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Journal club Feb 2015

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Jafar Ahmed

on 5 April 2016

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Transcript of Journal club Feb 2015

DCCM journal club Feb 2015
Jafar Ahmed

Why this study?
Pneumonia is the leading infectious cause of death in developed countries
Steroids in sepsis - recurrent theme in various forms
Recently a few medical, elderly'ish' patients with lower resp tract infection
Background
Pneumonia still has a very high mortality , especially those with severe pneumonia or treatment failure
Treatment failure can be used as a surrogate parameter for excess mortality
Excessive host response associated with treatment failure (during ICU stay) and mortality (IL6,8,10)
Corticosteroids modulate this inflammatory response in pneumonia
However use of steroids in clinical practice remains controversial


Study design
Multi-centre : 3 Spanish teaching hospitals
Prospective
Randomized
Double-blind
Placebo-controlled
June 2004 to Feb 2012
Local ethics committee approval
Written informed consent from participants or authorized representative
Inclusion/Exclusion
1. 18 years or older
2. Clinical symptoms (cough, fever, pleuritic CP, SOB)
3. New CXR infiltrate
4. Met severe CAP criteria by modified ATS criteria or class V for PSI
5. had a CRP >150 mg/L
Intervention
IV bolus of 0.5 mg/kg methylprednisolone every 12 hours for 5 days vs placebo started within 36 hours of admission

1:1 allocation of pre-numbered boxes. Patients, investigators and data assessors blinded to treatment allocation

Standard antibiotic treatment
Outcome measures
Statistics
Studies with steroids in CAP
Most studies did not include patients with severe CAP and all did not consider level of inflammation
Studies showing benefit
Confalonieri M, Urbino R, Potena A, et al.Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med. 2005; 171(3):242-248.
Garcia-Vidal C, Calbo E, Pascual V, Ferrer C,Quintana S, Garau J. Effects of systemic steroids in patients with severe community-acquired pneumonia. Eur Respir J. 2007;30(5):951-956.
Fernández-Serrano S, Dorca J, Garcia-Vidal C,et al. Effect of corticosteroids on the clinical course of community-acquired pneumonia: a randomized controlled trial. Crit Care. 2011;15(2):R96.
Meijvis SC, Hardeman H, Remmelts HH, et al.Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377(9782):2023-2030.

No benefit
Salluh JI, Soares M, Coelho LM, et al. Impact ofsystemic corticosteroids on the clinical course and outcomes of patients with severe community-acquired pneumonia: a cohort study. J Crit Care. 2011;26(2):193-200.
Hypothesis:
Corticosteroids may modulate cytokine release - reducing inflammation may be followed by decrease in treatment failure in CAP - those most likely to benefit "severe CAP and high inflammatory response"
1. Prior treatment with systemic steroids
2. nosocomial pneumonia
3. reported severe immunosuppression (HIV, medications/conditions)
4. Prior life expectancy <3 months
5. uncontrolled diabetes
6. major GI bleed in 3 months
7. Condition requiring higher dose of steroids
8. H1N1 influenzae
Primary end-points
Treatment failure
Early - clinical deterioration within 72 hrs (shock, new need for invasive ventilation or death)
Late -
radiographic progression (>50% of pulmonary infiltrates)
persistence of severe resp failure (PaO2:FIO2 <200mmHg with RR>30 in unintubated)
Development of shock
New need for invasive mechanical ventilation
death between 72 and 120 hours after Rx
Early or late
Secondary end-points
Time to clinical stability
Temp <37.2, HR <100, sBP >90, PaO2 >60 mmHg on air
Length of ICU and hospital stay
In hospital mortality

Oral switch - when IV switched to orals of the same class
Investigations
Microbiology - (on presentation) - Sputum, x2 Blood cultures, urine, Nasopharyngeal swab +/- thoracocentesis/ BAL

Standard bloods - renal/liver, BSL, CRP, Haem
ABG on presentation

Special tests - IL-6, IL-8, IL-10, procalcitonin, CRP on day 0, day 3, day 7
Adverse events
Hyperglycaemia
Superinfection
Gastrointestinal bleeding
Delerium
acute kidney injury
acute hepatic failure
Assumption - treatment failure 35% .

