A fresh trial shows considerable efficacy of dexamethasone in ARDS. This may come as a bit of a surprise, but it’s actually entirely consistent with prior evidence. To understand the study, we need to start with previous data…
Part I: Background: The Rabbit hole of ARDS, pneumonia, and septic shock
We often think about ARDS, pneumonia, and septic shock as separate entities. However, there’s an enormous amount of overlap between them. Starting from scratch with each different syndrome will therefore cause us to be continuously re-designing the wheel. Let’s take a quick look at the role of steroids in each of these conditions.
I-a: Steroid in ARDS
A recent individual patient data meta-analysis combined four RCTs evaluating prolonged methylprednisolone therapy for ARDS.1 This showed a reduction in mortality, with an increase in ventilator-free days (13 vs. 7, p<0.001)(figure above).
The SCCM/ESICM guidelines performed their own meta-analysis, which likewise showed that steroid reduced mortality and increased the number of ventilator-free days (shown above). Consequently they recommended steroid for patients with ARDS and PaO2/FiO2 <200.2 However, the referenced studies are rather small and have methodologic limitations, so equipoise remains about the use of steroid in ARDS. Furthermore, the guidelines recommend a moderate-dose steroid regimen with a 28-day taper, which is arduous and has never achieved broad popularity (shown below).
Steroid is ineffective as a salvage therapy for patients with persistent ARDS (e.g. when started >7 days after ARDS onset).3 The remainder of this post is about relative early steroid initiation (e.g. within ~1-2 days of ARDS onset).4
I-b: Steroid among intubated patients with septic shock
The ADRENAL trial was a large RCT evaluating the role of steroid among intubated patients with septic shock.5 35% of patients had pneumonia as a source of sepsis. Steroid accelerated weaning from ventilation and reduced the ICU length of stay:
APROCCHSS was another recent multi-center RCT evaluating steroid among patients with septic shock.6 92% of patients were intubated and 59% of patients had pneumonia as their source of sepsis. Once again, steroid accelerated weaning off ventilation and reduced the ICU length of stay (figures below). There was a mortality benefit found in this study, in comparison to none found in the ADRENAL trial.
I-c: Steroid in community acquired pneumonia
Steroid has shown benefit in severe pneumonia in several studies, causing it to be recommended by the SCCM/ESICM guidelines7 (although it wasn’t recommended by the IDSA/ATS guidelines).8 This discrepancy between the two guidelines was previously explored here (see #12).
A Cochrane meta-analysis found that steroid reduced the likelihood of early clinical failure:9
Additionally, steroid reduced the ICU length of stay:
And finally, steroid reduced the likelihood of requiring mechanical ventilation:
Steroid reduced mortality in this Cochrane analysis, but the result wasn’t robust (the 95% confidence interval for mortality was 0.47-0.92). Steroid increased the risk of hyperglycemia, but not other complications (in particular, there was no difference in rate of hospital-acquired infection).
Summary of background data on steroid in ARDS, pneumonia, and septic shock
When considering all of this data, the following general theme emerges:
- Steroid accelerates weaning from ventilation and reduces ICU length of stay.
- Steroid reduces mortality in some studies, but not others. This is a topic of perpetual, internecine struggle which will probably never be resolved.
- Steroid increases the rate of hyperglycemia, but not other complications (e.g. there is no increase in infection.)
Part II: the DEXA-ARDS trial
This is a multi-center trial in Spain investigating the use of dexamethasone for patients with ARDS10 Patients were included only if their PaO2/FiO2 ratio remained <200 after 24 hours of ventilator optimization (to avoid including patients with pseudoARDS). Patients were stunningly well-matched at baseline (table below). 77% of patients had either pneumonia or sepsis:
Patients were treated with a regimen of 20 mg dexamethasone IV daily for five days, followed by 10 mg daily for the next five days (with steroid discontinued when patients were extubated). The primary endpoint was ventilator-free days. Dexamethasone did accelerate weaning from ventilation, and also reduced mortality:
Some physiological variables are shown below. Once again, it’s striking how well matched the groups were at baseline. This degree of matching may have allowed the study to have a bit more statistical power than one might expect from a trial containing 277 patients.
The study has some weaknesses, but these would generally be expected to reduce the observed effectiveness of dexamethasone. Since the results are positive, these weaknesses may make the results even more impressive. Specifically:
- Patients were excluded if the treating physician felt that they could benefit from steroid (this was the most common exclusion criteria; see the trial profile below). Thus, patients included in the trial were those who were were not expected to benefit from steroid.
- The study was terminated early due to sluggish recruitment (which would be expected to reduce power and thereby increase the likelihood of a neutral trial). However, this isn’t a major problem, as they did reach 88% of their planned sample size.
