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Nonpulmonary Influences on Gas Exchange

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Abstract

There are several determinants governing arterial and mixed venous blood PO2 and PCO2. Ventilation‐perfusion imbalance, increased intrapulmonary shunt, and diffusion limitation to oxygen encompass the pulmonary factors. Alternatively, inspired oxygen concentration, overall ventilation, cardiac output, and oxygen consumption (uptake) are contemplated as the four most influential nonpulmonary determinants. All three pulmonary factors plus oxygen uptake cannot be directly modulated, but all the other remaining nonpulmonary determinants are. Inspired oxygen concentration, the amount and pattern of total ventilation, and cardiac output may be, at least in part, relatively well clinically controlled. Arterial PO2 (PaO2) may fall if inspired PO2, overall ventilation, and/or cardiac output decrease, and/or oxygen consumption increases, even though the pulmonary factors remain unchanged. Conversely, if inspired oxygen fraction, ventilation, and/or cardiac output increase, and/or oxygen consumption decreases, PaO2 may improve regardless of the changes operated at the level of the pulmonary determinants. Several pathophysiologic features deserve to be underlined. First, the importance of understanding the role played by mixed venous PO2 as a vital nonpulmonary determinant governing PaO2. Second, the response to 100% oxygen breathing repeatedly exhibits a consistent amount of agreement in the main findings. Third, there is always an interactive interplay between pulmonary and nonpulmonary determinants of PaO2 and arterial PCO2 (PaCO2) in any respiratory disease state following the use of pharmacologic or nonpharmacologic approaches. All in all both PaO2 and PaCO2 become the end‐point outcomes of the complex interaction of pulmonary and nonpulmonary factors modulating pulmonary gas exchange. This needs to be unraveled to improve the understanding and management of most acute and chronic respiratory disease states. © 2014 American Physiological Society. Compr Physiol 4:1455‐1494, 2014.

