Chapter 68: Controversies: Corticosteroids for ARDS: Friend or Foe?

The acute respiratory distress syndrome (ARDS) is a common and vexing problem faced by critical care providers worldwide. Despite extensive investigation over the last three decades, the impact of ARDS in terms of morbidity, mortality, and health care costs remains very high. In the United States alone, ARDS affects as many as 200,000 people per year with a mortality rate from 30% to 50% and costs in excess of $60,000 per hospitalization.^1,2 The management of patients with ARDS is essentially supportive using a lung protective ventilatory strategy and treatment of the precipitating cause.³ The use of corticosteroids in patients with ARDS is controversial with widely dissenting opinions on this topic.⁴ At least 6 meta-analyses have been performed with conflicting conclusions.^5,6,7,8,9,10 However, a summation of this data would suggest that glucocorticoids (GCs) improve oxygenation, increase the number of ventilator-free days, decrease intensive care unit (ICU) and hospital length of stay with a possible mortality benefit with no clear evidence of an increase in complications. Despite the potential benefit of GCs in patients with ARDS, survey data suggest that most clinicians do not prescribe these agents to their patients with ARDS.¹¹ The purpose of this review is to outline the rationale for GC treatment in ARDS, discuss the factors affecting response to treatment, review the results of clinical trials and the myths concerning GC-related side effects and outline a protocol for GC treatment based on the best available data.

ARDS develops rapidly, in most patients within 12 to 48 hours of developing an illness associated with severe systemic inflammation. Injury to the alveolar-capillary membrane (ACM) causes exudative neutrophilic inflammatory edema, resulting in severe gas exchange impairment and lung compliance abnormalities. The lung-injury score (LIS) quantifies the impaired respiratory physiology in ARDS by using a 4-point score based on the level of positive end-expiratory pressure (PEEP), ratio of partial arterial oxygen tension (PaO₂) to fraction of inspired oxygen (FiO₂) (PaO₂:FiO₂), the quasistatic lung compliance, and the degree of infiltration on chest radiograph.¹² Using these criteria, the evolution of ARDS can be divided into resolving and unresolving ARDS based on achieving a 1-point reduction in LIS by day 7.¹³

Experimental and clinical evidence has demonstrated a strong cause and effect relationship between persistence in systemic inflammation and progression (unresolving) of ARDS. At the cellular level, patients with unresolving ARDS have inadequate GC-GC receptor (GR)-mediated downregulation of inflammatory transcription factor nuclear factor-κB (NF-κB) despite elevated levels of circulating cortisol, a condition recently defined as critical-illness-related corticosteroid insufficiency (CIRCI).^14,15 Patients with unresolving ARDS have persistent elevation in both systemic and bronchoalveolar lavage (BAL) levels of inflammatory mediators, markers of fibrogenesis, and ACM permeability. At the tissue level, uninhibited increased NF-κB activation leads to ongoing tissue injury, intravascular and extravascular coagulation, and proliferation of mesenchymal cells, resulting in maladaptive lung repair and ultimately end-organ dysfunction and failure.¹⁴ The ability of activated GC-GR to downregulate systemic inflammation and restore tissue homeostasis can be significantly enhanced with exogenous GC treatment.¹⁶ In a randomized trial,¹⁷ longitudinal measurements of biomarkers provided compelling evidence that prolonged methylprednisolone treatment modifies CIRCI and positively affects all aspects of ARDS.¹⁸ Treatment with prolonged methylprednisolone was associated with increased GC-GRα activity and reduced NF-κB DNA binding and transcription of inflammatory mediators.¹⁶ In ARDS, methylprednisolone treatment led to rapid and sustained reduction in plasma and BAL levels of proinflammatory mediators,^16,19 chemokines and adhesion molecules, and markers of fibrogenesis²⁰ and ACM permeability¹⁹ while increasing the anti-inflammatory cytokine interleukin-10 (IL-10) and anti-inflammatory to proinflammatory cytokine ratios.

Duration of treatment is an important determinant of both efficacy and toxicity. Optimization of GC treatment is affected by 3 factors: (1) actual biological duration of the disease process (systemic inflammation and CIRCI), (2) recovery time of the hypothalamic-pituitary-adrenal (HPA) axis, and (3) cumulative risk associated with prolonged treatment (risk) and the essential role of secondary prevention (risk reduction).

1. Longitudinal measurements of plasma and BAL inflammatory cytokine levels in ARDS showed that inflammation extends well beyond resolution of respiratory failure.^14,21,22 One uncontrolled study found that, despite prolonged methylprednisolone administration, local and systemic inflammation persisted for 14 days (limit of study).¹⁹ Similar findings were reported in an randomized controlled trial (RCT) for inflammatory mediators on day 10 of treatment.¹⁶

2. Prolonged GC treatment is associated with downregulation of the GR levels and suppression of the HPA axis (reviewed later), affecting systemic inflammation after discontinuing treatment. Experimental and clinical literature underscores the importance of continuing GC treatment beyond clinical resolution of acute respiratory failure (extubation).⁹ In the recent ARDS Network trial, methylprednisolone was removed within 3 to 4 days of extubation and likely contributed, as acknowledged by the authors, to the deterioration in PaO₂:FiO₂ ratio and higher rate of reintubation and associated mortality.^9,23 In 2 other ARDS trials,^17,24 GC treatment was continued for up to 18 days to maintain reduction in inflammation.^17,24 This prolonged GC treatment was not associated with relapse of ARDS.

