Ineffective lung repair in patients with unresolving
acute respiratory distress syndrome (ARDS) is accompanied by progressive fibroproliferation, inability to improve
lung injury score (LIS), progressive
multiple organ dysfunction syndrome (
MODS), and an unfavorable outcome. Our aim was to investigate the relationship between fibrogenesis, pulmonary and extrapulmonary organ dysfunction, and outcome during the natural course of ARDS and in response to prolonged
methylprednisolone treatment. We investigated 29 patients with ARDS. We obtained serial measurements of plasma and BAL
procollagen aminoterminal propeptide type I (PINP) and type III (
PIIINP) levels and components of the
lung injury score (LIS) and MODS score. A reduction in LIS greater than one point from day 1 to day 7 of ARDS divided patients in improvers (group 1, n = 7) and nonimprovers (n = 22). Nonimprovers included those who were recruited (day 9 +/- 3 of ARDS) into a prospective, randomized, double-blind, placebo-controlled trial investigating prolonged
methylprednisolone therapy in unresolving ARDS (group 2, n = 17), and those who died (all by day 10 of ARDS) prior to meeting eligibility criteria for the randomized trial (group 3, n = 5). On day 1 of ARDS, plasma PINP or
PIIINP levels were elevated in all patients. By day 7 of ARDS, mean plasma PINP or
PIIINP levels were unchanged in group 1 but increased significantly in group 2 (p = 0. 0002) and group 3 (p = 0.03). On day 7, patients with plasma PINP levels less than 100 ng/ml were 2.5 times more likely to survive (95% CI: 0.855-7.314), and patients with plasma
PIIINP levels greater than 25 ng/ml were nine times more likely to die (95% CI: 1. 418-55.556). In group 2, patients taking placebo (n = 6) had no change in plasma PINP or
PIIINP levels over time, while patients treated with
methylprednisolone (n = 11) had a rapid and sustained reduction in mean plasma and bronchoalveolar lavage (BAL) PINP and
PIIINP levels. By day 3 of treatment, mean plasma PINP and
PIIINP levels (ng/ml) decreased from 100 +/- 9 to 45 +/- 8 (p = 0.0001) and 31 +/- 3 to 12 +/- 3 (p = 0.0008), respectively. After 8 to 15 d of
methylprednisolone, mean BAL PINP and
PIIINP levels (ng/ml) decreased from 63 +/- 25 to 6 +/- 23 (p = 0.002) and 42 +/- 5 to 10 +/- 3 (p = 0.003), respectively. Estimated partial correlation coefficients indicated that as plasma PINP and
PIIINP levels decreased over the first 7 d of
methylprednisolone treatment,
positive end-expiratory pressure,
creatinine,
bilirubin, and temperature also decreased, while PaO2:FIO2 increased. In early ARDS, plasma PINP and
PIIINP levels are elevated and continue to increase over time in those not improving. Among nonimprovers, those randomized to prolonged
methylprednisolone treatment had a rapid and significant reduction in plasma and BAL aminoterminal propeptide levels and similar changes in
lung injury and MODS scores. These findings provide additional evidence of an association between
biological efficacy and physiologic response during prolonged
methylprednisolone treatment of unresolving ARDS.