Background: Changes in oxygenation index, position (supine vs. prone), blood Pco2 values blood pH values and dosages of vasoactive drugs can all affect oxygenation during management of severe ARDS. When some or all of these changes occur amid iNO treatment, the validity and specificity of improved oxygenation as a response to iNO is uncertain. Objective: To test the hypothesis that in patients with severe ARDS, fluctuations in the aforementioned variables occur frequently and therefore improvement in oxygenation during iNO may be erroneously attributed to iNO effect. Patients and Methods: 16 patients were treated with iNO for pulmonary hypertension Six of these patients met our definition of severe ARDS (PaO2/FiO2 <110 and OI>19 prior to iNO initiation). We developed a post hoc analysis tool which included 6 criteria (figure) to determine whether an observed improvement in oxygenation can be attributed solely to iNO. We evaluated data points at predetermined intervals of iNO treatment during the first 72 hours. CRITERIA FOR RESPONSIVENESS TO iNO RESPONSE NONRESPONSE UNDETERMIND 1 Y Δ RATIO ≥ 15% Y Δ PF RATIO ≥ 15% Y Δ PF RATIO ≥ 15% 2 Y OI ↔ ↓ Y OI ↔ ↓ N OI ↔ ↓ 3 Y SAME POSITION N SAME POSITION SAME POSITION 4 Y PaCO2 ↔ ↑ N PaCO2 ↔ ↑ PaCO2 ↔ ↑ 5 Y pH ↔ ↓ N pH ↔ ↓ pH ↔ ↓ 6 Y VASOACTIVE DRUGS DOSE ↔ ↓ N VASOACTIVE DRUGS DOSE ↔ ↓ VASOACTIVE DRUGS DOSE ↔ ↓ ALL 6 QUESTIONS SHOULD BE ANSWERED "Y" (YES) 1 AND 2 SHOULD BE ANSWERED "Y" ONE OR MORE OF 3-6 SHOULD BE "N" (NO) 1 SHOULD BE ANSWERED "Y" 2 SHOULD BE ANSWERED "N" WHILE 3-6 BECOME IRRELEVANT Results: PaO2/FiO2 prior to initiation of iNO was 85±17 (range: 62-105) and OI was 31±9 (range 20-45). iNO doses ranged from 5 to 25 ppm. Four patients were treated with conventional mechanical ventilation and 2 with high frequency oscillatory ventilation. A total of 37 data points were evaluated within a 72 hour period of iNO treatment. In 12 data points (32%) the PaO2/FiO2 was less than 15% of the pre-iNO baseline value and thus did not meet the response criterion. In 10 data points (27%) the observed response was nonspecific, as other criteria specified in our analysis tool for "nonspecific response" were not met. In 1 data point (3%) the observed improvement in oxygenation could not be attributed to iNO (undetermined), as an increase in OI was also documented. In fourteen data points (38%) the increased PaO2/FiO2 ratio could be attributed to the iNO treatment as no other contributory factors were identified. Conclusions: In severe ARDS improvement in oxygenation amid iNO treatment is multifactorial Only in 38% of our evaluated data points the increase in PaO2/FiO2 could be attributed to iNO. We suggest that in future iNO studies, our described additional criteria should be taken into account for data analysis.