Comparison of non-invasive to invasive oxygenation ratios for diagnosing acute respiratory distress syndrome following coronary artery bypass graft surgery: a prospective derivation-validation cohort study

Circulatory and cardiovascular diseases (CVD) remain the leading cause of death globally [1]. In 2013, 17 million (32%) of NCD deaths were attributable to CVD, a number expected to rise to 11.1 million by 2020 [3], and > 23.6 million by 2030 [3‐5]. Coronary artery disease (CAD), the most common type of CVD, is the leading cause of death, morbidity and decline in quality-of-life (QoL) globally, and is predicted to remain so for the next 20 years [2, 3].

Coronary artery bypass graft (CABG) surgery is a common revascularization technique used to re-establish or improve flow to under-perfused regions of the heart. Predicting outcomes in postoperative cardiac surgery patients has proven to be an extremely difficult task. The severity-of-illness scoring systems that are commonly used in medical ICUs have not been very useful in predicting death in these patients, as high scores are often not associated with poor outcome [6‐8]. This may in part be due to our ability to normalize physiology by means of pharmacologic and/or mechanical support. The reported incidence of acute respiratory distress syndrome (ARDS) in patients undergoing open heart surgery with cardiopulmonary bypass (CPB) is 0.4–2.5%, with an associated mortality rate up to 68.4% [9‐12]. The current ARDS definition (Berlin Criteria) requires arterial blood gas (ABG) measurement to monitor the partial pressure of O₂ in arterial blood (P_aO₂) and includes a minimum PEEP value to account for the effect of mechanical ventilator settings on P_aO₂/F_iO₂ [13]. However, the Berlin definition is only slightly better than its predecessor for ARDS prognostication (receiver operating characteristic [ROC] area under the curve [AUC], 0.577 vs 0.536). This may be partially related to the dependence of both definitions on P_aO₂/F_iO₂ as the primary measure of ARDS severity. Multiple studies have shown that P_aO₂/F_iO₂ is not an independent mortality predictor in ARDS [14‐16]. The P_aO₂/F_iO₂ does not reflect other aspects of lung injury severity such as mechanical ventilation settings, changes in lung compliance, and pulmonary shunt [17]. Additionally, concerns about anemia, excessive phlebotomy, and a movement to minimally invasive approaches have led to fewer ABG measurements in critically ill patients [18]. We investigated the performance of the peripheral capillary oxygen saturation (S_pO₂)/F_iO₂ and partial pressure of alveolar O₂ (P_AO₂)/F_iO₂ oxygenation indices to P_aO₂/F_iO₂ (P/F) in identifying post-operative ARDS in CABG patients. Additionally, we seek to determine the threshold values for S_pO₂/F_iO₂ (S/F) and P_AO₂/F_iO₂ (P_A/F) that correlate with P/F ratios consistent with ARDS (mild 201–300; moderate 101–200; severe ≤100 mmHg).

A total of 729 eligible patients were screened for the study. See Figure 1 for the patient flow diagram. Fifty-eight did not meet inclusion criteria. Six-hundred Seventy-one patients consented to participate in the derivation (n = 244) and validation (n = 427) cohorts. Eighty-seven subjects died (derivation 42, validation 45), 51 were lost to follow-up (derivation 27, validation 24), and 533 were analyzed (derivation 175, validation 358). There were 18 (derivation 7, validation 11) instances where the S_PO₂ and ABG could not be sampled at the same time, in which case the nearest S_PO₂ was used (all within 30 min). Patient demographics, clinical features, and physiologic respiratory variables are summarized in Table 1. A total of 20 (28.2%) patients were ventilated during cardiopulmonary bypass. The mean pre-op LVEF was 47.75 ± 7.87% (P/F = 48.96 ± 8.60, S/F = 46.04 ± 7.80, P_A/F = 48.26 ± 7.17; p = 0.414). Subjects were transfused a mean of 2.06 ± 0.79 units of packed red cells (P/F mean = 1.92 ± 0.83, S/F n = 2.29 ± 0.75, P_A/F n = 1.96 ± 0.77; p = 0.20), of which 15 (21.1%) were allogeneic (P/F = 5 (20.8%), S/F = 5 (20.8%), P_A/F = 5 (21.7%); p = 0.996). Six (8.5%) received inotropes (P/F = 3 (12.5%), S/F = 2 (8.3%), P_A/F = 1 (4.3%); p = 0.604). Mean duration of post-operative intra-aortic balloon pump support was 67.38 ± 21.45 h (P/F 67.29 ± 16.68; S/F 70.00 ± 22.99; P_A/F 64.74 ± 24.61; p = 0.71).

Our data met the criteria only for the PF ratio for mild ARDS (PF 200–300). The mean time between charted P_aO₂ and S_PO₂ pairs was 50.27 ± 11.65 s (Derivation 50.21 ± 12.18; Validation 50.30 ± 11.40).

