Strictly Clinical
  • Role of Alveolar-Arterial Gradient in Partial Pressure of Oxygen and PaO2/Fraction of Inspired Oxygen Ratio Measurements in Assessment of Pulmonary Dysfunction

    Assessment of pulmonary dysfunction is vital to anesthetists. Measurements including the gradient between the alveolar partial pressure of oxygen (PAo2) and the arterial partial pressure of oxygen (Pao2), called the PAo2 – Pao2 , and the ratio of the Pao2 to the fraction of inspired oxygen (FIo2) (Pao2/FIo2 ratio) are useful in determining the extent of acute lung injury. A literature review via MEDLINE using the terms PAo2 – Pao2 , Pao2/FIo2 ratio, and pulmonary dysfunction was performed to identify articles on the use of these measures in the perioperative period. Both measures have been found to predict clinical outcomes in most settings. We also developed a mathematical model to calculate values of the PAo2 – Pao2 and the Pao2/FIo2 ratio. In model results, as in clinical findings, both respond appropriately to reflect worsening pulmonary dysfunction when shunt or diffusion barrier (alveolar Po2 – pulmonary capillary partial pressure of oxygen) is increased. However, both are also sensitive to the FIo2. The increase in the Pao2/FIo2 ratio as the FIo2 increases is particularly problematic because it could disguise a deterioration in the patient’s pulmonary status. The PAo2 – Pao2 and the Pao2/FIo2 ratio should be used with an understanding of their limitations.


    Keywords:
    PAo2 – Pao2, Pao2/FIo2 ratio, pulmonary dysfunction.

    Measures of pulmonary dysfunction are important to anesthetists caring for patients in the operating suite and assessing patients preoperatively. Such measurements allow quantification of the level of pulmonary dysfunction1 and identification of patients who are critically ill in the preoperative or postoperative periods.2,3 In the operating suite, serial determinations of measures of pulmonary dysfunction facilitate assessment of the impact of interventions such as denitrogenation,4 changes in position,5 or changes in ventilator settings6 on pulmonary function.

    Several measurement tools including the gradient between the alveolar partial pressure of oxygen (PAo2) and the arterial partial pressure of oxygen (Pao2), expressed as the PAo2 – Pao2 (or the AaDo2),7 and the ratio of the Pao2 to the fraction of inspired oxygen (FIo2)—the Pao2/FIo2 ratio—can be used to quantify pulmonary dysfuncton.1,2 Increasing values of the PAo2 – Pao2 and decreasing values of the Pao2/FIo2 ratio suggest deteriorating pulmonary function (Table 1).

    This article provides a review and critical evaluation of representative articles on the use of the PAo2 – Pao2 and the Pao2/FIo2 ratio as measures of pulmonary dysfunction with an emphasis on the perioperative period. Articles were identified via MEDLINE searches using the terms PAo2 – Pao2, Pao2/FIo2 ratio, and Pao2. We undertake this review because diseases that increase shunt (eg, atelectasis), or the diffusion barrier for oxygen from the alveoli to the blood (eg, pulmonary edema, pulmonary fibrosis, and heart failure), as well as factors other than pulmonary dysfunction (eg, changes in FIo2 and PCO2) can have an impact on these parameters. A review of these factors will demonstrate the clinical importance of these measures and facilitate their effective use.

    History and Review of Literature

    PAo2 – Pao2. The alveolar gas equation was first proposed by Wallace Fenn in 19468:

    PAo2 = FIo2 (PB – PH2O) – PACO2/R

    where

    PB (barometric [atmospheric] pressure) = 760 mm Hg

    at sea level

    PH2O (vapor pressure of water) = 47 mm Hg

    at body temperature and PB = 760 mm Hg

    PACO2 (alveolar PCO2) = PaCO2 under most circumstances R (respiratory coefficient) = 0.8 for people consuming a standard diet9

    This equation allows the calculation of the Po2 in the alveoli and reflects the following facts. (1) The partial pressure of inhaled oxygen = FIo2 × Barometric pressure. (2) Inhaled oxygen is diluted by water vapor as the inhaled gas is humidified in the airways. (3) Oxygen is replaced on virtually a molecule-for-molecule basis by carbon dioxide (CO2) in the alveoli. Because the Pao2 can be measured from arterial blood, calculation of the PAo2 allows the determination of the PAo2 – Pao2.