3. Table 68–1 shows potential complications masked by or associated with prolonged GC treatment and secondary prevention measures.

• Infection surveillance—Failed or delayed recognition of nosocomial infections in the presence of a blunted febrile response represents a serious threat to the recovery of patients receiving prolonged GC treatment. In 2 randomized trials^17,24 that incorporated infection surveillance, nosocomial infections were frequently (56%) identified in the absence of fever. The infection surveillance protocol incorporated bronchoscopy with bilateral BAL at 5- to 7-days intervals in intubated patients (without contraindication) and a systematic diagnostic protocol when patients developed clinical and laboratory signs suggestive of infection in the absence of fever.²⁵

• Increased risk for neuromuscular weakness with neuromuscular blocking agents—The combination of GCs and neuromuscular blocking agents versus GCs alone increases the risk for prolonged neuromuscular weakness.²⁶ Consequently the combined use of neuromuscular blocking agents and GCs were considered contraindicated. However, Papazian and colleagues randomized patients with severe ARDS to receive cisatracurium besylate or placebo for 48 hours.²⁷ In this study, about 40% of patients were concomitantly receiving GCs. The incidence of neuromuscular weakness was similar in both groups. This study suggests that it may be safe to use GCs together with a short course of a neuromuscular blocking agent; however, the prolonged use of a neuromuscular blocking agent should be avoided.

• GC treatment can impair glycemic control—It is well established that exogenous GCs administered as a bolus produce hyperglycemic variability, an independent predictor of ICU and hospital mortality.²⁸ Two studies have shown that GC infusion is superior to intermittent boluses in preventing glycemic variability by decreasing changes in insulin infusion rate.^29,30

• Avoidance of rebound inflammation—There is ample evidence^{20,31,32,33,34,35,36,37} that early removal of GC treatment may lead to rebound inflammation and an exaggerated cytokine response to endotoxin.³⁸ Experimental work has shown that short-term exposure of alveolar macrophages³⁹ or animals to dexamethasone is followed by enhanced inflammatory cytokine response to endotoxin.⁴⁰ Similarly, normal human subjects pretreated with hydrocortisone had significantly higher tumor necrosis factor alpha (TNF-α) and IL-6 response after endotoxin challenge compared to controls.⁴¹ Two potential mechanisms may explain rebound inflammation: homologous downregulation and GC-induced adrenal insufficiency. GC treatment downregulates the GR levels in most cell types, thereby decreasing the efficacy of the treatment. The mechanisms of homologous downregulation have been reviewed elsewhere.⁴² Downregulation takes place at both the transcriptional and translational level, and hormone treatment decreases receptor half-life by approximately 50%.⁴² In experimental animals, overexpression of GRs improves resistance to endotoxin-mediated septic shock while GR blockade increases mortality.⁴³ No study (to the best of our knowledge) has investigated recovery of GR levels and function following prolonged GC treatment in patients with sepsis or ARDS.

Eight controlled studies (5 RCTs and three cohorts) have evaluated the effectiveness of prolonged GC treatment initiated before day 14 of early ALI/ARDS (N = 334)^24,44,45,46 and late ARDS (N = 235).^{17,23,47,48,49} These trials consistently reported that treatment-induced reduction in systemic inflammation^{17,23,24,45,46,47,49} was associated with significant improvement in PaO₂:FiO₂,^{17,23,24,45,46,47,49} and significant reductions in multiple-organ dysfunction score,^{17,23,24,45,47,49} duration of mechanical ventilation,^{17,23,24,44,45,46} and ICU length of stay (all with P values < 0.05).^{17,23,24,44,45} Four of the 5 randomized trials provided Kaplan Meier curves for continuation of mechanical ventilation; each showed a 2-fold or greater rate of extubation in the first 5 to 7 days of treatment.^17,23,24,45 In the ARDS Network trial, the treated group—before discontinuation of treatment—had a 9.5-days reduction in duration of mechanical ventilation (14.1 ± 1.7 vs 23.6 ± 2.9; P = 0.006) and more patients discharged home after initial weaning (62% vs 49%; P = 0.006).²³ As shown in Figure 68–1, GC treatment initiated before day 14 of ARDS was associated with a marked reduction in the risk of death (Relative Risk (RR) = 0.68, 95%CI: 0.56-0.81; P < 0.001; I² 56%).⁹ There was, however, significant heterogeneity between studies. As a result of the marked differences in study design and patient characteristics, the limited size of the studies (fewer than 200 patients), the cumulative mortality summary of these studies should be interpreted with some caution. For this reason, a recent consensus statement recommended early initiation of prolonged GC treatment for patients with severe ARDS (PaO₂:FiO₂ < 200 on PEEP 10 cm H₂O) and before day 14 for patients with unresolving ARDS.¹⁵ The ARDS Network trial reported that treated patients had increased mortality when randomized after day 14 of ARDS (8% vs 35%; P = 0.01).²³ This subgroup (N = 48), however, had large differences in baseline characteristics, and the mortality difference lost significance (P = 0.57) when the analysis was adjusted for these imbalances.⁵⁰