Figure 1. Figure 1. Variations in end‐capillary PO2 and PCO2 in a single gas exchange lung unit as a function of ventilation‐perfusion ratio [with permission from Ref. ()] (for further explanation, see text).
Figure 2. Figure 2. Relationships between PaO2 and arterial‐venous oxygen content (CaO2‐CvO2) difference as a function of the severity of pulmonary shunt, expressed as percent of cardiac output [with permission from Ref. ()] (for further explanation, see text).
Figure 3. Figure 3. Relationships between FEV1 (X‐axis) and (A) ventilation‐perfusion imbalance (as expressed as the pulmonary blood flow dispersion, Log SDQ); and (B) the alveolar‐arterial PO2 difference P(A‐a),O2. In (A), abnormal Log SDQ is present even in asymptomatic asthma (represented by groups A and B), varies little until FEV1 reaches 40% predicted, and then deteriorates abrupt and markedly; in (B), the P(A‐a),O2 is essentially abnormal (compared to conventional normal limits) across the whole spectrum of bronchial asthma. Group A = mild asthma; B = asymptomatic asthma; C = chronically symptomatic out‐patients, moderately severe; D = chronically symptomatic out‐patients, severe; E = acute, severe asthma (hospitalized); and, F = acute, severe asthma (hospitalized). Dots with horizontal bars represent mean±SEM values at each time point [Reproduced with permission of the European Respiratory Society].
Figure 4. Figure 4. Significant relationships between the amount of ventilation‐perfusion imbalance, expressed as the dispersion of the blood flow distribution (Log SDQ) while breathing 100% oxygen (percentage change from baseline) (X‐axis), reflecting hypoxic pulmonary vasoconstriction release, with pulmonary artery pressure (A), overall degree of ventilation‐perfusion inequalities (expressed as DISP R‐E*) (B), and PaO2 during exercise (C) in idiopathic pulmonary fibrosis. During exercise, the amount of release of hypoxic vasoconstriction is associated with less pulmonary hypertension (A), less ventilation‐perfusion imbalance (B), and better arterial oxygenation (C) [with permission from Ref. ()].
Figure 5. Figure 5. Contributions of pulmonary and nonpulmonary determinants of PaO2 in severe acute pulmonary embolism. The actual, measured, PaO2 corresponds to 63 mmHg. Following successive modulations to take into account the most potential influential factors, such as oxygen diffusion limitation, pulmonary shunt, mixed venous PO2, and the amount of ventilation‐perfusion inequality, as assessed by the dispersion of pulmonary blood flow (i.e., Log SDQ), the final PaO2 eventually increased to 128 mmHg due to the additional influence of alveolar hyperventilation, a value well above normal limits. Note the negligible influence played by two of the three involved pulmonary factors (namely, diffusion limitation and shunt) in relation to that of ventilation‐perfusion mismatching (i.e., Log SDQ) [with permission from Ref. ()].
Figure 6. Figure 6. Time courses of the oxygen ratio (in mmHg), pulmonary shunt (in percentage of cardiac output), and dispersion of pulmonary blood flow distribution (dimensionless) in two different clinical conditions (gray circles represent patients with acute lung injury and closed squares those with COPD). All data points express mean±SEM values. Asterisks denote significant differences (P < 0.05) between each time point and baseline value within each subset. FIO2‐100% = 100% oxygen fraction; FIO2‐m = maintenance oxygen fraction; min = minute [with permission from Ref. ()] (for further explanation, see text).
Figure 7. Figure 7. Analysis of the relative contributions of the pulmonary and nonpulmonary factors that modulate the oxygen ratio (PaO2/FIO2) during COPD exacerbations. Values are the mean difference in the oxygen ratio measured under stable clinical conditions minus that predicted to result from a specific change, at the level corresponding to the exacerbation, in minute ventilation (V'E), cardiac output (Q'), oxygen consumption (V'O2), and ventilation‐perfusion (V'A/Q') imbalance (closed circles). The open square denotes the actual change in the oxygen ratio during exacerbations. Lines indicate the 95% confidence intervals [Reproduced with permission of the European Respiratory Society].
Figure 8. Figure 8. Mean±SEM values for pulmonary and nonpulmonary determinants of PaO2 and alveolar‐to‐arterial PO2 difference (AaPO2), namely, cardiac output (Q·T), oxygen uptake (V·O2), and ventilation‐perfusion imbalance, as expressed as the dispersion of pulmonary blood flow (Log SDQ) and as an overall index of ventilation‐perfusion heterogeneity (DISP R‐E*) (both dimensionless), before (baseline), and after nebulized salbutamol, during COPD exacerbation (closed circles and dashed lines) and while in convalescence (open squares and solid lines, respectively) for paired measurements. Asterisks denote significant differences between time point and baseline; p values correspond to differences between variables measured at exacerbation and while in convalescence. NS = not significant [with permission from Ref. ()].
Figure 9. Figure 9. Pathophysiologic algorithm for the interplay among bronchodilation, non‐pulmonary (Q·T = cardiac output; V·O2 = oxygen uptake) and pulmonary (ventilation‐perfusion mismatch = V·A/Q·) factors governing arterial blood gases in acute severe asthma following the administration of intravenous short‐acting ß2‐agonists (SABA). As a result of the interaction of the most influential effects of each of these factors, PaO2 varies or may decrease, remain unchanged, or even decrease, although PaO2 changes are always of small magnitude. A similar interaction is observed in COPD exacerbations while in convalescence () (see Fig. ).
Figure 10. Figure 10. Gas exchange response to oxygen (O2), nitric oxide (NO), intravenous and inhaled prostacyclin (PGI i.v. and PGI aero., respectively) and to calcium antagonists (CAAs) in pulmonary hypertension‐induced lung fibrosis. Dark columns and light columns represent mean±SEM values before and after each intervention, respectively, for arterial oxygen saturation (SaO2) and shunt flow (as a percentage of the amount of pulmonary blood flow, so‐called SHUNT). Asterisks denote significant differences before and after interventions; (+) denote significant linear contrast between responses to different interventions [with permission from Ref. ()].
Figure 11. Figure 11. Nitric oxide (NO) inhalation (40 ppm) decrease significantly PaO2 in patients with very severe COPD stage. Open symbols denote mean±SEM [with permission from Ref. ()] (for further explanation, see text).
Figure 12. Figure 12. Ventilation‐perfusion imbalance, as assessed by the dispersion of pulmonary blood flow distribution, versus mean pulmonary artery pressure (PAP) during inhalation of ambient air, nitric oxide (NO) (40 ppm), and 100% oxygen (O2). The slope of change in both parameters is greater on oxygen breathing than on NO inhalation for a given change in pulmonary artery pressure. Note that, however, 100% oxygen breathing deteriorates ventilation‐perfusion mismatching more than NO. Symbols denote mean±SEM [with permission from Ref. ()].
Figure 13. Figure 13. Individual PaO2 and pulmonary shunt values, measured with the inert (IG) gas approach, in acute respiratory distress syndrome, before and after almitrine infusion [with permission from Ref. ()] (for further explanation, see text).
Figure 14. Figure 14. Individual time courses (dashed lines) of tidal volume, breathing frequency, and PaCO2 throughout the study. Horizontal bold bars represent mean values at each time point [with permission from Ref. ()] (for further explanation, see text).
Figure 15. Figure 15. Effects of permissive hypercapnia application or dobutamine infusion on PaO2 and pulmonary shunt (Qs/QT) in acute respiratory distress syndrome. In general, individual PaO2 values significantly decrease from Phase 1 (ventilation with high tidal volume) to Phase 2 (low VT, i.e., permissive hypercapnia) and remain lower at Phase 3 (restoration of high tidal volume plus intravenous infusion of dobutamine). Note that individual PaO2 changes are variable in‐between patient; in contrast, the QS/QT response is consistent in each patient increasing markedly from Phase 1 to Phase 2; from Phase 2 to Phase 3, the response decreases in all but one patient while still remaining more elevated than in Phase 1. Open symbols denote mean vales while dashed lines, SEM values [with permission from Ref. ()].
Figure 16. Figure 16. Relationships between increases in PaO2 (top) and decreases in pulmonary shunt (bottom) with recruited volume (X‐axis) during protective ventilatory strategy (PVS) in ARDS. The solid lines denote the regression lines and dots correspond to individual patients [with permission from Ref. ()] (for further explanation, see text).
Figure 17. Figure 17. Mean±SD oxygen ratio (PaO2/FIO2) values one hour before (Sbf), during prone position (at first hour ‐PH1‐ and after 4 h ‐PH4‐), and one hour after returning to supine (Saft) in three subset of responders in ARDS. RP = persistent responders; RNP = nonpersistent responders; and, NR = nonresponders. Asterisks denote significant results compared to baseline (Sbf) [with permission from Ref. ()] (for further explanation, see text).
Figure 18. Figure 18. Mean±SEM values of the oxygen ratio (PaO2/FIO2) in acute respiratory distress syndrome of pulmonary (closed squares) and nonpulmonary (closed triangles) origin during each of the four interventions. SPNO denotes supine position while nitric oxide (NO) inhalation and PPNO, prone position and NO inhalation [with permission from Ref. ()] (for further explanation, see text).