    In animal models the PAo2 – Pao2 increased in ventilated dogs subjected to near-drowning, an effect attributed to increased right-to-left shunt or areas of low ventilation to perfusion matching (V/Q) caused by flooded alveoli.10 Also in ventilated dogs, PAo2 – Pao2 fell as the alveolar partial pressure of carbon dioxide (PACO2) was increased via hypoventilation, an effect the authors attributed to either the dilation of airways responsible for collateral ventilation or the decreased affinity of hemoglobin for oxygen (right-shift in the oxygen-hemoglobin dissociation curve) caused by increased PACO2 (and increasing PaCO2) or acidosis (Bohr effect).11

    Similar changes occur in humans. When healthy human participants varied their PaCO2 levels by changing their level of ventilation, the PAo2 – Pao2 fell as PaCO2 increased.7 In a second study, the PAo2 – Pao2 increased as the FIo2 was increased in patients with chronic obstructive pulmonary disease (COPD), suggesting that caution should be used in the interpretation of the PAo2 – Pao2 when the FIo2 changed.12 And in a third study, when healthy human participants used a rebreathing system with a CO2 absorber to induce hypoxia, reduction of the PAo2 caused a narrowing of the PAo2 – Pao2.13 Because the FIo2 is a driver of the PAo2, this result extends to healthy patients the findings reported earlier for patients with COPD on the impact of the FIo2 on PAo2 – Pao2.12

    The PAo2 – Pao2 also allows risk stratification in pulmonary disease and in the perioperative period. For patients hospitalized with community-acquired pneumonia, those with PAo2 – Pao2 90 mm Hg or higher had lower survival rates that those with lower PAo2 – Pao2 values.14 Similarly, another study of patients with community-acquired pneumonia found that patients who died had an average PAo2 – Pao2 at admission of 181 mm Hg and a Pao2/FIo2 ratio of 139, whereas those who survived had a lower average admission PAo2 – Pao2 (107 mm Hg) and a higher Pao2/FIo2 ratio (169).15 Thus, the PAo2 – Pao2 is useful in assessing prognosis in patients with community-acquired pneumonia.

    In patients with end-stage liver disease and portal hypertension being prepared for liver transplant, the PAo2 – Pao2 increased as the severity of the liver disease increased, with PAo2 – Pao2 of 27 mm Hg on room air in those with the most severe disease. The negative impact of end-stage liver disease on pulmonary function was attributed to high intra-abdominal pressures, pleural effusion, and interstitial pulmonary edema.16 During surgery, higher PAo2 – Pao2 (average PAo2 – Pao2 = 80.9 mm Hg at FIo2 of 0.4) were found in patients undergoing liver transplant if those patients also demonstrated shunt determined by echocardiography after injection of saline with air bubbles.17

    The PAo2 – Pao2 has also been used to assess the impact of positive end-expiratory pressure (PEEP) on oxygenation in patients undergoing laparoscopic prostatectomy in whom Trendelenburg positioning and the introduction of gas into the peritoneal cavity might compromise ventilation. A PEEP of 10 cm H2O produced the lowest PAo2 – Pao2 but at the expense of elevated airway pressure. The authors concluded that 7 cm H2O of PEEP produced adequate oxygenation without this unwanted result. The PAo2 – Pao2 values varied with surgical times but were generally in the range of 80 to 125 mm Hg at FIo2 of 0.5.18

    Postoperatively, the PAo2 – Pao2 was found to correlate with increasing shunt in patients after open heart surgery19 and has been used to compare the level of pulmonary dysfunction after coronary artery bypass grafting in patients whose procedures were performed with and without a bypass pump. Patients whose procedures were performed off-pump had lower PAo2 – Pao2 than those performed on-pump.20

