CASE CONFERENCES. The Clinical Physiologist Section Editors: John Kreit, M.D., and Erik Swenson, M.D.

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The Clinical Physiologist Section Editors: John Kreit, M.D., and Erik Swenson, M.D. Treating Hypoxemia with Supplemental Oxygen Same Game, Different Rules Darryl Y.

1 The Clinical Physiologist Section Editors: John Kreit, M.D., and Erik Swenson, M.D. Treating Hypoxemia with Supplemental Oxygen Same Game, Different Rules Darryl Y. Sue CASE CONFERENCES Division of Respiratory and Critical Care Physiology and Medicine, Department of Medicine, Harbor University of California Los Angeles Medical Center, Torrance, California; David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California; and Los Angeles Biomedical Research Institute, Torrance, California The Clinical Challenge Two patients with shortness of breath presented to the emergency department with identical arterial blood gas tensions. Patient 1 A 26-year-old man (Patient 1) presented with dyspnea, wheezing, and cough for 2 days. He had asthma since childhood and experienced several asthma exacerbations requiring additional treatment over the last 18 months. On physical examination, his blood pressure was 11/77 mm Hg, the heart rate was 115 beats/min, the respiratory rate was 24 breaths/min, the temperature was 37.8C, and the oxygen saturation as measured by pulse oximetry (Sp O2 )was89%while breathing ambient air. He had severe diffuse wheezing and was using accessory muscles of respiration. He had no inspiratory stridor or clubbing. An arterial blood gas measurement obtained while he breathed ambient air revealed a ph of 7.45, Pa CO2 of 31 mm Hg, Pa O2 of 55 mm Hg, and HCO 3 2 of 21 meq/l. His chest radiograph was normal (Figure 1). Patient 2 A 57-year-old man (Patient 2) came to medical attention because of fever, diffuse myalgias, nonproductive cough, and dyspnea of 4 days duration. His medical problems included moderate obesity and mild hypertension. Figure 1. Portable chest radiograph of patient 1. On physical examination, his blood pressure was 145/58 mm Hg, heart rate was 112 beats/min, respiratory rate was 24 breaths/min, temperature was 39.88C, and Sp O2 was 89% while breathing ambient air. Lung examination revealed diffuse crackles, and he was using accessory muscles of respiration. Heart examination was normal, except for tachycardia. There was a normal jugular venous pressure and no peripheral edema. An arterial blood gas measurement obtained while he breathed ambient air showed a ph of 7.45, Pa CO2 of 31 mm Hg, Pa O2 of 55 mm Hg, and HCO 3 2 of 21 meq/l. A chest radiograph is shown in Figure 2. The emergency department physician ordered a nebulized bronchodilator, an intravenous corticosteroid, and oxygen (Received in original form June 8, 216; accepted in final form August 9, 216 ) Correspondence and requests for reprints should be addressed to Darryl Y. Sue, M.D., Department of Medicine, Box 4, Harbor-UCLA Medical Center, 1 W. Carson Street, Torrance, CA dsue@ucla.edu Ann Am Thorac Soc Vol 13, No 12, pp , Dec 216 Copyright 216 by the American Thoracic Society DOI: /AnnalsATS CC Internet address: AnnalsATS Volume 13 Number 12 December 216

2 Figure 2. Portable chest radiograph of patient 2. administered through a face mask with FI O2.35 for patient 1 to achieve an Sp O2 of roughly 94%. For patient 2, the physician ordered oxygen via a non-rebreather mask at a flow rate of 15 L/min to achieve an Sp O2 of roughly 94%, oseltamivir, and broad-spectrum antibiotics. She also requested that the nurse prepare for possible endotracheal intubation. Questions 1. Why would two patients with the same Pa O2 breathing ambient air need different fractional concentrations of oxygen to reach the same target Sp O2? 2. How can this be explained by differences in the physiological mechanisms causing hypoxemia? [Continue onto next page for answers] Case Conferences: The Clinical Physiologist 2267

