.1 and +4.5.
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Ascent to altitude produces hypoxic induced changes in the chemoreflex regulation of breathing that lead to increasing ventilation and a reduction in PCO2 (54). However, central [H+] returns to normal after acclimatization (5). In his review Jennings (26) examined the case for the adjustment of central SID so as to maintain central [H+] during altitude acclimatization, using data from Ref. 5 and estimating CSF SID from measures of CSF [HCO3–]. Similar to the acid-base disturbances induced by dietary alterations in SID, Jennings found that, for the altitude acid-base disturbances, CSF PCO2 was directly related to CSF SID, and he argued that central [H+] was maintained by regulating central SID to compensate for the reduction in PCO2 (26).
Recently, we measured the ventilatory responses to carbon dioxide as well as blood acid-base variables at sea level and compared them to those after 5 days at an altitude of 3,480 m (57). Resting end-tidal PCO2 decreased by an average of 8.5 Torr, and resting PO2 at altitude was an average of 64 Torr. The pH of blood samples was not significantly different, and neither was the SID. However, [Alb] and phosphate concentration ([PO4–]) were significantly elevated by an average of 1.12 g/dl and 0.38 mM/l, respectively, a finding in agreement with another study (22).
To simulate the effects of altitude acclimatization, these changes in PO2, [Alb], and [PO4–] were applied to the chemoreflex model, and the equations used to predict the steady-state resting ventilation, arterial [H+], and PCO2 from the intersection of the ventilatory response to carbon dioxide and the metabolic hyperbola, i.e., the equilibrium point. It was assumed that central PCO2 was 6 Torr higher than arterial PCO2 and that this difference remained constant because cerebral blood flow and metabolism were unchanged (41). In addition, a carbon dioxide production of 0.3 l/min and a wakefulness drive of 7 l/min were assumed, and PO2 was 100 Torr at sea level and 64 Torr at altitude. The chemoreflex responses to [H+] were assumed to remain unaltered. In keeping with the experimental findings of a normal central [H+] (5), central SID was altered at altitude so as to maintain central [H+] at its sea level value as illustrated in Fig. 5 of Ref. 26. Additionally, the simulation was also performed without assuming a compensatory change in central SID to show the effects of the arterial blood changes alone.
The results of the simulation in terms of the steady-state equilibrium points and assumed parameters are listed in Table 1. Figure 8 shows the ventilation vs. PCO2 graphs with arterial changes only (altitude 1 line) and with both arterial and central changes (altitude 2 line). The inset shows example rebreathing responses from Ref. 57 illustrating the leftward shift in the ventilatory responses to carbon dioxide without a significant change in slope. For these rebreathing responses, end-tidal PCO2 corresponds to central PCO2, and so the response lines are shifted right relative to the model's responses, which are plotted against arterial PCO2.
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During chronic hyperventilation hypocapnia (14), the ventilatory response to PCO2 is shifted to the left (51), and, when chronic carbon dioxide retention producing hypercapnia occurs, the ventilatory response to PCO2 is shifted to the right (1, 3). These two states were simulated by increasing the wakefulness drive from 7 to 10 l/min for the former condition, and increasing inspired PCO2 from 0 to 10 Torr for the latter condition. In each case, arterial and central [Alb] and [PO4–] were assumed unaltered from normal, as were the chemoreflexes. Two compensatory scenarios were simulated. First, both arterial and central SID were adjusted to return arterial and central [H+] to normal values, simulating a complete renal and central compensation. Second, only a central compensation of SID to return central [H+] to normal was simulated.
Table 1 details the parameter settings and the resulting equilibrium values. The model predicted the steady-state ventilation vs. PCO2 response lines and equilibrium points during these compensated respiratory disturbances of acid-base balance, and Fig. 9 shows the resulting graphs. The inset shows mean steady-state ventilatory responses to carbon dioxide in humans for similar disturbances: the hyperventilation responses are those before and after 6 h of hyperventilation so as to reduce resting PCO2 by 10 Torr (51). The carbon dioxide retention response was derived by increasing the threshold of the control response line by 2.5 Torr, as the mean change reported to occur after 2 days when end-tidal PCO2 was increased by 8 Torr (3).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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As for all models, the success of predictions depends on the model parameter values chosen and the assumed changes in response to challenges. The parameters used for this model were derived as much as possible from experimental data obtained from the literature, as were the assumptions of the changes in these parameters for the simulations. However, they are still vulnerable to criticism as to the particular values chosen for the model, especially because there are large variations between individuals, and so the quantitative predictions of the model may differ from observations. In particular, there is a lack of data on central acid-base variables during the disturbances modeled here, and so comparisons of model predictions with experimental data are of necessity qualitative. Nevertheless, if the correctness of the general premises applied to the simulations (reviewed below) is accepted, then changes in the model parameter values will not alter the qualitative conclusions drawn from these simulations. These are as follows:
First, the primary effect of acid-base disturbances on the chemoreflex control of breathing is to change the partial pressure of carbon dioxide at which carbon dioxide begins to stimulate breathing, i.e., the ventilatory recruitment threshold PCO2, even though the threshold in terms of [H+] remains unchanged. Second, the model simulations demonstrate the importance of central SID in the regulation of breathing, as originally suggested by Jennings (25, 26). Third, changes in plasma phosphate or albumin will also produce changes in the ventilatory recruitment threshold. Finally, it should also be pointed out that, as the figures and tabled data show, the changes in the ventilatory response to carbon dioxide were dominated by changes in threshold, and changes in slope or sensitivity, although present, were minor in comparison.
