Do Steroids Decrease Mortality in Severe CAP?

Do steroids decrease mortality in patients with severe community acquired pneumonia?

Community acquired pneumonia is the leading cause of death from infection, approaching 10% mortality. In those patients who are mechanically ventilated, mortality may be as high as 30%. Glucocorticoids have been associated with positive effects in community acquired pneumonia, however they have not been shown to change mortality.

Dequin PF et al (1) conducted the Community-Acquired Pneumonia: Evaluation of Corticosteroids (CAPE COD) Trial.

What They did

This was a double-blind, randomised, controlled, superiority trial.
It was conducted in 31 French ICUs.
N=800
Intravenous hydrocortisone, 200mg, was given within 24 hours of onset of severity criteria (median time < 15 hours). It was continued for 4 days and then changed according to pre-defined criteria.

Severe community acquired pneumonia was defined by at least one of the following criteria being present:

• Initiation of invasive or non-invasive ventilation with a PEEP of > 5cm H2O
• Administration of Oxygen through HFNC with PaO2:FiO2 of < 300 where FiO2 > 50%.
• In patients with a non-rebreather mask PaO2:FiO2 of < 300
• Score >130 on the Pneumonia Severity Index. This is defined as a Risk Class V, which is associated with a 29% mortality.

The exclusion criteria included a diagnosis of influenza, (as it has been associated with worst outcomes when glucocorticoids are given) and septic shock.

Primary Outcomes
Death from any cause at 28 days

Secondary Outcomes

• Death from any cause at 90 days
• Length of ICU stay
• NIV or intubation in those who were not receiving any ventilation at baseline.
• Endotracheal intubation in those receiving non-invasive ventilation.
• Initiation of vasopressors at day 28
• Number of ventilator and vasopressor free days by day 28
• Change in PaO2:FiO2 by day 7
• Change in SOFA Score by day 7.

What did they find?

Primary outcome

At 28 days death rate was lower in the hydrocortisone group (6.9% vs 11.9%)

Secondary Outcomes

• Mortality by day 90 was lower in the hydrocortisone group (9.3% vs 14.7%)
• For patients with no mechanical ventilation at baseline, endotracheal intubation was performed in 18% in the hydrocortisone group vs 29.5% in the placebo group.
• For patients who had not received vasopressors at baseline, less patients required vasopressors in the hydrocortisone group (15.3% vs 25%)
• Patients in the hydrocortisone group required more insulin  (medial of 35.5 IU vs 20.5 IU)

Conclusions of this study
Hydrocortisone decreased mortality by day 28 for patients admitted to ICU. It was not associated with an increase in hospital acquired infections or gastrointestinal bleeding.

My take on this.
This is an interesting study and one that shows a significant positive effect of steroids in severe community acquired pneumonia as defined by the parameters of this study.

Prior trials, although showing positive effects of steroids, found that they had no effect on mortality. The largest trial before this, (2) was a double-blind, randomised, placebo-controlled trial, which was conducted in 42 centres in the US. N= 584. Patients were treated with 40mg of methylprednisolone within 72-96 hours after admission, for the first 7 days and then this was reduced as per protocols. In this trial the primary outcome was all-cause mortality at 60 days. Secondary outcomes included, vasopressor dependent shock, ARDS, ICU stay and more.

Their conclusion was no significant reduction in 60 day mortality (16% steroids vs 18% placebo) or mortality up to 1 year.

Why’s is there such a difference in findings between the two trials?

Some of the differences between these trials included:

• US vs French ICUs
• Time to first dose of steroids, within 24 hours in the French study vs up to 96 hours in the US study.
• Methylprednisolone 40mg vs Hydrocortisone 200mg ( although these are equivalent doses)
• Open-label glucocorticoids was given in < 5% of those who developed shock in the US trial
• A significant number of patients in the US study were men (96% vs 69%). There was subgroup analysis however that showed a greater benefit in women.

Final word
Previous trials have shown a trend towards a benefit when steroids are used in severe community acquired pneumonia, but no mortality benefit. This trial however does show a benefit. Given they was no increase in mortality, it’s reasonable to say that glucocorticoids should be considered at < 24 hours in patients meeting the criteria for severe community acquired pneumonia in the CAPE COD Trial, but not in septic shock or with influenza, that require ICU and needing high flow oxygen for respiratory failure.

References

1. Dequin PF et al. Hydrocortisone in Severe Community Acquired Pneumonia. NEJM 388;21 May 25 2023 pp1931-1941. https://pubmed.ncbi.nlm.nih.gov/36942789/
2. Meduri UG et al. Low-dose methylprednisolone treatment in critically ill patients with severe community- acquired pneumonia. Intensive care med (2002) 48:1009-10023. https://pubmed.ncbi.nlm.nih.gov/35723686/