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)
Brief Summary

Background: There are no proven therapies specific for pulmonary dysfunction in patientswith acute hypoxemic respiratory failure (AHRF) caused by infections (includingCovid-19). The full spectrum of AHRF ranges from mild respiratory tract illness to severepneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure, and death. Theefficacy of corticosteroids in AHRF and ARDS caused by infections remains controversial.Methods: This is a multicenter, randomized, controlled, open-label clinical trial testingdexamethasone in mechanically ventilated adult patients with established AHRF (includingARDS) caused by confirmed pulmonary or systemic infections, admitted in a network ofSpanish 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 primaryoutcome is 60-day mortality. The secondary outcome is the number of ventilator-free daysat 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.

Recruiting
Acute Hypoxemic Respiratory Failure

Drug: Dexamethasone

Intravenous dexamethasone (low vs. moderate doses) during 10 days
Other Name: Decadron,Dexasone,Diodex

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

Eligibility Gender
All
Eligibility Age
Minimum: 18 Years ~ Maximum: N/A
Countries
Spain
Locations

Hospital Universitario Mutua Terrassa (ICU)
Terrassa, Barcelona, Spain

Hospital General La Mancha Centro (ICU)
Alcazar de San Juan, Ciudad Real, Spain

Complejo Hospitalario Universitario de Santiago (Anesthesia)
Santiago De Compostela, La Coruña, Spain

Hospital General El Bierzo (ICU)
Ponferrada, León, Spain

Hospital Universitario del Henares (ICU)
Coslada, Madrid, Spain

Hospital Universitario de Getafe (ICU)
Getafe, Madrid, Spain

Hospital Universitario Severo Ochoa (ICU)
Leganés, Madrid, Spain

Hospital Universitario Puerta de Hierro (ICU)
Majadahonda, Madrid, Spain

Hospital Nuestra Señora del Prado (ICU)
Talavera De La Reina, Toledo, Spain

Hospital Universitario de Cruces (Anesthesia)
Barakaldo, Vizcaya, Spain

Hospital Universitario de Cruces (ICU)
Barakaldo, Vizcaya, Spain

Complejo Hospitalario Universitario de Albacete (ICU)
Albacete, Spain

Hospital Clinic de Barcelona (AVI)
Barcelona, Spain

Hospital Clinic de Barcelona (Cardiac ICU)
Barcelona, Spain

Hospital Clínic (Hepatic ICU)
Barcelona, Spain

Hospital Clínic de Barcelona (Anesthesia)
Barcelona, Spain

Hospital General de Ciudad Real (ICU)
Ciudad Real, Spain

Hospital Virgen de la Luz (ICU)
Cuenca, Spain

Hospital Universitario de A Coruña (ICU)
La Coruña, Spain

Complejo Asistencial Universitario de León (ICU)
León, Spain

Hospital Universitario La Princesa (ICU)
Madrid, Spain

Hospital Universitario Ramón y Cajal (Anesthesia)
Madrid, Spain

Hospital Clínico Universitario San Carlos (ICU)
Madrid, Spain

Hospital Universitario Fundación Jiménez Díaz (ICU)
Madrid, Spain

Hospital Universitario Doce de Octubre (ICU)
Madrid, Spain

Hospital Universitario La Paz (Anesthesia)
Madrid, Spain

Hospital Universitario La Paz (ICU)
Madrid, Spain

Hospital Universitario Virgen de Arrixaca (Anesthesia)
Murcia, Spain

Hospital Universitario Virgen de Arrixaca (ICU)
Murcia, Spain

Hospital Universitario Regional de Malaga Carlos Haya (ICU)
Málaga, Spain

Clínica Universidad de Navarra
Pamplona, Spain

Hospital Universitario Montecelo (Anesthesia)
Pontevedra, Spain

Hospital Universitario Nuestra Señora de Candelaria (ICU)
Santa Cruz De Tenerife, Spain

Hospital General de Segovia (ICU)
Segovia, Spain

Hospital Clinico Universitario de Valencia (Anesthesia)
Valencia, Spain

Hospital Clinico Universitario de Valencia (ICU)
Valencia, Spain

Hospital Clínico Universitario de Valladolid (Anesthesia)
Valladolid, Spain

Hospital Universitario Río Hortega (Anesthesia)
Valladolid, Spain

Hospital Universitario Río Hortega (ICU)
Valladolid, Spain

Hospital Virgen de la Concha (ICU)
Zamora, Spain

Contacts

Jesús Villar, MD
+34606860027
jesus.villar54@gmail.com

Arthur Slutsky, MD
+14168244000
Arthur.Slutsky@unityhealth.to

Jesús Villar, MD, Principal Investigator
Hospital Universitario Dr. Negrin

Dr. Negrin University Hospital
NCT Number
Keywords
acute respiratory failure
ARDS
Mechanical Ventilation
Infection
MeSH Terms
Infections
Respiratory Insufficiency
Dexamethasone