Dietary Acid-Base Disturbances
For the dietary changes in acid-base balance it was assumed that only SID changed and that there was no change in the chemoreflex responses to [H+]. These simulations are therefore the simplest in terms of premise and are supported by experimental observations in dogs (25, 26). That the model provides a qualitative prediction of the ventilatory recruitment threshold shifts observed in humans (23, 30, 46) argues for the correctness of the assumptions.
As the model also illustrates, alterations in the degree of change in arterial vs. central SID did not change the pattern of the results to any significant degree, primarily because of the dominance of central chemoreflex control at normal oxygen tensions, and so knowledge of central acid-base status is essential if the model is to be quantitatively assessed. Therefore, comparing the model prediction to the experimental responses (30) shown in the Fig. 6 inset, it appears that either the central changes in SID produced by the experimental diet were smaller than those assumed in the model or the model simulation is an overprediction of the threshold changes. These two possibilities cannot be distinguished, because experimental data describing the degree of central acid-base changes in SID are not available.
Similarly, the predictions shown in Fig. 7 illustrating the large changes in PCO2 with dietary alterations of SID with little change in [H+] cannot be compared with direct measurements. Nevertheless, assuming that changes in central [HCO3–] reflect central SID, as Jennings has proposed (25, 26), the model prediction is qualitatively similar to experimental observations (23).
The model therefore demonstrates that the chemoreflex control of PCO2 compensates for dietary disturbances in acid-base balance so as to regulate [H+] because the ventilatory recruitment threshold of the response to carbon dioxide is changed. This change occurs because of the altered relationship between PCO2 and [H+], not because of any change in the chemoreflexes or change in any other stimulus to ventilation.
Respiratory Acid-Base Disturbances
The respiratory changes in acid-base balance produced by hyperventilation and carbon dioxide inhalation were also simple in terms of the assumed changes in model parameters; wakefulness drive and inspired PCO2 were the only changes made in each model. However, both simulations assumed compensatory SID changes to correct central and arterial [H+]. Although the principle of defense of central [H+] is acknowledged (29), the complete correction of arterial [H+] by renal mechanisms may not be. Nevertheless, even if no renal arterial compensation is assumed, alterations in ventilatory recruitment threshold PCO2 are still predicted by the model as long as central [H+] is defended, again primarily because of the dominance of central chemoreflex control at normal oxygen tensions.
Although there are no experimental data on the central acid-base changes during these respiratory disturbances, so that quantitative comparisons cannot be made, nevertheless qualitative comparisons can be made, comparing the experimental data in the Fig. 9, inset with the model predictions. The ventilatory recruitment threshold was shifted upward for carbon dioxide retention and downward for hyperventilation, more so when both central and arterial SID were adjusted than when central SID alone was adjusted. These changes are therefore qualitatively similar to those observed in experiments (1, 3, 51).
With respect to the hyperventilation experiment to reduce PCO2 by 10 Torr (51), the reduction of arterial PCO2 in the model was of similar magnitude. However, the leftward shift of the carbon dioxide response line predicted by the model, assuming both central and arterial [H+] compensation, was greater than the experimentally determined line and similar to the predicted response line for central [H+] compensation only. Whether this agreement occurred because the model assumption of a central-only [H+] compensation is correct, or because the compensation in the experiments was incomplete in 6 h, cannot be determined.
With respect to the experiments elevating end-tidal PCO2 by 8 Torr (3), the model predictions of PCO2 with central compensation alone and with both central and arterial compensation bracket the experimentally observed increase in PCO2. It might therefore be expected that the model carbon dioxide response lines should also bracket the experimentally observed response line; however, as for the hyperventilation experiments, the model prediction is in closest agreement when only central [H+] compensation is assumed. Without central acid-base data this question cannot be resolved.