3 Clinical Reasoning Patient 1 was having an asthma exacerbation. The physician reasoned that his hypoxemia was caused by _V= _Q mismatching with an increased contribution from low _V= _Q ratio lung units. She expected that hypoxemia would be satisfactorily corrected by a relatively small increase in FI O2 and that nebulized bronchodilators and corticosteroids would treat the exacerbation of his asthma in a short time. The history, examination, and chest imaging for Patient 2 suggested severe influenza or bacterial pneumonia. The physician reasoned that hypoxemia was caused by right-to-left shunting and very low _V= _Q units and anticipated a relatively small increase in Pa O2 despite higher FI O2. She expected that the patient would require intubation and mechanical ventilation to correct the hypoxemia and take over the work of breathing. The Clinical Solution While receiving supplemental oxygen, the Pa O2 of Patient 1 increased to 86 mm Hg. He improved quickly with bronchodilators and corticosteroids and was discharged from the emergency department 6 hours later. CO 2 Content, ml/1 ml The Pa O2 of Patient 2 increased only to 64 mm Hg. He remained severely dyspneic, and he was subsequently intubated in the emergency department. In the intensive care unit 12 hours later, the Pa O2 was 66 mm Hg on pressure-regulated volume control mechanical ventilation with a tidal volume of 45 ml (6 ml/kg ideal body weight), FI O2 of.8, and positive endexpiratory pressure of 12 cm H 2 O. A nasal swab sent for rapid molecular assay was positive for influenza A. The Science behind the Solution In practice, clinicians frequently estimate the needed amount of supplemental oxygen on the basis of the physiological cause(s) of hypoxemia. As in the cases described above, the physician correctly chose a relatively low amount of oxygen supplementation for the first patient and anticipated a poor response to even higher oxygen concentrations in the second patient. Mechanisms of Hypoxemia Hypoxemia results from (1) reduction in the alveolar partial pressure of O 2, and/or (2) increased venous admixture. Reasons O 2 Content, ml/1 ml Figure 3. O 2 CO 2 diagram showing O 2 and CO 2 content derived for different lung units at various _ V= _ Q ratios for FI O2.21 and normal mixed venous O 2 and CO 2 contents. The curve is determined by the intersection of lines (not shown) representing addition of CO 2 and removal of O 2 from inspired gas at a constant ratio (gas exchange ratio R) and removal of CO 2 and addition of O 2 to mixed venous blood at the same ratio (blood exchange ratio R). The intersections are points at which the amount of O 2 exchanged between gas and blood is equal and the amount of CO 2 exchanged is equal for that R. From these data, the ratio of ventilation to perfusion can be calculated (small numbers on graph) for a lowered alveolar PO 2 include inhalation of gas that has a low partial pressure of O 2 (reduced atmospheric pressure or displacement of oxygen by another gas) or hypoventilation (low alveolar ventilation). Venous admixture happens when some amount of deoxygenated systemic venous blood is added to systemic arterial blood without having become fully oxygenated in the lungs. This happens in three ways: (1) via a right-to-left shunt (intra- or extrapulmonary) in which blood bypasses all contact with inspired gas, (b) by passing through a part of the lung in which there is a low ratio of ventilation to perfusion, or (3) by failure of alveolar capillary PO 2 equilibrium (diffusion limitation). The physician in the emergency department was aware that patients with mild to moderate _V= _Q mismatching causing hypoxemia generally have a steep(er) increase in Pa O2 when supplemental oxygen is administered, such as in Patient 1, and respond nicely with improvements in arterial oxygen content and hemoglobin saturation. In contrast, she recognized that Patient 2 likely had significant right-toleft shunting and/or contributions from very low _V= _Q units. The Pa O2 in such patients generally does not increase much until greater amounts of oxygen are given, thereby defining these patients as having relatively refractory hypoxemia. The O 2 CO 2 Diagram and _V= _ Q Mismatching In the 194s, Hermann Rahn, Wallace Fenn, Arthur Otis, Richard Riley, Andre Cournand, and others developed mathematical analyses of pulmonary gas exchange. They recognized that quantitative gas exchange for O 2 and CO 2 could be conceptualized in terms of the relative amounts of ventilation and blood flow to notional lung units and the pooled contributions of these lung units to overall gas exchange. Using equations linking PO 2 and PCO 2 to blood O 2 and CO 2 content (and considering the Bohr and Haldane effects) and maintaining mass balance exchange of gas between alveolar gas and pulmonary capillary blood (gas exchange ratios), a graphical solution (O 2 CO 2 diagram) allowed determination of expected PO 2,PCO 2,O 2 content, and CO 2 content given starting conditions of mixed venous O 2 and CO 2 content and inspired 2268 AnnalsATS Volume 13 Number 12 December 216

