The most common indication for preadmission oral corticosteroid use was history of solid organ transplant (33%), followed by hematologic malignancy with or without hematopoietic stem cell transplant (21%), and autoimmune disease (24%) (Table 1). The median daily dose of oral corticosteroids, in prednisone equivalents, was 10 mg (IQR, 5–30 mg).
The incidence of ARDS within 96 hours of ICU admission was 35% among patients receiving preadmission oral corticosteroids compared with 42% among those who were not (p = 0.107). Before adjusting for potential confounders, ICU length of stay among patients receiving preadmission oral corticosteroids was shorter (median and IQR, 5 d [3–10] vs 6 d [3–11]; p = 0.047) and in-hospital mortality was higher (31% vs 22%; p = 0.018).
In multivariable analysis controlling for prespecified confounders, preadmission oral corticosteroids were associated with a lower incidence of ARDS in the 96 hours after ICU admission (odds ratio [OR], 0.53; 95% CI, 0.33–0.84; p = 0.008) (Table 2 and Fig. 2). In multiple sensitivity analyses as detailed in the “Methods section,” preadmission corticosteroids were consistently significantly associated with a lower rate of ARDS with a similar point estimate for the OR, including when patients with malignancy, hematopoietic stem cell transplant, or solid organ transplant were excluded from the analysis (OR, 0.44; 95% CI, 0.21–0.94; p = 0.034) (e-Fig. 1 and e-Tables 1–5, Supplemental Digital Content 1, http://links.lww.com/CCM/C419). Additionally, preadmission corticosteroids were associated with a reduction in the composite endpoint of ARDS or death within 96 hours of ICU admission (OR, 0.62; 95% CI, 0.39–0.98; p = 0.040), and in a model treating the development of ARDS and death as competing risks, receipt of preadmission corticosteroids continued to be associated with a reduced risk of ARDS development (HR, 0.69; 95% CI, 0.52–0.91; p = 0.008) (e-Fig. 1 and e-Tables 6 and 7, Supplemental Digital Content 1, http://links.lww.com/CCM/C419). Pulmonary versus nonpulmonary source of sepsis did not modify the effect of preadmission corticosteroid receipt on the development of ARDS (p for the interaction = 0.916). Higher doses of preadmission oral corticosteroids were associated with a lower incidence of ARDS (OR of ARDS for patients on 30 mg of prednisone to patients on 5 mg, 0.53; 95% CI, 0.32–0.86) (Fig. 3) (e-Table 8, Supplemental Digital Content 1, http://links.lww.com/CCM/C419). In multivariable analysis controlling for prespecified confounders, preadmission oral corticosteroids were not associated with incidence of in-hospital mortality (OR, 1.41; 95% CI, 0.87–2.28; p = 0.164), ICU length of stay (OR, 0.90; 95% CI, 0.63–1.30; p = 0.585), or VFDs (OR, 1.06; 95% CI, 0.71–1.57; p = 0.783) (Fig. 2) (e-Tables 9–11, Supplemental Digital Content 1, http://links.lww.com/CCM/C419).
In our study of over 1,000 septic ICU patients, preadmission oral corticosteroids were associated with a lower incidence of ARDS. Corticosteroids were not associated with hospital mortality or other clinical outcomes. With a growing emphasis on prevention of ARDS, our study raises the question of whether modest doses of oral corticosteroids given at the onset of inflammatory insult might mitigate progression from sepsis to ARDS.
Corticosteroids for the treatment of ARDS have been advocated based on experimental and clinical randomized studies showing that exogenous corticosteroids, in comparison to placebo, significantly reduce systemic and pulmonary inflammation by increasing glucocorticoid receptor-α number and function leading to reduction in NF-κB DNA-binding and transcription of inflammatory cytokines (6). A recent patient-level meta-analysis suggested lower mortality, earlier resolution of inflammation, and earlier achievement of unassisted breathing with early corticosteroid therapy in ARDS (11). A logical extension of this line of investigation is whether early corticosteroid administration in at-risk patients might prevent ARDS.
Recent studies have shown favorable outcomes for the use of early corticosteroids in community-acquired pneumonia. A 2015 trial by Blum et al (22) randomizing hospitalized patients with community-acquired pneumonia to 50 mg of prednisone or placebo daily found corticosteroids led to earlier clinical stability, but the study population was not sufficiently ill to address the question of ARDS prevention. A study by Torres et al (23) of placebo versus methylprednisolone 0.5 mg/kg every 12 hours for 5 days in patients with severe community-acquired pneumonia enrolled a sicker population and found that corticosteroids decreased radiographic progression, suggesting a potential impact on ARDS development. A recent trial-level meta-analysis found corticosteroid use among patients with severe pneumonia to be associated with reduced progression to ARDS, receipt of mechanical ventilation, and mortality (24). Another meta-analysis of corticosteroids for “Pneumocystis” pneumonia in HIV also showed a mortality benefit (25).