Figure 1. Variations in end‐capillary PO2 and PCO2 in a single gas exchange lung unit as a function of ventilation‐perfusion ratio [with permission from Ref. ()] (for further explanation, see text).


Figure 2. Relationships between PaO2 and arterial‐venous oxygen content (CaO2‐CvO2) difference as a function of the severity of pulmonary shunt, expressed as percent of cardiac output [with permission from Ref. ()] (for further explanation, see text).


Figure 3. Relationships between FEV1 (X‐axis) and (A) ventilation‐perfusion imbalance (as expressed as the pulmonary blood flow dispersion, Log SDQ); and (B) the alveolar‐arterial PO2 difference P(A‐a),O2. In (A), abnormal Log SDQ is present even in asymptomatic asthma (represented by groups A and B), varies little until FEV1 reaches 40% predicted, and then deteriorates abrupt and markedly; in (B), the P(A‐a),O2 is essentially abnormal (compared to conventional normal limits) across the whole spectrum of bronchial asthma. Group A = mild asthma; B = asymptomatic asthma; C = chronically symptomatic out‐patients, moderately severe; D = chronically symptomatic out‐patients, severe; E = acute, severe asthma (hospitalized); and, F = acute, severe asthma (hospitalized). Dots with horizontal bars represent mean±SEM values at each time point [Reproduced with permission of the European Respiratory Society].


Figure 4. Significant relationships between the amount of ventilation‐perfusion imbalance, expressed as the dispersion of the blood flow distribution (Log SDQ) while breathing 100% oxygen (percentage change from baseline) (X‐axis), reflecting hypoxic pulmonary vasoconstriction release, with pulmonary artery pressure (A), overall degree of ventilation‐perfusion inequalities (expressed as DISP R‐E*) (B), and PaO2 during exercise (C) in idiopathic pulmonary fibrosis. During exercise, the amount of release of hypoxic vasoconstriction is associated with less pulmonary hypertension (A), less ventilation‐perfusion imbalance (B), and better arterial oxygenation (C) [with permission from Ref. ()].