4 CO 2 Content, ml/1 ml CO 2 Content, ml/1 ml O 2 Content, ml/1 ml O 2 Content, ml/1 ml Figure 4. O 2 CO 2 diagrams showing O 2 and CO 2 content derived for different lung units at various _ V= _ Q ratios for FI O2.21 (solid circles),.5 (solid squares), and.95 (open triangles), and normal mixed venous O 2 and CO 2 contents. The curves are determined as in Figure 3. Right panel is an expanded view of the top portion of left panel created by narrowing the range of CO 2 contents on the y-axis. The blood O 2 content coming from a lung unit with _ V= _ Q has an O 2 content of only 16.4 ml/1 ml of blood when FI O2 is.21, compared with about 22.7 ml/1 ml of blood when FI O2 is.95. gas partial pressures. (In fact, a graphical solution was the only feasible method of solving these equations until faster computers could use iterative methods to find compatible solutions satisfying the necessary equations.) The O 2 CO 2 diagram also permitted calculation of the ratios of ventilation to perfusion ( _V= _Q ratio) as shown in Figure 3. Thereafter, models corresponding to a patient with hypoxemia or hypercapnia could be created by distributing total alveolar ventilation and pulmonary blood flow to combinations of lung units having a suitable range of _V= _Q ratios. perfusion and ventilation, and its effect on overall gas exchange, so in these examples the mixed venous blood is assumed to be unchanged. In Figure 4, it can be seen that the O 2 content of blood resulting at a _V= _Q ratio of (a low _V= _Q unit) is considerably higher for FI O2 of.5 (2.6 ml O 2 /1 ml blood) and FI O2 of.95 (22.7 ml O 2 /1 ml blood) than for FI O2 of.21 (16.4 ml O 2 /1 ml blood). 23 When the O 2 content of blood leaving a lung unit with a particular _V= _Q ratio is plotted against _V= _Q ratio, the influence of increased FI O2 can be readily seen (Figure 5). Thus, from a lung unit with _V= _Q of 1., the blood O 2 content ranges from just under 21 ml/1 ml (FI O2,.21) to almost 23 ml/1 ml (FI O2,.95).Whenthe _V= _Q ratio is somewhat lower (e.g., _V= _Q of ), the blood O 2 content is only about 16.3 ml/1 ml, with FI O2.21. However, when FI O2 is raised from _V= _ Q Mismatching and Supplemental Oxygen The left-hand side of Figure 4 shows O 2 CO 2 diagram solutions for FI O2 of.21,.5, and.95. The right-hand side shows an expanded scale of the same values. Starting points for inspired gas reflect the higher FI O2 values. As a convenience, mixed venous values for O 2 and CO 2 content are not different between the curves. This assumption is not entirely rigorous, because at a higher FI O2, mixed venous O 2 content may increase if arterial O 2 content increases and oxygen consumption, carbon dioxide production, and cardiac output remain constant. However, any change in total arterial O 2 content cannot be predicted without knowing the overall distribution of O 2 Content, ml/1 ml V/Q Ratio Figure 5. O 2 content, ml/1 ml, plotted against _ V= _ Q ratio for different values of FI O2 :.21 (solid circles),.3 (open triangles),.5 (solid squares),.7 (open circles),.85 (open squares), and.95 (no marker). Case Conferences: The Clinical Physiologist 2269