    Pao2/FIo2 Ratio. The Pao2/FIo2 ratio has gained popularity as a simple measure of pulmonary dysfunction among critically ill patients that can be used to predict disease outcome. Among patients with trauma, when patients with acute lung injury were classified by the Pao2/FIo2 ratio, patients with severe injury (Pao2/FIo2 ratio < 100) had much higher mortality rates than those with less severe dysfunction (Pao2/FIo2 ratio > 250).21 Similarly, a Pao2/FIo2 ratio less than 250 was used as one criterion for defining hypoxia in patients admitted to the hospital with community-acquired pneumonia. Hypoxia was then employed as part of a combined measure (along with vital signs and chest radiography results) that predicted the necessity for invasive respiratory or vasopressor support.22 However, the Pao2/FIo2 ratio is not always useful for predicting clinical outcomes. In patients receiving mechanical ventilation for hypoxic respiratory failure, this ratio failed to predict successful extubation.23 The FIo2 was not specified and probably varied in these 3 studies.

    Despite its limitations, the importance of the Pao2/FIo2 ratio as a predictor of clinical outcomes in critically ill patients is illustrated by its inclusion in the currently accepted definition of acute respiratory distress syndrome (ARDS), the Berlin Definition (Table 2). The level of ARDS was then used to suggest appropriate treatment.1 Because both the FIo2 and the level of PEEP can influence the Pao2/FIo2 ratio, some authors have recommended standardizing these to improve on the Berlin Definition of ARDS.24 This serves as a reminder that the impact of the FIo2 on the Pao2/FIo2 ratio must be considered whenever this ratio is used.

    The categories of the Pao2/FIo2 ratio used to define the severity of ARDS (see Table 2) have seen wide application. A Pao2/FIo2 ratio less than 202 at 3 hours after admission to the intensive care unit (ICU) was found to predict increased mortality in cardiac surgical patients.2 In brain-dead patients being considered for lung transplant, a Pao2/FIo2 ratio less than 200 was deemed to indicate unacceptably poor lung function.25 A Pao2/FIo2 ratio below 300 was used to define acute lung injury in patients with acute brain injury undergoing dilatational tracheostomy. In this retrospective analysis, one-third of the patients met the Berlin Definition of ARDS preoperatively and one-tenth of the patients with ARDS experienced intraoperative hypoxia. The average Pao2/FIo2 ratio improved from the preoperative to the postoperative period, and the procedure was deemed safe.3

    Several studies used the Pao2/FIo2 ratio to investigate the impact of specific anesthesia interventions on intraoperative pulmonary dysfunction. Two studies evaluated obese patients undergoing laparotomy under general anesthesia, who are at particular risk of intraoperative impairment of oxygenation from compression atelectasis and resultant increased intrapulmonary shunt.4,26 The authors found that these patients maintained their Pao2/FIo2 ratio when diffusion atelectasis was minimized by avoiding the use of nitrous oxide, either by using 50% oxygen and 50% nitrogen in isoflurane anesthesia4 or by using xenon in oxygen anesthesia.26

    The Pao2/FIo2 ratio has also been used to assess the impact of intraoperative ventilation strategies during 1-lung ventilation. One study searched for a ventilation strategy that avoids excessive tidal volumes and airway pressures during 1-lung ventilation. Higher tidal volume ventilation (tidal volume = 8 mL/kg of ideal body weight) was compared with lower tidal volume ventilation (5 mL/kg of ideal body weight) with PEEP adjusted to maintain similar airway plateau pressures. The Pao2/FIo2 ratio was lower with the low tidal volume regimen, so this approach did not produce a benefit.6 A meta-analysis included studies comparing the Pao2/FIo2 ratio of patients undergoing thoracotomy and 1-lung ventilation with pressure-controlled ventilation vs volume-controlled ventilation and studies comparing conventional ventilation (tidal volume ≥ 7 mL/kg ideal body weight) with protective ventilation (tidal volume ≤ 6 mL/kg ideal body weight).27 Neither pressure-controlled ventilation nor protective ventilation improved intraoperative oxygenation as measured by the Pao2/FIo2 ratio.27