- Some patients randomized to receive no steroid were found to have steroid-responsive disorders and were treated with off-protocol steroid.
The primary limitation of the study is that it wasn’t blinded. However, given equipoise regarding steroid and the hard nature of endpoints, this probably isn’t a problem.
Dexamethasone administration was safe. Specifically, there was no evidence of increased infection. 59% of patients received paralytics, implying that dexamethasone is still beneficial even in the presence of paralytics (suggesting that clinically significant myopathy wasn't a common problem).
Part III: Deep thoughts on DEXA-ARDS
III-a: Who should get steroid?
At this point, there is a fair body of evidence that patients with severe pneumonia or septic shock may benefit from steroid (in the absence of contraindications). Whether mortality benefit occurs is contentious, but it does seem that steroid accelerates ventilator weaning and ICU discharge (which are meaningful, patient-centered outcomes). So steroid makes sense for patients with {pneumonia+ARDS} or {sepsis+ARDS}. That isn’t a change in my practice.
The real question is whether patients with ARDS who don’t have pneumonia or sepsis should be treated with steroid. This remains murky. Patients may need to be judged on a case-by-case basis (depending on whether the suspected cause of ARDS is thought to be a steroid-responsive process). In the absence of any clear-cut answer, one possible approach is to use CRP as a signal for patients with systemic inflammation who might benefit from steroid. There is some precedent for this in the literature, as one RCT of pneumonia used CRP as a cutoff to adjudicate whether steroid would be used.11
More work needs to be done looking at different subsets of patients with ARDS, since this is a heterogeneous syndrome (rather than a true disease with a unified pathophysiology). For example, it’s a bit dubious whether steroid would benefit patients with ARDS in the context of trauma. Thus, blanket statements such as “steroid is beneficial in ARDS” currently lack validity.
III-b: Is the mortality benefit real?
Maybe. Or maybe not. Mortality benefit is a very slippery endpoint in critical care trials. Historically, mortality benefit from steroid has been difficult to pin down (tending to be poorly replicable).
Overall, this is a moot point and probably not worthy of extensive debate. If steroid is safe and accelerates recovery, then that’s plenty of rationale for its use. It’s probably most productive to focus on endpoints that show consistent and robust signals – as these are less likely to be subject to reversal in the future.
III-c: What steroid & how much?
The choice of dexamethasone here is clever, for a few reasons. Perhaps most notably, dexamethasone is a pure glucocorticoid, which may achieve the anti-inflammatory effects that we’re looking for without some of the side-effects of a mineralocorticoid:
- Mineralocorticoid stimulation will cause sodium retention, promoting volume overload. Volume retention is particularly undesirable in ARDS patients (because a dry lung is a happy lung). From the perspective of a #DiuresisJedi, stimulating the mineralocorticoid receptors seems misguided.
- There are some very weak hints in the literature that mineralocorticoid stimulation with aldosterone could exacerbate ARDS.12 In animal models, blockade of the mineralocorticoid receptors with spironolactone appears beneficial in ARDS.13,14 It’s hard to know what to make of this very data, but from a less-is-more standpoint it’s conceivable that a more targeted steroid would have fewer side-effects.
Another advantage of dexamethasone is that it has a long biological half-life. Thus, dexamethasone can be easily stopped when patients are extubated. Over time, the dexamethasone will auto-taper on its own. Gradual auto-tapering provides a compromise between short-term steroid use and the extensive regimens recommended by SCCM/ESICM guidelines.
So dexamethasone could be a rational choice here – both theoretically and based on evidence from the DEXA-ARDS trial. However, the choice of steroid probably isn’t mission-critical, because meta-analyses have found benefits using a variety of different steroids.
The next question is: what is the ideal dose? DEXA-ARDS started with a dose of 20 mg IV daily, which is a fair dose of steroid (it’s equivalent to ~100 mg of methylprednisolone, ~130 mg prednisone, or ~500 mg of hydrocortisone). This dose is consistent with prior studies of ARDS (which used methylprednisolone regimens dosed at 1-2 mg/kg/day initially). For patients at increased risk of steroid complications, beginning with a somewhat smaller steroid dose might be sensible (e.g. 10 mg/day dexamethasone initially).
- There is considerable overlap between ARDS, severe pneumonia, and intubated patients with septic shock. Studies regarding these conditions may be best understood in the greater context of all three conditions (otherwise we are continually re-designing the wheel).
- Prior evidence shows that steroid reduces duration of ventilation in ARDS and in intubated septic patients. Likewise, steroid may decrease ICU length of stay and the likelihood of requiring intubation in severe pneumonia. Some studies suggest mortality benefit, whereas others don’t.