Altitude
The model provides a qualitative prediction of the decrease in the ventilatory recruitment threshold shift and the fall in resting PCO2 observed in altitude experiments (21, 52, 57). However, there may be other parameter changes that were not modeled. Although the chemoreflex characteristics are likely to remain unaltered in acid-base disturbances produced by dietary changes, or respiratory induced changes in PCO2 by hyperventilation and carbon dioxide retention, there is evidence from altitude studies that after long-term exposure to hypoxia the peripheral chemoreceptor response is enhanced (52), and laboratory studies of exposure to hypoxia show that over several hours ventilation increases, especially if normocapnia is maintained (e.g., Ref. 59). The increased ventilation appears to be due to a decrease in ventilatory recruitment threshold PCO2 associated with the peripheral chemoreceptors (35). In the present simulation the chemoreflex responses were assumed to be unaltered and so this assumption may explain the underprediction of the decrease in the ventilatory recruitment threshold. If such an increase in responsiveness were to be applied to the model, there would be a further leftward shift of the ventilation vs. PCO2 graph, again assuming an adjustment of central SID to correct central [H+].
The other major assumption for the model at altitude was that the arterial to central difference in PCO2 remained unchanged. This difference is primarily determined by cerebral blood flow, and, although experimental evidence suggests that cerebral blood flow is unchanged at altitude (41), nevertheless it is of interest to speculate what would occur if it were increased and consequently the arterial to central difference in PCO2 were decreased. Then central PCO2 would be decreased and so would central [H+]. With a defense of central [H+] by decreasing SID, the ventilation vs. PCO2 response line would be shifted still further to the left.
The simulated compensations for this respiratory induced hypocapnia included increases in [Alb] and [PO4–] and decreases in central SID. Both of these assumptions are supported by experimental evidence. However, as mentioned previously, although the principle of the regulation of central [H+] by altering central SID is acknowledged (29), that of the partial compensation of arterial [H+] by increased plasma anion buffering, although supported by one study (57), remains to be investigated further. Nevertheless, even without the assumed changes in plasma [Alb] and [PO4–], the model prediction is qualitatively similar to the changes in the ventilatory response to carbon dioxide observed between sea level and after altitude acclimatization (57).
Conclusion
The simulation scenarios chosen for illustration here are but a few of those possible using the model. The model can also be extended to other scenarios in which acid-base changes occur to examine how resting ventilation and PCO2 are altered. Examples include the changes of SID during pregnancy and with progesterone over the menstrual cycle (18) and the acid-base disturbances occurring in renal failure (17). Further extensions to the model could include the incorporation of the dynamics involved in acid-base adjustments to predict the time course of respiratory and acid-base changes.
These model simulation experiments demonstrate that the relationship between PCO2 and [H+] should not be neglected in modeling the chemoreflex control of breathing. They illustrate the perhaps obvious but neglected point that because pulmonary ventilation controls PCO2 rather than [H+], the actual stimulus to the chemoreceptors, changes in their relationship will alter the ventilatory recruitment threshold PCO2 and thereby the steady-state resting ventilation and PCO2.
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APPENDIX A |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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Central chemoreceptor drive to breathe.
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Peripheral chemoreceptor drive to breathe.
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The rectangular hyperbolic relation between Sp and PO2 is described by the following equation:
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 | (A4) |
 | (A5) |
CO2 is the metabolic production of carbon dioxide (ml/min), K is a proportionality constant (1.33), E is ventilation (l/min), PACO2 is alveolar PCO2 = arterial PCO2 (Torr), and PICO2 is inspired PCO2 (Torr). The proportionality constant, K, adjusts for the conversion of ventilation to alveolar ventilation and partial pressures to fractional concentrations and was arbitrarily calculated so that, at a resting metabolic production of 300 ml/min carbon dioxide and a resting arterial PCO2 of 40 Torr, ventilation was 10 l/min.
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APPENDIX B |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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 | (B1) |
 | (B2) |
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APPENDIX C |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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| (C1) |
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APPENDIX D |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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Central chemoreceptor drive to breathe.
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Peripheral chemoreceptor drive to breathe.
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX AAPPENDIX BAPPENDIX CAPPENDIX DGRANTSACKNOWLEDGMENTSREFERENCES |
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, left scale) and [H+] (
, right scale) resulting from changes in arterial and central SID of plus and minus 5 mM/l. Other model assumptions are as for 
, sea level; 
and 
, altitude] from study (