DISCUSSION

　　With two goals in mind—to assess the usefulness of Spo2 as a prognostic marker in patients with SSc-ILD and to determine whether an arterial line is needed to accurately assess oxygenation—we conducted a study to first examine agreement between Spo2 and Sao2 at rest and maximal exercise and then to analyse the ability of Spo2to predict mortality in patients with SSc-ILD. We hypothesised that, in subjects with SSc-ILD, Spo2 would inaccurately reflect Sao2 at rest and the disparity would be even greater at maximal exercise. In contrast, we found that Spo2 was an accurate reflection of Sao2 both at rest and maximal exertion in these subjects. Moreover, we observed that Spo2, a simple non-invasive and inexpensive measure to collect, was a predictor of mortality in patients with SSc-ILD.

　　Recently there has been a groundswell of attention on the use of non-invasive markers of exertional blood oxygenation (eg, nadir Spo2 during a 6-minute walk test (6MWT) or statistical manipulations of Spo2 over the course of a timed walked test) as outcome measures in therapeutic trials and clinical studies enrolling subjects with ILD.7 14 15 This increased attention raises three important distinct but related questions regarding the use of Spo2 at maximal exercise as an outcome metric:

　　Is it valid—does it in fact measure what it is purported to measure (eg, true blood oxygenation or Sao2)?

　　Is it reliable—if it is measured at two separate time points in a subject whose clinical status has not changed, will it produce similar results?

　　Is it responsive to underlying change—if a subject’s blood oxygenation at maximal exercise changes from baseline, will Spo2 reflect those changes?

　　The current study shows that Spo2 at maximal exercise is a valid measure of blood oxygenation at maximal exercise in patients with SSc-ILD, and Spo2 does in fact accurately track changes in Sao2.

　　The Bland-Altman plots reinforce this finding. These plots give a graphical presentation of the agreement between two methods of measurement; they depict an estimate of the bias (or systematic error which is simply the overestimation or underestimation of one measure compared with the other) as the mean difference between the two measures. The precision of that estimate is reflected in its standard deviation. Whereas correlation coefficients express the relationship between two variables, Bland-Altman plots depict agreement between them. When one is trying to determine the accuracy with which one measure (eg, Spo2) reflects another (eg, Sao2) or whether one measure might be used in place of another measure, correlation may not tell the true story—there can be extremely high correlation between two measures but, at the same time, poor agreement. This study shows that, for patients with SSc-ILD, Spo2 is an accurate reflection of Sao2 at rest or maximal exercise.

　　Several studies have examined the agreement between Spo2 and Sao29 but, to our knowledge, this is the first in a cohort with SSc-ILD. The importance and clinical relevance of this study centres on the peripheral circulation issues in SSc that make most clinicians reluctant to place an arterial line (digits have been lost as a consequence) and wary of Spo2 accuracy in these patients. There is therefore a need to validate Spo2 in SSc-ILD. In general, Spo2 may either overestimate or underestimate Sao2. In a meta-analysis Jensen and colleagues9 reported that, among 23 studies for which bias and precision estimates were available, the absolute mean (SD) bias was 1.99 (0.23) (ie, on average, Spo2 overestimated Sao2 by 1.99 points). In those studies the mean (SD) difference between Spo2 and Sao2 ranged from −13.2 (8.0) to 12.0 (13.3). The authors commented that severe or rapid desaturation; hypotension, hypothermia, or other unstable haemodynamic or low perfusion states; dyshaemoglobinaemia or use of vital dyes; and motion may all confound agreement between Spo2 and Sao2. The mean differences between Spo2 and Sao2 in the current study fall well within the range mentioned in that analysis.

　　The results of the current study not only suggest that Spo2 is a valid surrogate for Sao2 in patients with SSc-ILD, but also suggest that desaturation, as measured by Spo2, is a significant predictor of mortality in this patient group. Our results are in line with the work by Lama and colleagues8 that suggested desaturation (as measured by Spo2) during a 6MWT is an important prognosticator in patients with idiopathic interstitial pneumonia. In so far as the 6MWT accurately reflects functional exercise capacity in patients with SSc-ILD—it does so in patients with fibrotic idiopathic interstitial pneumonia10—we hypothesise that our results would hold for measures of Spo2 collected during the 6MWT in this patient population. Not surprisingly, we found Tlco% to be a strong driver of Spo2max (data not shown); in fact, among several candidate variables including age, gender, FVC% and baseline Spo2, Tlco% was the only significant predictor. Like other investigators,1 we also found Tlco% to be a potent predictor of survival in our cohort (data not shown). Because of the strong relationship between Tlco% and Spo2max, and because our goal was merely to begin to examine Spo2max as a prognostic marker, we performed our survival analysis adjusting for FVC% and not Tlco%.

　　Although the results are novel and clinically relevant, this study has limitations. This is a retrospective analysis of data collected prospectively over a period of three decades. Different pulse and co-oximeters were used during different time periods; however, each instrument is purported to be accurate within two percentage points for Sao2 values from 70–100% so we can be confident in the readings. Data for this study were collected at a centre situated 5280 feet above sea level. In Denver, patients probably “live” closer to the steep portion of the oxygen dissociation curve (probably on or very close to the shoulder) than patients at lower altitudes. How this affects the results merits consideration and examination in future studies. Given the lack of systematic examinations for pulmonary hypertension and the changes in available technology to assess for pulmonary hypertension over the study period, we cannot be certain how many subjects truly had the condition. Even more complex is the issue of exercise-induced pulmonary hypertension: how many subjects had it is unknown but, as with other studies of subjects with ILD, the possibility of its presence and its effects on exercise Spo2 must be considered. Given these limitations, we believe the results should be viewed as hypothesis-generating and will hopefully spark continued investigation in this area. These results will need prospective confirmation at other altitudes. Future studies should examine whether Spo2 values collected during the 6MWT are as meaningful as those collected during cardiopulmonary exercise tests, and efforts should be made to further delineate the relationship between resting or exercise-induced pulmonary hypertension and Spo2.