Efficacy of DEXamethasone in Patients With Acute Hypoxemic REspiratory Failure Caused by INfEctions

Official title

Efficacy of Higher vs. Lower Doses of Dexamethasone in Patients With Acute Hypoxemic Respiratory Failure (Including ARDS) Caused by Infections (Including COVID-19)

Overview

Background: There are no proven therapies specific for pulmonary dysfunction in patients with acute hypoxemic respiratory failure (AHRF) caused by infections (including Covid-19). The full spectrum of AHRF ranges from mild respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure, and death. The efficacy of corticosteroids in AHRF and ARDS caused by infections remains controversial. Methods: This is a multicenter, randomized, controlled, open-label clinical trial testing dexamethasone in mechanically ventilated adult patients with established AHRF (including ARDS) caused by confirmed pulmonary or systemic infections, admitted in a network of Spanish ICUs. Eligible patients will be randomly assigned to receive dexamethasone: either 6 mg/d x 10 days or 20 mg/d x 5 days followed by 10 mg/d x 5 days. The primary outcome is 60-day mortality. The secondary outcome is the number of ventilator-free days at 28 days. All analyses will be done according to the intention-to-treat principle.

Detailed description

Acute hypoxemic respiratory failure (AHRF), and its more severe form termed the acute respiratory distress syndrome (ARDS), is a catastrophic illness of multifactorial etiology characterized by a severe inflammatory process of the lung leading to hypoxemic respiratory failure requiring mechanical ventilation (MV). Pulmonary infections are the leading causes of AHRF and ARDS. Translational research has established a strong association between dysregulated systemic and pulmonary inflammation and progression or delayed resolution of AHRF.2 Glucocorticoid receptor-mediated downregulation of systemic and pulmonary inflammation is essential to accelerate disease resolution and restore tissue homeostasis, and can be enhanced with glucocorticoid treatment.

The COVID-19 pandemic is a critical moment for the world, in which even industrially advanced countries have rapidly reached intensive care units (ICUs) saturation, and intensivists are forced to make difficult ethical decisions that are uncommon outside war zones. As with other bacterial or viral infections, severe pneumonia is the main condition leading to AHRF and ARDS requiring weeks of MV with high mortality (35-55%) in critically ill patients. There has been great interest in the role of corticosteroids to attenuate the pulmonary and systemic damage in ARDS patients because of their potent anti-inflammatory and antifibrotic properties.3 Corticosteroids have been off patent for greater than 20 years, they are cheap, and globally equitable. However, the efficacy of corticosteroids in AHRF (including ARDS) caused by infections remains controversial.

Only two large randomized clinical trials (RCT) have shown that the administration of dexamethasone is able to reduce mortality in patients with AHRF. Villar et al in Spain observed that moderate doses of dexamethasone (10-20 mg/d x 10 days) caused a 15% absolute reduction of 60-day mortality in patients with established moderate-to-severe ARDS from multiple etiologies. Horby et al in the RECOVERY trial in Great Britain reported that dexamethasone at low doses (6 mg/d x 10 days) reduced 28-day mortality in patients with AHRF caused by COVID-19. These findings confirmed that corticosteroid therapy is associated with a sizable reduction in duration of MV and hospital mortality. These two RCTs will change clinical practice for the management of AHRF and ARDS. However, there is a reasonable doubt whether dexamethasone at moderate doses (10-20 mg/d) would cause a greater reduction in mortality than 6 mg/d. Our goal in this study is to respond this question.

Interventions

• Drug Dexamethasone
  Intravenous dexamethasone (low vs. moderate doses) during 10 days

Primary outcome measures

• 60-day mortality [Time frame: 60 days]

Secondary outcome measures (1)

• Ventilator-free days [Time frame: 28 days]

Eligibility criteria

Inclusion criteria

• age 18 years or older;
• intubated and mechanically ventilated;
• acute onset of AHRF (as defined by a PaO2/FiO2 ≤300 mmHg during at least 6 hours from diagnosis. For the measurement of PaO2 and calculation of PaO2/FiO2 ratio, the minimum accepted value for PEEP is 5 cmH2O and for FiO2 is 0.3. ARDS is defined by Berlin criteria,4 which includes: (i) having pneumonia or worsening respiratory symptoms, (ii) bilateral pulmonary infiltrates on chest imaging (x-ray or CT scan), (iii) absence of left atrial hypertension or no clinical signs of left heart failure, and (iv) hypoxemia, as defined by a PaO2/FiO2 ≤300 mmHg on positive end-expiratory pressure (PEEP) of ≥5 cmH2O, regardless of FiO2.
• Pulmonary or systemic infectious etiology of AHRF.

Exclusion criteria

• Patients with a known contraindication to corticosteroids,
• Patient included in another therapeutic clinical trial
• Lack of informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 40 centers

• Hospital Universitario Mutua Terrassa (ICU) — Terrassa
• Hospital General La Mancha Centro (ICU) — Alcázar de San Juan
• Complejo Hospitalario Universitario de Santiago (Anesthesia) — Santiago de Compostela
• Hospital General El Bierzo (ICU) — Ponferrada
• Hospital Universitario del Henares (ICU) — Coslada
• Hospital Universitario de Getafe (ICU) — Getafe
• Hospital Universitario Severo Ochoa (ICU) — Leganés
• Hospital Universitario Puerta de Hierro (ICU) — Majadahonda
• … and 32 more centers

Publications

• Villar J, Ferrando C, Martinez D, Ambros A, Munoz T, Soler JA, Aguilar G, Alba F, Gonzalez-Higueras E, Conesa LA, Martin-Rodriguez C, Diaz-Dominguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Anon JM, Fernandez RL, Gonzalez-Martin JM; dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled PMID 32043986
• RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693- PMID 32678530

Identifiers

NCT: NCT04545242 · ICI20-00062

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