To our knowledge, the current study is only the second to examine the role of preadmission oral corticosteroids and ARDS development. The first, a retrospective cohort study by Karnatovskaia et al (13), enrolled adult inpatients with a diverse set of risk factors for ARDS including sepsis, pancreatitis, trauma, or high-risk surgery, excluding patients on inhaled corticosteroids or with ARDS at the time of admission. They observed no difference in the in-hospital development of ARDS between patients with and without preadmission oral corticosteroids. There are important differences between our study and the study by Karnatovskaia et al (13) that may explain the discrepancy in findings. First, we restricted our cohort to critically ill patients with sepsis as a risk factor for ARDS, generating a more homogeneous patient group with a much higher baseline severity of illness (median APACHE II score, 27 vs 9) and higher overall rate of ARDS (41% vs 7%). Second, because we studied oral corticosteroid exposure that predated the acute illness requiring hospitalization, we included patients who met the ARDS outcome at the time of admission. Preadmission corticosteroids might be expected to influence the risk of ARDS development early in the time course when risk for ARDS is highest (26), so an effect of corticosteroids on ARDS development might have been missed by excluding patients with ARDS at enrollment in the study by Karnatovskaia et al (13).
Our study also contributes to the literature by examining the association between the daily dose of preadmission corticosteroids and likelihood of ARDS development. We observed a nonlinear relationship between oral prednisone dose equivalents and ARDS risk which might be consistent with a dose-response effect at lower doses and a plateauing of effect when approaching total daily dose of 50 mg of oral prednisone equivalents (Fig. 3). This raises the question whether doses of oral corticosteroids up to 50 mg daily of prednisone could provide a favorable risk-benefit profile for ARDS prevention in patients with sepsis without exposing them to the risks associated with higher doses. One might wonder whether other immune-modulating drugs would similarly reduce the risk of developing ARDS although we did not find an association between T-cell inhibitory medications and development of ARDS in our cohort.
In addition to oral corticosteroids, inhaled formulation corticosteroids have been posited as a potential tool for ARDS prevention. Festic et al (12) performed a retrospective cohort study out of the same population as the Karnatovskaia et al (13) study examining the association of preadmission ICS and ARDS development and found no association in adjusted analyses. In contrast, the prospective, randomized Lung Injury Prevention Study with Budesonide and Beta Agonist (Formoterol) study of ICS combined with long-acting beta agonist therapy found a potentially large treatment benefit for ARDS, but the study was small with marked differences in baseline illness (27). In our investigation, incorporation of preadmission ICS into the model did not influence the association of preadmission oral corticosteroid use with developing ARDS (e-Fig. 1, Supplemental Digital Content 1, http://links.lww.com/CCM/C419).
Compared with a typical retrospective design, our study is strengthened by the use of a prospectively collected cohort including prospective identification of sepsis as a risk factor and two physician adjudication of the ARDS diagnosis, both without knowledge of whether prehospital steroids had been received. In addition, we evaluated the development of ARDS from ICU admission up to ICU day 4, which encompasses the time period during which at-risk patients most frequently develop ARDS (26). Our study has some limitations. Although multivariable regression may partially correct for baseline differences in risk between groups, unmeasured variables may confound the identified association, particularly given the large baseline imbalances with regard to hematopoietic malignancy and solid organ transplantation. We performed a secondary analysis excluding the patients with malignancy, solid organ transplant, or hematopoietic stem cell transplant, and the multivariate analysis remained significantly in favor of preadmission oral corticosteroids, suggesting that the data applies to the cohort as whole rather being a consequence of including immunosuppressed patients.
Furthermore, the retrospective medication review can only identify patients known to have corticosteroids on their preadmission medication list—compliance with medication by patients at home and duration of corticosteroid use is unknown. Although best efforts are made by clinicians to correctly identify the preadmission medications for patients, their accuracy may be less than perfect. Attempting to mitigate this limitation, we used all available data including the formal preadmission medication list in the electronic chart, the history and physical completed by the admitting physician(s), and other documentation around the time of admission including recent clinical encounters. Some may criticize the use of the AECC definition of ARDS for the primary outcome, but the definition was current at the time of cohort creation, and patients may have ARDS in the absence of mechanical ventilation (19, 28–30). Furthermore, to better conform with the Berlin criteria for ARDS, we performed a sensitivity analysis with the outcome of ARDS requiring mechanical ventilation, and the results remained unchanged (OR, 0.47; 95% CI, 0.22–0.75; p = 0.004) (e-Fig. 1 and e-Table 1, Supplemental Digital Content 1, http://links.lww.com/CCM/C419).
Although the potential for prevention of ARDS with corticosteroids is an important finding, it is worth noting that the development of ARDS is not itself a patient-centered outcome. Indeed, in this study, we did not identify an increase in VFDs, reduction in ICU length of stay, or reduction in in-hospital mortality. As previously suggested, any prospective trial for the prevention of ARDS should include meaningful patient-centered outcomes (31).
