COVID-19 infection is overwhelming Italian healthcare. There is an urgent need for a solution to the lack of ICU beds and increasing deaths day after day. A recent retrospective Chinese paper (JAMA Intern Med, online March 13, 2020) showed impressive positive effect of methylprednisolone (MP) on survival of SARS-CoV-2 critically ill patients. Moreover, the Italian Infectious Disease leading institution guidelines for COVID-19 clinical management included as an option for patients with "incipient worsening of respiratory functions" methylprednisolone treatment at an approximate dose of 80mg. The main objective of this multi-centre observational trial is to analyse the association of low dose prolonged infusion of methylprednisolone (MP) for patients with severe acute respiratory syndrome with composite primary end-point (ICU referral, need for intubation, in-hospital death at day 28).
Comparison of two groups of patients SARS-CoV-2 positive with severe acute respiratory
syndrome:
1. Exposed to low prolonged doses of Methylprednisolone
2. Not exposed to corticosteroids (standard of care alone)
The two group will be weighted by means of a propensity score according to:
1. Sex
2. Age
3. C-reactive protein (CRP) at baseline
4. Sequential Organ Failure Assessment (SOFA) score at baseline
5. PaO2/FiO2 ratio at baseline (ratio of arterial oxygen partial pressure to fractional
inspired oxygen)
Anti-viral agents, chloroquine, respiratory support (any), and antibiotics (any) are allowed
in each study group. Corticosteroids use, other than per-protocol Methylprednisolone in the
exposed group is a reason for dropout.
1. The exposed group is treated with Methylprednisolone at study entry (baseline) according
to a protocol based on the Italian national recommendations for COVID-19 management: a
loading dose of 80 mg IV, followed by an infusion of 80 mg/day in 240 mL normal saline
at 10 mL/h. The infusion is continued for at least eight days and until achieving either
a PaO2:FiO2 > 350 mmHg or a CRP < 20 mg/L. Treatment is then switched to oral
administration of Methylprednisolone 16 mg or 20 mg IV twice daily until CRP returns to
< 20% of normal range and/or PaO2:FiO2 > 400 or SatHbO2 ≥ 95%. The decision to apply the
protocol to Covid-19 is left to the discretion of the treating team for each individual
patient.
2. Unexposed patients will be selected from concurrent consecutive COVID-19 patients with
the same inclusion and exclusion criteria and blinded to outcome data.
Drug: Methylprednisolone
Usual standard of care plus Methylprednisolone (MP) 80 mg/kg IV bolus, followed by MP infusion of 80 mg/day in 240 mL normal saline at 10 mL/h. The infusion is continued for at least eight days and until achieving either a PaO2:FiO2 > 350 mmHg or a CRP < 20 mg/L. Treatment is then switched to oral administration of Methylprednisolone 16 mg or 20 mg IV twice daily until CRP returns to < 20% of normal range and/or PaO2:FiO2 > 400 or SatHbO2 ≥ 95%. The decision to apply the protocol to Covid-19 is left to the discretion of the treating team for each individual patient.
Other: standard care
usual standard of care:
oxygen therapy (regular or high-flow) and monitoring
empiric antibiotic therapy
mechanical ventilation (invasive or noninvasive)
ECMO when needed and available
pronation when possible
other treatment which can be used are: antivirals, chloroquine, vitamins
Inclusion Criteria:
1. SARS-CoV-2 positive
2. Age >17 years and < 80 years
3. P/F < 250 mmHg
4. Bilateral pneumonia (infiltrates/interstitial)
5. CRP >10mg/dL (or >100mg/L)
6. Alternatively to 4-5-6 criteria a diagnosis of ARDS according to the Berlin definition
(Ranieri M, et al. JAMA 2012)
Exclusion Criteria:
- Heart failure as predominant cause of acute respiratory failure
- Decompensated liver cirrhosis
- Cancer
- Organ transplantation
- HIV+
- dialysis
- long-term oxygen therapy, home mechanical ventilation
- Idiopathic pulmonary fibrosis
- Progressive neuromuscular disorders (e.g. Duchenne, Pompe, ALS)
- Dementia or decompensated psychiatric diseases
- immunosuppressive treatments
- Chronic use of corticosteroids
- Use of Tocilizumab
- pregnancy
Marco Confalonieri
Trieste, TS, Italy
Marco Confalonieri, MD, Principal Investigator
University of Trieste