    The Pao2/FIo2 ratio has also been used to assess the impact of ventilation strategy on blood oxygenation for patients under general anesthesia in the sitting position. Use of the sitting position for patients undergoing shoulder arthroscopy reduces anatomical distortion but can compromise cerebral perfusion. Cerebral perfusion can be maintained by inducing mild hypercapnia via hypoventilation, but this, in turn, can produce atelectasis and impaired oxygenation. A study of healthy patients undergoing shoulder arthroscopy under general anesthesia in the sitting position with sevoflurane maintenance without nitrous oxide compared the Pao2/FIo2 ratios of patients ventilated to normocapnia with those ventilated to mild hypercapnia (end-tidal CO2 = 45 mm Hg). There was no decrease in the Pao2/FIo2 ratio with mild hypercapnia while regional brain oxygen saturation was maintained, suggesting a benefit for mild hypercapnia for this procedure.5

    Another use of the Pao2/FIo2 ratio in patients under general anesthesia involved burn patients with ARDS maintained on a regimen of high-frequency oscillatory ventilation in the burn unit and transported to the operating suite for burn excision or wound grafting. The authors found that continuing high-frequency oscillatory ventilation in the operating suite did not result in a significant fall in Pao2/FIo2 ratio.28

    Discussion of State of the Art

    For the anesthetist, the most important questions about the Pao2/FIo2 ratio and the PAo2 – Pao2 are the following. (1) What are the normal values of these parameters? (2) How do these values respond to changes in ventilator settings, age, and pulmonary disease? (3) What are the values of concern? To inform the discussion of these questions, we created a mathematical model that uses accepted pulmonary function equations (Table 3) to compute the Pao2/FIo2 ratio and the PAo2 – Pao2 (Table 4). These equations reflect the facts that (1) the oxygen content of the arterial blood is a weighted average of the content of the blood oxygenated in the pulmonary capillaries and the oxygen content of the shunted blood9 and (2) there is an empirical relationship between hemoglobin saturation and Po2.29

    Two models using similar equations have been developed previously. In both models, the Pao2/FIo2 ratio rose continuously as the FIo2 increased when the shunt was 0.02 of the cardiac output,30,31 as is the case in the model reported here (see Table 4, lines 1-5). The model we present includes 2 features not found in the other models cited: (1) It allows variation of the diffusion barrier across the respiratory membrane (as defined in Table 3) and (2) it computes both the Pao2/FIo2 ratio and the PAo2 – Pao2, allowing comparisons of these measures.

    Normal Values of Pao2/FIo2 Ratio and PAo2 – Pao2—and Their Response to Changes in Ventilator Settings. Measurements of the PAo2 – Pao2 in healthy participants were reported more than 50 years ago. These reports were before the Pao2/FIo2 ratio was in use, but the ratio could be calculated from the data provided in these studies. The results (Table 5) demonstrate that both the Pao2/FIo2 ratio (approximately 450 at FIo2 of 0.21) and the PAo2 – Pao2 (< 10 mm Hg at FIo2 of 0.21 for younger patients) increase as the FIo2 increases.32,33 These experimental measurements are in remarkably good agreement with our model results (see Table 4), suggesting that our model results are clinically meaningful. The PAo2 – Pao2 increases and the Pao2/FIo2 ratio decreases with increasing age (see Table 5).32,33