In the derivation cohort, the S/F and P_A/F ratios could be predicted well from P/F, described by the linear regression models S/F = 71.149 + 0.8PF and P_A/F = 38.098 + 2.312PF, respectively. According to the linear regression equation, a P/F ratio of 300 equaled an S/F ratio of 311 (R² 0.857, F 1035.742, < 0.0001) and a P_A/F ratio of 732 (R² 0.576, F 234.887, < 0.0001). The scatter plots for the (S/F vs P/F) and (P_A/F vs. P/F) ratios for the derivation and validation data sets is shown in Figs. 2 and 3 respectively.

The S/F threshold of 311 had 90% sensitivity, 80% specificity, LR+ 4.50, LR- 0.13, PPV 98, and NPV 42.1 for the diagnosis of mild ARDS. The P_A/F threshold of 732 had 86% sensitivity, 90% specificity, LR+ 8.45, LR- 0.16, PPV 98.9, and NPV 36 for the diagnosis of mild ARDS. S/F had excellent discrimination ability for mild ARDS (AUC ± SE = 0.92 ± 0.017; 95% CI 0.889 to 0.947) as did P_A/F for mild ARDS (AUC ± SE = 0.915 ± 0.018; 95% CI 0.881 to0.942).

ARDS manifests as acute refractory hypoxemia, bilateral pulmonary infiltrates and non-cardiogenic pulmonary edema, and has a very high mortality [23]. The Berlin Criteria (2012) [13, 24] defines ARDS by 4 main characteristics: (1) Timing within 1 week of known clinical insult or new or worsening symptoms; (2) Chest imaging with bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules; (3) Origin of edema not fully explained by cardiac failure or fluid overload; and Oxygen impairment defined as mild (200 mmHg < P/F ≤ 300 mmHg, with PEEP or CPAP ≥5 cmH₂O), moderate (100 mmHg < P/F ≤ 200 mmHg, with PEEP ≥5 cmH₂O), or severe (P/F ≤ 100 mmHg, with PEEP ≥5 cmH₂O).

It is known, however, that ARDS criteria may be met in post-op CABG patients in the absence of true ARDS. Thus, a need exists to improve diagnostic specificity [25]. Owing to concerns about anemia, excessive phlebotomy, and a movement to minimally invasive approaches, we investigated whether non-invasive indices of oxygenation (S/F, P_A/F) performed equal to or better than P/F in identifying post-operative ARDS in patients post-CABG.

Despite wide recognition of the high morbidity and mortality associated with ARDS, few interventions have been observed to decrease either. One reason for this may be late or delayed diagnosis, rendering the S/F ratio a rapid, convenient, and useful diagnostic tool. A study by of 1742 matched measurements of S_pO₂ and P_aO₂ in adult patients undergoing general anesthesia sought to identify a correlation between the S/F and P/F ratios by incorporating the S/F into the respiratory component of the SOFA score and found that both predicted similar outcomes [26]. Results were less convincing in the pediatric population, where only a weak correlation between S/F and P/F was noted in children with acute lung injury (age 1 month to 18 years) [27]. In an analysis of patients from the ARDS Network, S/F ratios of 235 and 315 correlated with PF ratios of 200 and 300 respectively [20]. Our findings were in keeping with prior reports that S/F ratios correlate with P/F ratios [18, 28‐30], supporting our finding that an S/F ratio of 311 correlates with a P/F of 300 (Sensitivity 90%, Specificity 80%).

Advantages of using the S/F (aka S_pO₂/F_iO₂) ratio in the diagnosis of ARDS are many. It may allow for real-time monitoring, is dynamic allowing for rapid identification of oxygenation changes, and may allow for earlier diagnosis. Additionally, it allows for a decrease in phlebotomy, blood loss, fewer skin breaks, fewer vascular punctures, and less associated pain. Furthermore, it is affordable, time saving, and already standard practice in most ICUs [31, 32].

Despite obvious advantages and utility of S/F, its use may not be appropriate for all situations. For example, some factors that limit the accuracy of pulse oximetry include methemoglobinemia, oximeter location, cardiogenic shock and temperature [30]. Other factors to consider include patient position andcognitive status (eg. delirium, agitation), which may alter measurements due to movement. Therefore, to decrease the risk of error and resultant misdiagnosis, a steady wave form as described in our study should be used.

In conclusion, cardiac surgery with cardiopulmonary bypass elicits a systemic inflammatory response that increases the risk for ARDS. P_aO₂ and S_aO₂ correlated in the diagnosis of ARDS, with a P/F of 300 correlating to an S/F of 311 (Sensitivity 90%, Specificity 80%). The S/F ratio may allow for early real-time rapid identification of ARDS, while decreasing the cost, phlebotomy, blood loss, pain, skin breaks, and vascular punctures associated with ABG measurements.