Figure 5. Contributions of pulmonary and nonpulmonary determinants of PaO2 in severe acute pulmonary embolism. The actual, measured, PaO2 corresponds to 63 mmHg. Following successive modulations to take into account the most potential influential factors, such as oxygen diffusion limitation, pulmonary shunt, mixed venous PO2, and the amount of ventilation‐perfusion inequality, as assessed by the dispersion of pulmonary blood flow (i.e., Log SDQ), the final PaO2 eventually increased to 128 mmHg due to the additional influence of alveolar hyperventilation, a value well above normal limits. Note the negligible influence played by two of the three involved pulmonary factors (namely, diffusion limitation and shunt) in relation to that of ventilation‐perfusion mismatching (i.e., Log SDQ) [with permission from Ref. ()].


Figure 6. Time courses of the oxygen ratio (in mmHg), pulmonary shunt (in percentage of cardiac output), and dispersion of pulmonary blood flow distribution (dimensionless) in two different clinical conditions (gray circles represent patients with acute lung injury and closed squares those with COPD). All data points express mean±SEM values. Asterisks denote significant differences (P < 0.05) between each time point and baseline value within each subset. FIO2‐100% = 100% oxygen fraction; FIO2‐m = maintenance oxygen fraction; min = minute [with permission from Ref. ()] (for further explanation, see text).


Figure 7. Analysis of the relative contributions of the pulmonary and nonpulmonary factors that modulate the oxygen ratio (PaO2/FIO2) during COPD exacerbations. Values are the mean difference in the oxygen ratio measured under stable clinical conditions minus that predicted to result from a specific change, at the level corresponding to the exacerbation, in minute ventilation (V'E), cardiac output (Q'), oxygen consumption (V'O2), and ventilation‐perfusion (V'A/Q') imbalance (closed circles). The open square denotes the actual change in the oxygen ratio during exacerbations. Lines indicate the 95% confidence intervals [Reproduced with permission of the European Respiratory Society].


Figure 8. Mean±SEM values for pulmonary and nonpulmonary determinants of PaO2 and alveolar‐to‐arterial PO2 difference (AaPO2), namely, cardiac output (Q·T), oxygen uptake (V·O2), and ventilation‐perfusion imbalance, as expressed as the dispersion of pulmonary blood flow (Log SDQ) and as an overall index of ventilation‐perfusion heterogeneity (DISP R‐E*) (both dimensionless), before (baseline), and after nebulized salbutamol, during COPD exacerbation (closed circles and dashed lines) and while in convalescence (open squares and solid lines, respectively) for paired measurements. Asterisks denote significant differences between time point and baseline; p values correspond to differences between variables measured at exacerbation and while in convalescence. NS = not significant [with permission from Ref. ()].


Figure 9. Pathophysiologic algorithm for the interplay among bronchodilation, non‐pulmonary (Q·T = cardiac output; V·O2 = oxygen uptake) and pulmonary (ventilation‐perfusion mismatch = V·A/Q·) factors governing arterial blood gases in acute severe asthma following the administration of intravenous short‐acting ß2‐agonists (SABA). As a result of the interaction of the most influential effects of each of these factors, PaO2 varies or may decrease, remain unchanged, or even decrease, although PaO2 changes are always of small magnitude. A similar interaction is observed in COPD exacerbations while in convalescence () (see Fig. ).


Figure 10. Gas exchange response to oxygen (O2), nitric oxide (NO), intravenous and inhaled prostacyclin (PGI i.v. and PGI aero., respectively) and to calcium antagonists (CAAs) in pulmonary hypertension‐induced lung fibrosis. Dark columns and light columns represent mean±SEM values before and after each intervention, respectively, for arterial oxygen saturation (SaO2) and shunt flow (as a percentage of the amount of pulmonary blood flow, so‐called SHUNT). Asterisks denote significant differences before and after interventions; (+) denote significant linear contrast between responses to different interventions [with permission from Ref. ()].


Figure 11. Nitric oxide (NO) inhalation (40 ppm) decrease significantly PaO2 in patients with very severe COPD stage. Open symbols denote mean±SEM [with permission from Ref. ()] (for further explanation, see text).


Figure 12. Ventilation‐perfusion imbalance, as assessed by the dispersion of pulmonary blood flow distribution, versus mean pulmonary artery pressure (PAP) during inhalation of ambient air, nitric oxide (NO) (40 ppm), and 100% oxygen (O2). The slope of change in both parameters is greater on oxygen breathing than on NO inhalation for a given change in pulmonary artery pressure. Note that, however, 100% oxygen breathing deteriorates ventilation‐perfusion mismatching more than NO. Symbols denote mean±SEM [with permission from Ref. ()].