    The impact of changes in the FIo2 on both the Pao2/FIo2 ratio and the PAo2 – Pao2 even without changes in pulmonary function are of clinical importance. The increase in PAo2 – Pao2 as the FIo2 is increased12,13,32 could lead a practitioner to conclude that a patient’s pulmonary status was deteriorating when it was not. However, the increase in the Pao2/FIo2 ratio as the FIo2 is increased, both in experimental work32 and in models,30,31 falsely suggests improved pulmonary function. The model presented here replicates these results. As the FIo2 increased from 0.2 to 1.0 in the normal case, the PAo2 – Pao2 rose from 5 to 45 mm Hg, and the Pao2/FIo2 ratio rose from 440 to 618 (see Table 4, lines 1-5). This phenomenon undoubtedly had an impact on the results of several clinical studies discussed in this article and complicates the application of Pao2/FIo2 ratio values in the Berlin Definition of ARDS (see Table 2). One solution that has been suggested to this problem is reporting the Pao2/FIo2 ratio only at a very high FIo2.24,34

    To understand the clinical importance of the impact of FIo2 on measures of pulmonary dysfunction, consider a patient receiving mechanical ventilation at a lower FIo2 in the ICU transported to the operating suite for general anesthesia. If the FIo2 used in the operating suite is higher than that used in the ICU (as might often be the case), this could cause absorption atelectasis, increased shunt, and worsening pulmonary dysfunction. However, if the anesthetist relied on the Pao2/FIo2 ratio to assess pulmonary dysfunction, found a constant or slightly lower level of this parameter in the operating suite compared with the value calculated in the ICU, and ignored the expected increase in the Pao2/FIo2 ratio as the FIo2 increased, the deterioration in this hypothetical patient’s pulmonary function might be missed. In this case, a calculation of the PAo2 – Pao2 would be a more appropriate measure because it would reveal the deterioration in function when the Pao2/FIo2 ratio did not.

    The PACO2 (and thus the PaCO2) also influences both the Pao2/FIo2 ratio and the PAo2 – Pao2. In our model, the Pao2/FIo2 ratio falls (from 528 to 470) and the PAo2 – Pao2 also falls slightly (from 30 to 28 mm Hg) as the PaCO2 rises from 35 mm Hg to 55 mm Hg (see Table 4, lines 6-8). Experimental work in dogs11 and in humans7 found an inverse relationship between PACO2 and the PAo2 – Pao2, suggesting that the PAo2 – Pao2 rather than the Pao2/FIo2 ratio should be used to assess pulmonary function as the PaCO2 changes. Interestingly, the decreases in PAo2 – Pao2 as the PACO2 increased were much larger in these studies than could be accounted for by our model alone, suggesting that this effect may indeed be caused by a right-shift in the oxygen-hemoglobin dissociation or the dilation of some airways as suggested by the authors of the study in dogs.11

    Impact of Shunt and Diffusion Barrier. Shunt, although low in the normal lung,7 becomes substantial and reduces Pao2 when atelectasis is present, as might occur with retained secretions35 under general anesthesia or from chronic bronchitis. The model presented here shows that increasing shunt from 0.05 to 0.4 of the cardiac output will cause a widening of the PAo2 – Pao2 from 69 to 173 mm Hg and reduce the Pao2/FIo2 ratio from 415 to 155 at an FIo2 of 0.4 (see Table 4, lines 9-13). Confirmation of the impact of shunt on measures of pulmonary dysfunction is found in the previously cited experimental work in dogs, in which atelectasis and shunt induced by near-drowning caused a widening of the PAo2 – Pao210 and in studies of patients after open heart surgery in whom a widening of the PAo2 – Pao2 was seen as a sign of increased shunt.19 In ARDS, a syndrome in which alveolar collapse causes increased shunt and reduced Pao2, the Pao2/FIo2 ratio has become a major measure of the degree of pulmonary dysfunction (ie, shunt).1

    In the model presented here, both the PAo2 – Pao2 and the Pao2/FIo2 ratio respond to increases in shunt at a constant FIo2 by indicating poorer pulmonary function. Thus, it is reasonable that prevention of both an increase in the PAo2 – Pao218 and a decrease in the Pao2/FIo2 ratio4 have been used in clinical settings as indicators that specific ventilation strategies prevent atelectasis and increased shunt under general anesthesia. Thus, either would seem an adequate measure of pulmonary dysfunction at a constant FIo2 if shunt is the major concern.