Neumofail group - total treatment failure rate of 15% and mortality rate of 25% with treatment failure

80% power to detect an ARR 20% in treatment failure - sample size - 60 in each

Not powered to detect mortality, assumed treatment failure important
Interim analysis - no significant difference with groups

Efficacy data - ITT (all randomised patients who received at least one dose of the study drug vs per-protocol analysis (all randomised patients who received at least 6 doses of study drug and no serious deviation from protocol)

The primary and secondary outcomes were analysed both without adjustment for variables and potential confounders- 2 predefined year or admission and centre and all variables with imbalance between two at baseline.

Post-hoc sub analysis according to treatment failure and late treatment failure that did not include radiological progression.

Standard statistical tools or categorical and continuous (normal and normal distribution). 95% confidence intervals

Results
Patient Allocation and exclusion
519 patients screened
120 randomised
112 (93%) completed study
Baseline characteristics
Lower levels of procalcitonin and IL-10 at day 1, lower proportion of septic shock in methylprednisolone

No difference in time to first antiobiotics (in patients with or without shock) or duration of antibiotics (wherever the patient)

Antibiotic treatment similar in both groups (Ceftriaxone + levoflox + Azi)

Rate of etiological diagnosis higher in MP group (Strep pneumo) but distribution of pathogens didn't differ

Initial adequacy of Abx treatment (according to guidelines) similar (97%)- where microbiology available - 16/17 (94%) placebo group vs all 26 patients in MP
Clinical outcomes
Less treatment failure in MP 8 (13%) vs placebo 18 (31%) - due to fewer cases of late treatment failure (mainly radiological progression)
Similar results on per-protocol analysis

Post hoc subanalysis - ITT significant difference in late failure that didn't include radiological progression [8 (14%) vs 2 (3%)]
Per-treatment protocol no significant difference p=0.05

Logistical regression analysis - Methylpred reduced treatment failure both without adjustment for baseline variables and with adjustment for septic shock, procalcitonin and IL-10. Late treatment failure - both intention to treat and per-protocol

Time to treatment failure differed significantly between groups

Proportion of patients with septic shock or mechanical ventilation didn't differ
Secondary outcomes and adverse events
No significant differences in secondary outcomes

In hospital mortality didn't differ [6(10%) vs 9(15%), p0.37] even after adjustment for confounders and causes of death similar

At day 3 , CRP and IL-10 decreased more in MP and this was sustained at day 7. Patients with persistently high inflammation at day 7 had higher treatment failure and mortality

Hyperglycaemia - [11(18%) vs 7(12%)] AKI - [8 vs 8]

1 event of superinfection,delerium and hepatic failure in MP and 1 event of GI bleeding in placebo

Conclusion
There was a reduction in late treatment failure , mainly driven by a decrease in radiological progression and possibly late appearance of septic shock
10-35% mortality
"The results demonstrated that the acute administration of methylprednisolone was associated with less treatment failure and a lower inflammatory response in a prospectively identified population of patients with both severe community acquired pneumonia and a high inflammatory response"
Appraisal
Strengths
Weaknesses
Is a reduction in radiological progression good enough?
Post hoc analysis would suggest that even after excluding radiology , beneficial effects of steroids remain in treatment failure, not mortality

Study not powered to demonstrate a mortality difference

Generally consistent with the meta-analyses and biomarkers improve

No significant adverse events
Is it a surrogate marker of mortality?
Well-designed - clear protocol
Well defined population
Allocation valid
Low drop-out
Similar groups (co-intervention)

Targeted severe CAP


Only applicable to severe CAP
?Appropriate duration of treatment and follow-up
?Appropriate outcome - not powered for mortality
?Appropriate sample size - lower failure in placebo than anticipated
Long duration of recruitment - ? changing disease pattern/treatment
THIS STUDY -
IMPROVEMENT IN A FEW SURROGATE MARKERS BUT NO HARD OUTCOMES
Thank you
Full transcript