5 .21 to.5, the same lung unit with _V= _Q of contributes blood with O 2 content about 2 ml/1 ml. Finally, for a very low _V= _Q ratio unit, the effect of increased FI O2 is markedly less until at much higher FI O2. Therefore, for a _V= _Q of.1,theo 2 content for FI O2.21 is barely above the mixed venous value, and at FI O2.5, the O 2 content rises only to about 15.5 ml/1 ml. But, when FI O2 is increased to.95, the blood O 2 content leaving the unit with _V= _Q of.1 corrects to nearly 22 ml/1 ml. A true right-to-left shunt would contribute blood with an O 2 content equal to mixed venous blood, and no amount of increased FI O2 would make any difference. This is the basis for the physiological principle that the Pa O2 with a right-to-left shunt does not (cannot) correct when the patient is given FI O2 of 1.. In other words, the patient s Pa O2 is refractory to increased FI O2. However, from the analysis above, it becomes clear why the patient with appreciable contributions from low _V= _Q ratios units (but not right-to-left shunt) can partially correct Pa O2 when FI O2 is increased. As seen in Figure 5, even very low _V= _Qratio units that cause hypoxemia at FI O2.21 or.3 would produce much higher O 2 content blood when FI O2 is raised to.5 and higher. Such a patient can be said to be responsive to increased FI O2 and thereby does not have refractory hypoxemia. Putting it Together With relationships between FI O2,O 2 content, and PO 2 (and PCO 2 ) from lung units exchanging gas at different _V= _Q ratios established, we can model a patient s gas exchange by varying the distribution of alveolar ventilation and pulmonary perfusion to these units. Normal resting alveolar ventilation is about 4 L/min (body temperature, ambient pressure, saturated with water vapor), and total pulmonary blood flow is about 5 L/min at rest; the normal overall _V= _Q ratio is about.8. Most lung units in a normal subject generally have _V= _Q ratios close to.8 and distribute most blood and ventilation to these relatively well-matched lung units and there would be no hypoxemia or hypercapnia. In disease, however, ventilation might be low in some lung units (bronchospasm, airway obstruction), whereas perfusion might be low in others because of pulmonary vascular or heart disease. If perfusion is maintained in units with low ventilation or ventilation is PaO 2 PaO FIO 2 Figure 6. Estimated Pa O2 for different FI O2 for pure right-to-left shunts of, 5, 1, 15, and 2% from top to bottom FIO 2 Figure 7. Pa O2 at different values of FI O2 derived from a hypothetical 14-compartment gas exchange model with blood flow and ventilation distributed to units with _ V= _ Q ranging from to 1,. Three curves (open triangles, open circles, open squares) show relatively mild maldistribution, increasing in severity from left to right, and demonstrate a relatively steep response of Pa O2 when increased FI O2 is given. In contrast, the other two curves (solid circles, solid squares) show more severe maldistribution of ventilation and perfusion with a much flatter response to increased FI O2. The thinner solid lines show expected Pa O2 for pure right-to-left shunts of 5, 1, 15, and 2% (isoshunt lines) from top to bottom. Of note is that the Pa O2 response to increased FI O2 of patients with varying degrees of _ V= _ Q mismatching may cross isoshunt lines. In addition, the flat response to increased FI O2 for patient 2 behaves similarly to a large right-to-left shunt except at higher FI O AnnalsATS Volume 13 Number 12 December 216