    Oxygen transport from the alveolus to the pulmonary capillary is perfusion limited in the normal lung but becomes diffusion limited with a resultant increased diffusion barrier in patients with pulmonary diseases including pulmonary fibrosis as well as interstitial pneumonia, autoimmune diseases,35 and heart failure.36 Both the PAo2 – Pao2 and the Pao2/FIo2 ratio respond appropriately to increasing levels of diffusion barrier for oxygen between alveoli and pulmonary capillaries (defined in Table 3) in the model presented here. As the diffusion barrier increases from 25 to 150 mm Hg, the PAo2 – Pao2 rises from 52 to 163 mm Hg and the Pao2/FIo2 ratio falls from 458 to 189 (see Table 4, lines 14-18), so either measure provides an assessment of worsening pulmonary dysfunction of this type at a constant FIo2.

    Values of Concern for PAo2 – Pao2 and Pao2/FIo2 Ratio. In the Berlin Definition, ARDS is associated with Pao2/FIo2 ratios less than 300 (see Table 2), so values this low are certainly of concern for any patient. To translate this into PAo2 – Pao2, note that a Pao2/FIo2 ratio of 305 correlates with an PAo2 – Pao2 equal to 113 mm Hg when pulmonary dysfunction is modeled by increased shunt or diffusion barrier (see Table 4, lines 10 and 13). Although PAo2 – Pao218 and Pao2/FIo2 ratio26 values in this range can occur intraoperatively, even less dramatic changes indicate deteriorating pulmonary function and may necessitate intervention.4 These findings suggest that serial determinations of measures of pulmonary dysfunction may be warranted, particularly in patients at risk by persisting disease or the nature of the surgical procedure.

    Conclusion

    This article reviews the use of the PAo2 – Pao2 and the Pao2/FIo2 ratio as measures of pulmonary dysfunction. The broad use of these parameters in the laboratory, ICU, and operating suite demonstrates their popularity. and the predictive value of these indexes in many clinical settings suggests their importance. The factors influencing these parameters are summarized in Table 6.

    The PAo2 – Pao2 expresses a physiologic phenomenon: the gradient in partial pressure of oxygen between the alveolus and the arterial blood. The Pao2/FIo2 ratio, although it does not reflect an aspect of physiology, is easy to calculate and to understand. These facts and the finding that increases in Pao2/FIo2 ratio as the FIo2 increases could mask deterioration in pulmonary function probably contribute to the PAo2 – Pao2 being identified as a “very relevant” measure of acute lung injury in animal models, whereas the Pao2/FIo2 ratio less than 200 is deemed “somewhat relevant”.37 In model results (see Table 4, lines 9-18), as in experimental and clinical findings, both respond appropriately to reflect worsening pulmonary dysfunction when shunt or diffusion barrier are increased at a fixed FIo2. Thus, both are useful in identifying patients who are at risk of poor outcomes and in determining the impact of a particular procedure. However, both are also sensitive to the FIo2. The increase in the Pao2/FIo2 ratio as the FIo2 increases, even in the absence of changes in patient condition (see Table 4, lines 1-5), is particularly problematic because it could mask a deterioration in the patient’s pulmonary status. Thus, the PAo2 – Pao2 and the Pao2/FIo2 ratio are both useful measures of pulmonary function, but the anesthetist should use these measures with a full understanding of their limitations.

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    AUTHORS

    David E. Harris, PhD, RN, is a faculty member at the University of New England Nurse Anesthesia Program in Portland, Maine where he teaches advanced physiology, advanced pathophysiology, and other basic science content. Email: dharris2@une.edu.

    Maribeth Massie, PhD, MS, CRNA, is program director of the Columbia University School of Nursing Nurse Anesthesia Program. She is the American Association of Nurse Anesthetists Region 1 director for 2017 to 2019.

    DISCLOSURES

    The authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did not discuss off-label use within the article. Disclosure statements are available for viewing upon request.

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