Figure 13. Individual PaO2 and pulmonary shunt values, measured with the inert (IG) gas approach, in acute respiratory distress syndrome, before and after almitrine infusion [with permission from Ref. ()] (for further explanation, see text).


Figure 14. Individual time courses (dashed lines) of tidal volume, breathing frequency, and PaCO2 throughout the study. Horizontal bold bars represent mean values at each time point [with permission from Ref. ()] (for further explanation, see text).


Figure 15. Effects of permissive hypercapnia application or dobutamine infusion on PaO2 and pulmonary shunt (Qs/QT) in acute respiratory distress syndrome. In general, individual PaO2 values significantly decrease from Phase 1 (ventilation with high tidal volume) to Phase 2 (low VT, i.e., permissive hypercapnia) and remain lower at Phase 3 (restoration of high tidal volume plus intravenous infusion of dobutamine). Note that individual PaO2 changes are variable in‐between patient; in contrast, the QS/QT response is consistent in each patient increasing markedly from Phase 1 to Phase 2; from Phase 2 to Phase 3, the response decreases in all but one patient while still remaining more elevated than in Phase 1. Open symbols denote mean vales while dashed lines, SEM values [with permission from Ref. ()].


Figure 16. Relationships between increases in PaO2 (top) and decreases in pulmonary shunt (bottom) with recruited volume (X‐axis) during protective ventilatory strategy (PVS) in ARDS. The solid lines denote the regression lines and dots correspond to individual patients [with permission from Ref. ()] (for further explanation, see text).


Figure 17. Mean±SD oxygen ratio (PaO2/FIO2) values one hour before (Sbf), during prone position (at first hour ‐PH1‐ and after 4 h ‐PH4‐), and one hour after returning to supine (Saft) in three subset of responders in ARDS. RP = persistent responders; RNP = nonpersistent responders; and, NR = nonresponders. Asterisks denote significant results compared to baseline (Sbf) [with permission from Ref. ()] (for further explanation, see text).


Figure 18. Mean±SEM values of the oxygen ratio (PaO2/FIO2) in acute respiratory distress syndrome of pulmonary (closed squares) and nonpulmonary (closed triangles) origin during each of the four interventions. SPNO denotes supine position while nitric oxide (NO) inhalation and PPNO, prone position and NO inhalation [with permission from Ref. ()] (for further explanation, see text).
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FURTHER READING

Barberà JA, Peinado VI, Rodriguez-Roisin R. Mechanisms of pulmonary vascular changes. In: COPD. Cellular and molecular mechanisms, edited by Barnes PJ. Boca Raton: Taylor & Francis, 2005, p. 63-492.

Ferrer A, Rodriguez-Roisin R. Ventilation-perfusion distributions in disease. In: The physiological basis of respiratory disease, edited by Martin JG. Hamilton: BC Decker Inc, 2005, p. 185-202.

Rodriguez-Roisin R, Barberà JA. Pulmonary vessels. In: Asthma and COPD: Basic mechanisms and clinical management, edited by Barnes PJ, Drazen JM, Rennard SE, Thompson NC. London: Elsevier Ltd, Academic Press, 2009, p.249-256.

Rodriguez-Roisin R, Echazarreta AL, Gómez FP, Barberà JA. The physiology of gas exchange. In: COPD, edited by Stockley RA, Rennard S, Celli BR, Rabe K. Oxford: Blackwell Publishing Ltd, 2007, p.102-115.

Rodriguez-Roisin R, Ferrer A. Effect of mechanical ventilation on gas exchange. In: Principles and practice of mechanical ventilation, edited by Tobin MJ. Third edition. New York: McGraw-Hill Inc, 2013, p. 851-867.

Soler-Cataluña JJ, Rodriguez-Roisin R. Managing exacerbations: an overview. In: Clinical Management of COPD, edited by Rennard SE, Rodriguez-Roisin R, Huchon G, Roche N. New York: Informa Healthcare USA, Inc., 2007, p. 347-370.


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Roberto Rodriguez‐Roisin. Nonpulmonary Influences on Gas Exchange. Compr Physiol 2014, 4: 1455-1494. doi: 10.1002/cphy.c100001