By James E. McFeely, MD

Medical Director, Critical Care Units, Alta Bates Summit Medical Center, Berkeley, CA

Dr. McFeely reports no financial relationships relevant to this field of study.

Mortality rates from acute respiratory distress syndrome (ARDS) remain high, even as therapy has improved over the last decade. Recent guidelines for management center on mechanical ventilation, with initial therapy beginning upon identification and treatment of the underlying cause of the ARDS.1,2 There is reasonable consensus regarding the use of lung-protective strategies, such as low tidal volume ventilation, prone positioning for those meeting criteria for severe ARDS, and restrictive fluid management after the initial resuscitation.1,2

However, for patients with the most severe disease, these treatments often are not completely effective, and we look for other therapies that might help. Because ARDS often is a highly inflammatory disease, corticosteroids are suggested frequently as a potential effective treatment modality. Steroids are indicated to treat some of the underlying illnesses that can result in ARDS (e.g., acute eosinophilic pneumonia, community-acquired pneumonia, diffuse alveolar hemorrhage).

Does the current evidence support a role for corticosteroids in the treatment of patients with ARDS for whom the standard guidelines are not effective? If so, when should corticosteroids be used, at what dose, and for what duration?

For years, many investigators have studied the use of corticosteroids in ARDS.3-6 These authors used modest initial doses of steroids (commonly 1-2 mg/kg/day of methylprednisolone) tapered over about 28 days. (See Table 1.) Four of the largest trials have been reanalyzed using individual patients’ data and a combined trial-level meta-analysis incorporating additional trials in which hydrocortisone was used in early ARDS.7 Individually, the trials showed improvements in inflammatory markers, ICU length of stay, and ventilator-free days. (See Table 2.) In the meta-analysis, the combined trials showed statistically important improvements in some clinically relevant endpoints, including oxygenation, ventilator-free days, and, for those randomized within 14 days of the onset of illness, survival.

However, it has been more difficult to show a consistent mortality benefit overall. While the meta-analysis showed a mortality benefit, the largest trial included in that analysis did not show such a benefit as an individual study. In addition, the meta-analysis included trials with significant differences in study design, such as different primary endpoints, different steroid dose and duration (the most common was 28-32 days), and differences in routine care.

Combined, the studies appear to show an improvement in mortality if steroids are started within the first 14 days of illness. However, there is a suggestion that more rapid tapering of steroids may have resulted in an exacerbation of inflammation-related organ failure and increased adverse outcomes. Also, there is a strong signal from the largest study that starting steroids after 14 days increases mortality.6

Several investigators studied the most common steroid-related side effects. They did not find a statistically significant increase in infections or hyperglycemia. The authors of the largest randomized study found an increase in neuromuscular weakness when steroids were started after 14 days.6 Theoretical concerns remain for other steroid-related side effects, including sodium and fluid retention, which were not addressed in these studies.

There are many different pathways to ARDS. It is a syndrome, not a disease. Many trials use entry and stratification criteria such as PaO2/FiO2, which would not be expected to predict a responsive phenotype for any given pharmacologic intervention. The Berlin definition of ARDS has improved our ability to describe the severity of the lung injury, but it doesn’t distinguish ARDS due to direct injuries (e.g., pneumonia, inhalation injury) from ARDS due to indirect injuries (e.g., pancreatitis, trauma, non-pulmonary sepsis).8

Biological markers are under investigation to define subtypes of patients who might benefit from specific interventions.9,10 One subtype appears to be hyperinflammatory and hypercoagulable, while the other is hypoinflammatory.

Perhaps agents tested in the past with negative results (e.g., statins, albuterol, growth factors) will be worth reevaluating once a more appropriate subset of ARDS patients with the target phenotype can be identified. We don’t necessarily need bigger ARDS trials, just trials with more accurate biological indications and targets for therapy.11 For now, the role of steroids remains uncertain. Current society guidelines offer conflicting recommendations. Some weakly recommend the use of methylprednisolone at 1-2 mg/kg/day, started within the first 14 days of illness and tapered over at least 28 days. Others do not recommend steroids. High-level vigilance for hyperglycemia, infection, and tight fluid balance are recommended. Moreover, steroids started more than 14 days into the illness increase mortality. Hopefully, the identification of subphenotypes of ARDS patients in the future will allow us to direct these therapies toward patients most likely to benefit from them.

REFERENCES

  1. Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med 2017;377:562-572.
  2. Fan E, Brodie D, Slutsky AS. Acute respiratory distress syndrome: Advances in diagnosis and treatment. JAMA 2018;319:698-710.
  3. 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.
  4. Rezk NA, Ibrahim AM. Effects of methylprednisolone in early ARDS. Egyptian J Chest Dis Tuberc 2013;62:167-172.
  5. 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.
  6. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671-1684.
  7. 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.
  8. Ferguson ND, Fan E, Camporota L, et al. The Berlin definition of ARDS: An expanded rationale, justification, and supplementary material. Intensive Care Med 2012;38:1573-1582.
  9. Calfee CS, Delucchi K, Parsons PE, et al. Subphenotypes in acute respiratory distress syndrome: Latent class analysis of data from two randomized controlled trials. Lancet Respir Med 2014;2:611-620.
  10. Famous KR, Delucchi K, Ware LB, et al. Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med 2017;195:331-338.
  11. Shankar-Hari M, McAuley DF. Acute respiratory distress syndrome phenotypes and identifying treatable traits. The dawn of personalized medicine for ARDS. Am J Respir Crit Care Med 2017;195:280-281.

Table 1. Randomized Trials of Corticosteroids in Acute Respiratory Distress Syndrome

Study

Number of
Patients

Randomization

Initial
Methylprednisolone Dose (mg/kg/day)

Duration of Steroids (Days)

Mean Tidal Volume (mL/kg)

Meduri 1998

22

2:1

2

31

10

Rezk 2013

27

2:1

1

28

Not stated

Meduri 2007

91

2:1

1

28

11

Steinberg 2006

177

1:1

1

28

7

Table 2. Outcomes of Randomized Trials of Corticosteroids in Acute Respiratory Distress Syndrome

Study

Inflammatory
Markers

Ventilator
Days

ICU Length
of Stay

Mortality

Meduri 1998

Decreased

Decreased

Not Stated

Decreased

Rezk 2013

Decreased

Decreased

Not Stated

Decreased

Meduri 2007

Decreased

Decreased

Decreased

Decreased

Steinberg 2006

Not Stated

Decreased

Decreased

No effect when started < 14 days
Increased when started > 14 days