CAPE-COD: Hydrocortisone in Severe CAP
Clinical Question
In patients with severe community acquired pneumonia (CAP) does the use of hydrocortisone compared to a placebo reduce 28-day mortality?
Type of Trial: Placebo controlled multi-centre randomized control trial
Blinding: Double blind
Setting: 31 French centres from October 2015-March 2020
PICO
Population:
800 randomized >18 years old, admitted to ICU, CAP diagnosed suggested by >/= 2 (cough, purulent sputum, chest pain, dyspnea), focal shadowing on CXR/CT scan, Severe disease defined by one of four criteria (Pulmonary severity index>130, mechanical ventilation, HFNC with FiO2>0.5 and P/F<300, rebreathing mask with P/F ratio dependent on O2 flow (e.g. >10L the P/F<300), at least one dose of abx given
Excluded:
treated by vasopressors for septic shock at time of inclusion, clinical history suggesting aspiraiton, on vent>14 days, >7 days antibiotics prior, PCR positive for influenza, use of >15mg prednisone or equivalent for >/= 30 days, pregnancy, CF, TB or fungal infection, active viral hepatitis
Intervention:
Hydrocortisone
200mg/day for 4 days
Treating team using predefined criteria decided whether to administer for a total of 8 or 14 days with a prespecified tapering plan
8 days total if all of the following met on day 4: P/F > 200, breathing spontaneously and day 4 SOFA ≤ the SOFA score on day 1
Median duration 5 days
Control:
Treatment discontinued on ICU discharge
Other management (including choice of respiratory support) at discretion of treating teams but should follow standard therapy
Outcome:
1st Primary outcome: death by day 28
Hydrocortisone 6.2% vs Placebo 11.9% (p=0.006)
2nd Primary outcome:
Median daily dose of insulin by day 7: 35.5 in intervention group vs 20.0 IU/day in placebo
Death by day 90: 9.3% in intervention group vs 14.7%
Cumulative incidence of endotracheal intubation by day 28: 18.0 in intervention group vs 29.5%
Cumulative incidence of endotracheal intubation by day 28 in those not receiving at baseline: 19.5% in intervention group vs 27.7%
Cumulative incidence of vasopressor initiation by day 28 in those not receiving at baseline: 15.3 in intervention group vs 25.0%
Conclusions
Early treatment with hydrocortisone reduced 28-day mortality in those admitted to the ICU with severe CAP. Following this trial, I will now strongly consider the use of steroids in patients admitted with severe CAP.
Strengths
Multi-centre, double blind, placebo-controlled trial
Balanced baseline characteristics – especially with respect to other classically steroid responsive conditions such as COPD and asthma
Early initiation of hydrocortisone – initiated within ~20 hours from hospital admission
Minimal apparent selection bias – of the 5148 excluded, very few were for reasons other than the pre-defined exclusion criteria (n = 276 “medical team declined” and n = 79 “no reason provided”)
Minimal loss to follow up (2 patients)
The exclusion of septic shock sensible given potential benefits shown with the use of steroids in this patient cohort
Included patients who clearly had severe CAP with respect to ventilatory support required at randomisation and PSI score
High level of adherence to protocol with very few protocol violations
Only 6% received open label steroids
Weaknesses
Single country
Although 800 patients randomised there were lower mortality numbers than predicted
Only 72 deaths across both arms with a fragility index 6 patients
Optimal steroid and steroid regimen (e.g. tapered or not) yet to be determined especially with differing pharmacological properties
The benefit of dexamethasone shown in COVID-19 in the RECOVERY trial and ARDS patients in DEXA-ARDS trial
Microbiological investigation not standardized
~45% no pathogen identified
The subgroup in which no pathogens were isolated trended to favouring steroid use compared to those in whom a pathogen was isolated (Figure S3)
Sources:
https://www.thebottomline.org.uk