- DEXA-ARDS is a new, multi-center RCT investigating dexamethasone for patients with ARDS (77% of whom had pneumonia or sepsis as the cause of ARDS). Dexamethasone both accelerated liberation from ventilation and reduced mortality.
- This study provides further support for the use of steroid in patients with both ARDS and either pneumonia or sepsis. It remains unclear whether steroid could benefit other subsets of ARDS patients (e.g. ARDS following trauma).
- Since dexamethasone is a pure glucocorticoid (with no mineralocorticoid activity), it could act as a cleaner anti-inflammatory agent than most steroids. Its ability to auto-taper is also convenient.
related on the blog:
- DEXA-ARDS study manuscript.
- Steroid for pneumonia
- Steroid for Septic shock:
references
- 1.Meduri G, Siemieniuk R, Ness R, Seyler S. Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS. J Intensive Care. 2018;6:53. doi:10.1186/s40560-018-0321-9
- 2.Annane D, Pastores S, Rochwerg B, et al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017;45(12):2078-2088. doi:10.1097/CCM.0000000000002737
- 3.Efficacy and Safety of Corticosteroids for Persistent Acute Respiratory Distress Syndrome. N Engl J Med. April 2006:1671-1684. doi:10.1056/nejmoa051693
- 4.Meduri G, Golden E, Freire A, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007;131(4):954-963. doi:10.1378/chest.06-2100
- 5.Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808. doi:10.1056/NEJMoa1705835
- 6.Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-818. doi:10.1056/NEJMoa1705716
- 7.Pastores SM, Annane D, Rochwerg B. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part II): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. October 2017:474-477. doi:10.1007/s00134-017-4951-5
- 8.Metlay J, Waterer G, Long A, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67. doi:10.1164/rccm.201908-1581ST
- 9.Stern A, Skalsky K, Avni T, Carrara E, Leibovici L, Paul M. Corticosteroids for pneumonia. Cochrane Database Syst Rev. 2017;12:CD007720. doi:10.1002/14651858.CD007720.pub3
- 10.Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. The Lancet Respiratory Medicine. February 2020. doi:10.1016/s2213-2600(19)30417-5
- 11.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(7):677-686. doi:10.1001/jama.2015.88
- 12.Ruthman C, Festic E. Emerging therapies for the prevention of acute respiratory distress syndrome. Ther Adv Respir Dis. 2015;9(4):173-187. doi:10.1177/1753465815585716
- 13.Yavag G. The impact of spironolactone on the lung injury induced by concomitant trastuzumab and thoracic radiotherapy. International Journal of Radiation Research. 2019;17(1):87-95. doi:10.18869/acadpub.ijrr.17.1.87
- 14.Atalay C, Dogan N, Aykan S, Gundogdu C, Keles M. The efficacy of spironolactone in the treatment of acute respiratory distress syndrome-induced rats. Singapore Med J. 2010;51(6):501-505. https://www.ncbi.nlm.nih.gov/pubmed/20658111.
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Well, my principal concern it’s about, as you said, the only meta analysis about dexa and ARDS was before lung protective parameters ventilation, so how to demonstrate statistically that the clinical effects is because of dexa and no for lung protective parameters?
Thanks
Fragility index is 6 for mortality and there’s an odd imbalance in the causes of mortality. 4 patients in the control arm died of brain death vs none in the dex group. Not sure there is really strong biologic premise that steroids should reduce the risk of brain death in ARDS. The difference in death from multisystem organ failure, however, makes sense. If this study cohort was enriched in hyperinflammatory ARDS endotypes, the results would make a lot of sense. As you say, mortality end points in ARDS are challenging and should be interpreted extremely cautiously in a study like… Read more »
Hi:
another consideration is that dexamethasone has 30 times the anti inflammatory potency of hydrocortisone and methylpred has only 5 times the potency
you might comment on steroid use in flu and covid 19
Hi Josh,
great overview to a difficult subject. However, as steroids are supposedly potentially harmful in viral pulmonary disease, should these be avoided (i.e. Covid-19)?
Interested to hear your take. Thanks for taking the time, stay safe and keep up the great work.
J.
Brilliantly exposed, even me and my residents understood it. It seems to confirm the results RECOVERY Trial advanced today.
It’s been hypothesized that COVID19 does not behave like ARDS, do you think this holds true now that we know more of the disease?
what do you mean when you say that dexa will taper on its own?
It has such a long half-life that as it gets metabolized it will auto-taper
Hi,
I have a question about septic shock and corticosteroid in patients with ARDS. To keep a mineralocorticoid effect, do you add fludrocortisone alone or hydrocortisone and dexamethasone ?
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