The most commonly cited complications that might temper enthusiasm for GC treatment include increased risks of infection and neuromuscular weakness. Substantial evidence has accumulated showing that systemic inflammation is also implicated in the pathogenesis of these complications,^51,52,53 suggesting that treatment-induced downregulation of systemic inflammation could theoretically prevent, or partly offset, their development and/or progression.

• GC treatment does not increase infection risk—Contrary to older studies investigating a time-limited (24-48 hours) massive daily dose of GCs (methylprednisolone, up to 120 mg/kg/day),^54,55 recent trials have not reported an increased rate of nosocomial infections. In fact, new cumulative evidence indicates that downregulation of life-threatening systemic inflammation with prolonged low-to-moderate dose GC treatment improves innate immunity^37,56 and provides an environment less favorable to the intracellular and extracellular growth of bacteria.⁵⁷ GCs, however, do blunt the signs and symptoms of infection as detailed above (Table 68–1).

• GC treatment does not increase the risk of neuromuscular weakness—The incidence of neuromuscular weakness is similar between groups treated with or without prolonged GCs (17% vs 18%).⁷ Two recent studies found no association between prolonged GC treatment and electrophysiologically or clinically proven neuromuscular dysfunction.^58,59 Given that neuromuscular dysfunction is an independent predictor of prolonged weaning⁶⁰ and ARDS randomized trials have consistently reported a significant reduction in duration of mechanical ventilation,^{17,23,24,45,46} clinically relevant neuromuscular dysfunction caused by GC or GC-induced hyperglycemia seems highly unlikely. It should be noted that the combination of GCs and neuromuscular blocking agents versus steroids alone significantly increases the risk for prolonged neuromuscular weakness (Table 68–1).²⁶

We have reviewed data showing that the benefit-risk of GC treatment in ARDS is largely determined by the drug dosage, timing and duration of administration, weaning protocol, and implementation of secondary preventive measures. The results of one randomized trial in patients with early severe ARDS²⁴ indicates that 1 mg/kg/day of methylprednisolone given as an infusion and tapered over 4 weeks is associated with a favorable risk-benefit profile when secondary preventive measures are implemented. Treatment response should be monitored with daily measurement of LIS and multiple-organ dysfunction syndrome (MODS) scores and C-reactive protein level.^24,45 Secondary prevention is important to minimize complications. GC treatment should be administered as a continuous infusion (while the patient is in ICU) to minimize glycemic variations.^29,30 GC treatment blunts the febrile response; therefore, infection surveillance is essential to identify early and treat nosocomial infections (as outlined above). Finally, a slow GC dosage reduction (9-12 days) after a complete course allows recovery of GR numbers and the HPA axis, thereby reducing the risk of rebound inflammation. Laboratory evidence of physiologic deterioration (ie, worsening PaO₂:FiO₂) associated with rebound inflammation (increased serum C-reactive protein) after the completion of GC treatment may require reinstitution of treatment.

As GCs have demonstrated a benefit in patients with established ARDS is has been postulated that these agents may be useful in preventing ARDS. Four studies have tested this hypothesis; however, this strategy was associated with a trend to an increase in both the odds of developing ARDS and the risk of mortality in those who developed ARDS.⁵ The reason for the seemingly differential effect of preventative and therapeutic steroid therapy in ARDS is unclear. In a propensity-based analysis of a large hospital database, the concurrent use of corticosteroids at the time of hospitalization did not reduce the risk of developing ARDS nor did it affect the requirement for mechanical ventilation or influence mortality.⁶¹

In this review, we presented a rationale for the use of GC treatment in ARDS. Based on molecular mechanisms and physiologic data, a strong association between dysregulated inflammation and progression of ARDS has been established. Further, these data support a strong association between treatment with exogenous GCs leading to regulation of the inflammatory response, improvement in organ physiology (LIS, MODS), and resolution of ARDS. The available clinical trials of prolonged GC treatment show favorable effects on clinical outcomes including ventilator-free days, ICU-free days, and mortality. Although the balance of the available data from controlled trials provides strong evidence for improvement in patient-centered outcomes (sizable reduction in duration of mechanical ventilation and ICU length of stay) and weak evidence for a survival benefit, the findings recently reported with low-dose methylprednisolone (1 mg/kg/day) in early severe ARDS²⁴ should be replicated in a larger trial of patients with ALI/ARDS.