Rationale for Prolonged Glucocorticoid Use in Pediatric ARDS: What the Adults Can Teach Us

Abstract

Based on molecular mechanisms and physiologic data, a strong association has been established between dysregulated systemic inflammation and progression of acute respiratory distress syndrome (ARDS). In ARDS patients, glucocorticoid receptor-mediated downregulation of systemic inflammation is essential to restore homeostasis, decrease morbidity and improve survival and can be significantly enhanced with prolonged low-to-moderate dose glucocorticoid treatment. A large body of evidence supports a strong association between prolonged glucocorticoid treatment-induced downregulation of the inflammatory response and improvement in pulmonary and extrapulmonary physiology. The balance of the available data from eight controlled trials (n = 622) provides consistent strong level of evidence for improving patient-centered outcomes and hospital survival. The sizable increase in mechanical ventilation-free days (weighted mean difference, 6.48 days; CI 95% 2.57-10.38, p < 0.0001) and intensive care unit-free days (weighted mean difference, 7.7 days; 95% CI, 3.13-12.20, p < 0.0001) by day 28 is superior to any investigated intervention in ARDS. For treatment initiated before day 14 of ARDS, the increased in hospital survival (70 vs. 52%, OR 2.41, CI 95% 1.50-3.87, p = 0.0003) translates into a number needed to treat to save one life of 5.5. Importantly, prolonged glucocorticoid treatment is not associated with increased risk for nosocomial infections (22 vs. 27%, OR 0.61, CI 95% 0.35-1.04, p = 0.07). Treatment decisions involve a tradeoff between benefits and risks, as well as costs. This low-cost, highly effective therapy is familiar to every physician and has a low risk profile when secondary prevention measures are implemented.

Keywords: acute respiratory distress syndrome; glucocorticoid treatment; mechanical ventilation; survival.

Figure 1

Interaction between NF-κB and the activated glucocorticoid receptor. Reproduced from Ref. (3) with permission from S. Karger AG, Medical and Scientific Publishers (Allschwilerstrasse 10, 4009 Basel, Switzerland). When cells are stimulated by inflammatory signals, specific kinases phosphorylate the inhibitory protein IκB and cause its rapid degradation. The activated form of NF-κB then moves to the nucleus initiating the transcription of mRNA of inflammatory cytokines, chemokines, cell adhesion molecules, and inflammation-associated enzymes (cyclooxygenase, phospholipase A2, and inducible nitric oxide). Cortisol or exogenous glucocorticoids freely cross into the cytoplasm and bind to their specific glucocorticoid receptors (GRα) to form the activated receptor (GC-GRα). GC-GRα complexes may influence NF-κB activity in five major ways: (1) physically interacting with the p65 subunit with formation of an inactive (GC-GRα/NF-κB) complex (4, 5), (2) inducing the synthesis of the inhibitory protein IκBα via interaction with glucocorticoid-responsive element DNA in the promoter of the IκB gene (–7), (3) blocking degradation of IκBα via enhanced synthesis of IL-10 (–10), (4) impairing TNF-α-induced degradation of IκBα (11, 12), and (5) competing for limited amounts of GR coactivators, such as CREB-binding protein (CBP) and steroid receptor coactivator-1 (SRC-1) (13). IκBα, in addition to holding NF-κB in an inactive cytoplasmic state (–7), also translocates into the nucleus, where it binds activated NF-κB complexes to induce their export to the cytoplasm (4). GC-GRα may also decrease the stability of mRNA of several inflammatory cytokines and other molecules (14). Products of the genes that are stimulated by NF-κB activate this transcription factor. Thus, both TNF-α and IL-1β activate and are activated by NF-κB, by forming a positive regulatory loop that amplifies and perpetuates inflammation (15). Regulated response: GC-GRα activation sufficient to maintain NF-κB levels in homeostasis and achieve a reduction in transcription of inflammatory mediators over time is shown. In ARDS improvers, both GC-GRα binding to NF-κB and nuclear GC-GRα binding increased significantly over time, indicating an excess activation of GC-GRα compared to NF-κB (GC-GRα-driven response). Dysregulated response: an excess of NF-κB activation is shown, leading to protracted transcription of inflammatory mediators over time. In ARDS non-improvers, GC-GRα binding to NF-κB was modestly increased while nuclear NF-κB binding increased substantially over time and nuclear GC-GRα and cytoplasmic IκBα levels declined (NF-κB-driven response).

Figure 2

Longitudinal relation on natural logarithmic scales between mean levels of nuclear NF-κB and nuclear GRα: resolving vs. unresolving ARDS (left) and after randomization to methylprednisolone vs. placebo (right). Data shown are from Ref. (3, 25). Left: plasma samples from patients with sustained elevation in cytokine levels over time (triangles) elicited only a modest longitudinal increase in GC-GRα-mediated activity (P = 0.04) and a progressive significant (P = 0.0001) increase in NF-κB nuclear binding over time (dysregulated, NF-κB-driven response). In contrast, in patients with regulated inflammation (squares), an inverse relation was observed between these two transcription factors, with the longitudinal direction of the interaction shifting to the left (decreased NF-κB) and upward (increased GC-GRα). The first interaction is defined as NF-κB-driven response (progressive increase in NF-κB–DNA binding and transcription of TNF-α and IL-1β) and the second interaction as GRα-driven response (progressive increase in GRα-DNA binding and transcription of IL-10 and repression of TNF-α and IL-1β). Right: longitudinal relation on natural logarithmic scales between mean levels of nuclear NF-κB and nuclear GRα observed by exposing naive PBL to plasma samples collected at randomization (rand) and after 3, 5, 7, and 10 days in the methylprednisolone (squares) and placebo (triangles) groups. With methylprednisolone, contrary to placebo, the intracellular relation between the NF-κB and GRα signaling pathways changed from an initial NF-κB-driven and GR-resistant state to a GRα-driven and GR-sensitive one. It is important to compare the two figures to appreciate how methylprednisolone supplementation restored the equilibrium between activation and suppression of inflammation that is distinctive of a regulated inflammatory response.

Figure 3

Patients, in each trial, alive on study day 8, 15, 22, and 29 that received at least 7, 14, 21, and 28 days of methylprednisolone treatment. N value within each column reports patients alive on the specified day. *P < 0.001 in comparison to the other three trials. Reproduced with permission (58).

Figure 4

Probability of achieving unassisted breathing from randomization (methylprednisolone vs. placebo) to hospital discharge or day 28. Estimated cumulative incidence of achieving (initial) unassisted breathing by day 28 for patients with ARDS (n = 322) receiving either prolonged methylprednisolone treatment (blue solid line) or usual care (green dashed line). Death before achieving unassisted breathing is considered a competing risk. By day 28, the methylprednisolone group achieved initial UAB earlier (12.4 ± 0.61 vs. 19.8 ± 0.78 days; HR 2.59, 95% CI 1.95–3.43, p < 0.001). Reproduced with permission (58).