Among septic ICU patients, preadmission oral corticosteroids were associated with a lower incidence of ARDS during the first 4 ICU days. Prospective studies of early administration of low-dose corticosteroids for the prevention of ARDS in high-risk populations should be considered.
We thank the patients who contributed their data to Validating Acute Lung Injury Markers for Diagnosis cohort, making this study possible.
1. Bellani G, Laffey JG, Pham T, et al; LUNG SAFE Investigators; ESICM Trials Group: Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016; 315:788–800
2. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342:1334–1349
3. Parsons PE, Eisner MD, Thompson BT, et al; NHLBI Acute Respiratory Distress Syndrome Clinical Trials Network: Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005; 33:1–6; discussion 230
4. Kor DJ, Carter RE, Park PK, et al; US Critical Illness and Injury Trials Group: Lung Injury Prevention with Aspirin Study Group (USCIITG: LIPS-A): Effect of aspirin on development of ARDS in at-risk patients presenting to the emergency department: The LIPS-A randomized clinical trial. JAMA 2016; 315:2406–2414
5. Gong MN, Thompson BT. Acute respiratory distress syndrome: Shifting the emphasis from treatment to prevention. Curr Opin Crit Care 2016; 22:21–37
6. Meduri GU, Annane D, Chrousos GP, et al. Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy. Chest 2009; 136:1631–1643
7. Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967; 2:319–323
8. Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: Results of a randomized controlled trial. Chest 2007; 131:954–963
9. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: A randomized controlled trial. JAMA 1998; 280:159–165
10. ARDSnet Investigators: Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354:1671–1684
11. Meduri GU, Bridges L, Shih MC, et al. Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: Analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med 2016; 42:829–840
12. Festic E, Ortiz-Diaz E, Lee A, et al; United States Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS): Prehospital use of inhaled steroids and incidence of acute lung injury among patients at risk. J Crit Care 2013; 28:985–991
13. Karnatovskaia LV, Lee AS, Gajic O, et al; U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG–LIPS): The influence of prehospital systemic corticosteroid use on development of acute respiratory distress syndrome and hospital outcomes. Crit Care Med 2013; 41:1679–1685
14. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003; 29:530–538
15. Siew ED, Ware LB, Gebretsadik T, et al. Urine neutrophil gelatinase-associated lipocalin moderately predicts acute kidney injury in critically ill adults. J Am Soc Nephrol 2009; 20:1823–1832
16. Janz DR, Bastarache JA, Peterson JF, et al. Association between cell-free hemoglobin, acetaminophen, and mortality in patients with sepsis: An observational study. Crit Care Med 2013; 41:784–790
17. Kangelaris KN, Calfee CS, May AK, et al. Is there still a role for the lung injury score in the era of the Berlin definition ARDS? Ann Intensive Care 2014; 4:4
18. Wang CY, Calfee CS, Paul DW, et al. One-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome. Intensive Care Med 2014; 40:388–396
19. Kangelaris KN, Ware LB, Wang CY, et al. Timing of intubation and clinical outcomes in adults with acute respiratory distress syndrome. Crit Care Med 2016; 44:120–129
20. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818–824
21. The ARDS Definition Task Force: Acute respiratory distress syndrome: The Berlin definition. JAMA 2012; 307:2526–2533
22. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: A multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385:1511–1518
23. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A randomized clinical trial. JAMA 2015; 313:677–686
24. Siemieniuk RA, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: A systematic review and meta-analysis. Ann Intern Med 2015; 163:519–528
25. Ewald H, Raatz H, Boscacci R, et al. Adjunctive corticosteroids for Pneumocystis jiroveci
pneumonia in patients with HIV infection. Cochrane Database Syst Rev 2015; 4:CD006150
26. Shari G, Kojicic M, Li G, et al. Timing of the onset of acute respiratory distress syndrome: A population-based study. Respir Care 2011; 56:576–582
27. Festic E, Carr G, Cartin-Ceba R, et al. Lung Injury Prevention Study with Budesonide and Beta Agonist, Formoterol (LIPS-B): A multicenter randomized clinical trial. Am J Respir Crit Care Med
28. Cely CM, Rojas JT, Maldonado DA, et al. Use of intensive care, mechanical ventilation, both, or neither by patients with acute lung injury. Crit Care Med 2010; 38:1126–1134
29. Quartin AA, Campos MA, Maldonado DA, et al. Acute lung injury outside of the ICU: Incidence in respiratory isolation on a general ward. Chest 2009; 135:261–268
30. Flori HR, Glidden DV, Rutherford GW, et al. Pediatric acute lung injury: Prospective evaluation of risk factors associated with mortality. Am J Respir Crit Care Med 2005; 171:995–1001
31. Rubenfeld GD. Who cares about preventing acute respiratory distress syndrome? Am J Respir Crit Care Med 2015; 191:255–260
acute lung injury; acute respiratory distress syndrome; corticosteroids; sepsis
Supplemental Digital Content
Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.