6 maintained in units with low perfusion, there will be lung units with much lower and higher _V= _Q ratios than.8 despite overall normal alveolar ventilation and pulmonary perfusion. Overall gas exchange depends on how much ventilation and perfusion are distributed to which lung units. For example, compared with normal subjects with most blood flow and ventilation going to lung units with relatively matched _V and _Q, we might create a model by distributing some perfusion to units with a _V= _Q of.1, some to units with a _V= _Q ratio of 1, and some to units with _V= _Q of 1., as long as we account for 1% of blood flow and ventilation. By adding the perfusion-weighted O 2 content from all regions, we can determine the arterial O 2 content and arterial PO 2. Finally, by varying the FI O2, we can see how the model responds to FI O2 changes and compare those responses to a patient s response to assess the validity of our model. Gas Exchange Models in Our Two Patients Mathematical models that behave like the two patients described above, namely having equal Pa O2 and Pa CO2 while breathing FI O2.21, but with one having a steep and one having a flat Pa O2 response to increasing FI O2, can be created. One simple model of gas exchange assumes that all pulmonary blood flow passes through a lung unit with _V= _Q equal to the overall _V= _Q or through a right-toleft shunt; any hypoxemia is explained by right-to-left shunting. Changes in Pa O2 in response to increased FI O2 are shown in Figure 6 for different proportions of blood diverted through a right-to-left shunt. In contrast to this model, Figure 7 shows the predicted Pa O2 versus FI O2 for increasingly maldistributed ventilation and pulmonary blood flow to a range of low to high _V= _Q ratio lung units. The Pa O2 response to increasing FI O2 for Patient 1 generally follows one of the steeper curves in Figure 7, consistent with relatively mild maldistribution of ventilation and perfusion. For Patient 2, with somewhat refractory hypoxemia in response to increased FI O2, gas exchange could be characterized as either moderate right-to-left shunt or more severe maldistribution of ventilation and perfusion. These models, useful in understanding lung gas exchange, are explicitly not unique. For example, a different distribution of ventilation and perfusion can result in the same clinical findings. The validity of a given model depends on how accurately it predicts what happens both under the initial conditions and when a variable such as FI O2 is altered. In summary, patients with primarily mild ventilation perfusion mismatching ( _V= _Q mismatching) as the cause of hypoxemia generally have a steep(er) increase in Pa O2 when supplemental oxygen is administered. In contrast, a patient whose mechanism of hypoxemia is chiefly right-to-left shunt or who have contributions from very low _V= _Q lung units often have a flat increase in Pa O2 with supplemental oxygen. On the basis of these principles of hypoxemia, clinicians often intuitively anticipate how much supplemental O 2 their patients will require, but should always use the patient s clinical presentation and response to therapy to guide management. Answers 1. Why would two patients with the same Pa O2 breathing ambient air need different fractional concentrations of oxygen to reach the same target Sp O2? Even when two hypoxemic patients have the same Pa O2 while breathing ambient air, the physiological mechanisms causing hypoxemia may be very different. 2. How can this be explained by differences in the physiological mechanisms causing hypoxemia? A patient with a mild degree of ventilation perfusion mismatching causing hypoxemia on ambient air often responds well to relatively small increases in FI O2. On the other hand, if the cause of hypoxemia is more severe ventilation perfusion mismatching and/or right-to-left shunt, increasing FI O2 may have only a small effect on Pa O2, and higher FI O2 may be required. n Author disclosures are available with the text of this article at Recommended Reading Helmerhorst HJ, Schultz MJ, van der Voort PH, Bosman RJ, Juffermans NP, de Wilde RB, van den Akker-van Marle ME, van Bodegom-Vos L, de Vries M, Eslami S, et al. Effectiveness and clinical outcomes of a twostep implementation of conservative oxygenation targets in critically ill patients: a before and after trial. Crit Care Med 216;44: O Driscoll BR, Howard LS, Davison AG; British Thoracic Society. BTS guideline for emergency oxygen use in adult patients. Thorax 28;63:vi1 vi68. Petersson J, Glenny RW. Gas exchange and ventilation-perfusion relationships in the lung. Eur Respir J 214;44: Paulev PE, Siggaard-Andersen O. Clinical application of the po( 2 )-pco( 2 ) diagram. Acta Anaesthesiol Scand 24;48: Rahn H, Fenn WO. A graphical analysis of the respiratory gas exchange: the O 2 CO 2 diagram. Washington DC: The American Physiological Society, Subramani S, Kanthakumar P, Maneksh D, Sidharthan A, Rao SV, Parasuraman V, Tharion E. O2-CO2 diagram as a tool for comprehension of blood gas abnormalities. Adv Physiol Educ 211;35: West JB. The physiological legacy of the Fenn, Rahn, and Otis school. Am J Physiol Lung Cell Mol Physiol 212;33:L845 L851. West JB. Ventilation-perfusion inequality and overall gas exchange in computer models of the lung. Respir Physiol 1969;7: West JB. A century of pulmonary gas exchange. Am J Respir Crit Care Med 24;169: Case Conferences: The Clinical Physiologist 2271

PICU Resident Self-Study Tutorial The Basic Physics of Oxygen Transport. I was told that there would be no math!

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