The results of this study demonstrate that noninvasive methods of oxygenation assessment, utilizing pulse oximetry as a substitute for Pao2, can be calculated and used as a surrogate for the diagnosis of ALI and ARDS in children. Additionally, because mechanical ventilation can largely influence the resultant oxygenation for a delivered percentage of oxygen, the OSI likely represents a more robust measure of lung disease severity. These parameters may be used potentially in the clinical diagnosis of ALI and ARDS and, after prospective validation, may serve as entry criteria for lung injury studies to assure that the study population mimics the target population.
The use of these parameters in recruitment of pediatric patients in interventional and epidemiologic studies of ALI and ARDS has the potential to reduce or even eliminate one of the major obstacles of pediatric lung injury clinical trialists: the failed enrollment of the target population of children with both ALI and ARDS. In two of the largest ALI/ARDS trials in children, both studies enrolled children with a much more severe level of lung injury than was targeted. In a study of exogenous calfactant administration (3
), the entry criteria stated that subjects only required a persistent OI of >7, yet the study population demonstrated severe lung disease, represented by an OI of >20, and a P/F ratio of <130. Similarly, in the study of prone positioning for lung injury in children (5
), the target entry criteria of P/F ratio of <300 (ALI criteria) was not represented in the study group, which demonstrated a P/F ratio of 100. Therefore, it is conceivable that a large number of subjects who had severe enough hypoxia to be eligible and potentially benefit from the intervention were not eligible due to lack of the Pao2
measurement. As our endeavors into larger ALI/ARDS studies continue to grow, it is clear that a new method to diagnose these potential subjects, without the need for Pao2
measurement, is needed. Based on the results described in this report, the OSI is a tool that, if prospectively validated, can achieve these goals.
There are other issues that require study in the pediatric ALI/ARDS population. Presently, pediatric critical care practitioners have adopted the consensus criteria definitions of ALI and ARDS, even though it is plausible that the pathophysiology may be different in children. It has been suggested that severity of hypoxia is correlated with mortality in children (7
), with a stepwise increase in mortality with decreasing P/F ratio. Therefore, the use of hypoxia measures seems to be a reliable indicator of severity of illness, and likely a good target for use in the diagnosis of ALI and ARDS. Because the OI takes into account a general measure of respiratory system support (Paw), many practitioners in pediatrics feel it more clearly defines the degree of hypoxia in children with lung injury. Further prospective studies aimed at the validity and accuracy of OI in predicting outcome from lung injury are required. However, even the substitution of OI, instead of P/F ratio, for diagnosis does not alter the requirement for arterial blood sampling and the resultant underdiagnosis of ALI and ARDS in children. The use of the OSI, however, will alleviate both issues of the P/F ratio described above. This tool has not been described in either pediatric or adult lung injury subjects to date, and will require well-designed, prospective validation before legitimate use in clinical diagnosis as well as entry criteria into clinical trials.
There are limitations of the data presented in this report which deserve discussion. First, although the data elements collected in both the development and the validation data sets were collected prospectively, the analysis was done post hoc
. Although this post hoc
analysis likely does not affect the mathematical modeling or the validity of the calculations, it is possible that the most accurate measurements were not made during the collection of these data. This concern is lessened by the prospective nature of the data collection as well as the rigor of the study protocols (8
). A prospective study of data collection, with close attention to the variance of the pulse oximeter and the exact timing of the arterial blood gas measurement with the recording of the Spo2
, is required in future validation studies of these measures. Another limitation is that, again due to the use of Spo2
data that were gathered in the conduct of large-scale clinical trials, it is conceivable that issues, such as poor oximeter waveform, unclean oximetry probe, and patient movement, may have affected the accuracy of the measurement. However, as these patients were enrolled in large, academic pediatric intensive care units with a wealth of experience with oximetry, this is less likely to be a concern. Third, the oxygen-hemoglobin dissociation curve and thus the relationship between Pao2
are known to be affected by a variety of variables, including pH, temperature, Paco2
, and concentration of 2,3 diphosphoglycerate (9
). These variables were measured but not linked to Spo2
or arterial blood gas data and, therefore, were not used in the modeling; these measurements will require close monitoring during the prospective validation of this model. However, despite this, the correlation between the Pao2
seems to be acceptable in these coupled measurements. Again, prospective data collection with collection of these potential confounding variables is necessary to validate the values derived in this present study. Finally, our ALI and ARDS diagnostic variables were derived and validated from a data set that only included samples ≤97% saturated. This was due to the flattening of the oxygen-hemoglobin dissociation curve at the upper end of saturation. Therefore, the S/F ratio and the OSI can only be utilized in patients <98% saturated. As these variables will be used to diagnose lung disease with significant hypoxemia by definition, this should not limit the clinical utility of these measures.
In conclusion, the data presented in this study determine that an OSI of 6.5 and 7.8 may be substituted for P/F ratio for defining ALI and ARDS in children with satisfactory, but not optimal, sensitivity and specificity. Further prospective research is required in this area of study to determine whether values can be calculated with higher sensitivity and specificity and still maintain the clinical usefulness. Compared with the other models, OSI would be the preferable method, as it has the advantage of including the Paw and also utilizing the noninvasive measure of oxygenation (Spo2). Although these values require validation in a prospective trial, utilizing this new criterion clinically has the potential to allow a more accurate diagnosis of ALI and ARDS in children and allow investigators to gain a true incidence of these lung diseases in pediatric populations. From a clinical trial perspective, use of the OSI as entry criteria in clinical trials is likely to increase the number of eligible children enrolled and allow investigators to enroll a more reasonable target population. This has the potential to impact the study of acute lung disease in children.