Mervyn Mer
Transcript of Mervyn Mer
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Department of Medicine & ICU
Johannesburg Hospital
University of the Witwatersrand
Corticosteroids in Severe CAP
Mervyn Mer
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Introduction
Much controversy and debate regarding the
use of corticosteroids (CS) in clinical medicine
CS use in CAP controversialand unclear
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Definition of Pneumonia
Inflammatorycondition of the lung parenchyma,
caused by an infectious agent/s
Introduction
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Introduction
Community-acquired pneumonia common
Leading infectious cause ofdeath
Consistently among top 5 causes of death in both
developed and under-developed countries At least 20% cases CAP will require hospitalisation
- 25% of these will require ICU admission
Mortality of up to 50%
Almirall J, et al. Eur Resp J 2000; 15: 757-763
Alvarez-Lemma F, Torres A. Curr Opin Crit Care 2004; 10: 369-74
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Introduction
Mortality rates CAP relatively unchanged past halfcentury
Landmark study: Austrian and Gold 1964- deaths occurring within 1st 5 days of rx
notdue to failure to eradicate micro-organism
- suggested due to specific inflammatory responseof host
Evans GM, Gainsford WF. Lancet 1938; 2: 14-19
Austrian R, Gold J. Ann Intern Med 1964; 60 :759-770
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Introduction
...inflammatory response of the host may be
more important than the specific micro-
organism causing the infection or the type ofantibiotic administered
Rano A, Torres A, et al. Curr Opin Infect Dis 2006; 19: 179-84
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Mechanism of Action
CS modulate the inflammatory response
Inhibit the production of key substances inthe inflammatory pathway which contribute
to vascular permeability, oedema, leucocyte
migration and fibrin deposition
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Mechanism of Action
CS modulate the inflammatory response
- halt activation of various transcription
factors including NF- KB
- occurs via an inhibitory action on histone
acetylation and stimulation of histone
deacetylation
Barnes PJ. Allergy 2001; 56: 928-36
Marik P. Chest 2009
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Histone deacetylationCS stimulate
CBP / p300
HAT
CS/GR
AP-1
STATs
NF-KB
Histone acetylationCS inhibit
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Feldman C, et al. SAMJ 2007; 97: 1295-1306
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Severe CAP
CURB-65 score
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Treatment of Severe CAP
Amoxicillin-clavulanate or2nd or 3rd generation cephalosporin
&
Aminoglycoside
&
Macrolide / azalideAlternative : Flouroquinolone + another agent
Management of CAP in Adults Guideline. Feldman C, et al. SAMJ 2007; 97: 1295-1306
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ATS / IDSA Guideline on CAP
Mandell LA, et al. Clin Infect Dis 2007; 44 Supp2: S27-72
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ATS / IDSA Guideline on CAP
Hypotensive, fluid resuscitated patients with
severe CAP should be screened for occult CIRCI
Mandell LA, et al. Clin Infect Dis 2007; 44 Supp2: S27-72
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History
Initial description
1956
Effects of hydrocortisone upon coursepneumococcal pneumonia treated with penicillin
Wagner HNJ, et al. Bull John Hopkins Hosp 1956; 98: 197-215
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Severe Community Acquired Pneumonia
(CAP)
Pneumonia leading cause
of community-acquired
infection requiring ICUadmission
Mortality remains high
despite advances in
antimicrobials &supportive measures
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Hydrocortisone in Severe CAP : Outcome
Outcome
variable
Placebo Hydrocortisone p Value
ICU mortality 7 (30%) 0 (0%) 0.009
Hospital
mortality
7 (30%) 0 (0%) 0.009
60-d mortality 8 (38%) 0 (0%) 0.001
Length of ICU
stay, d
18 (3-45) 10 (4-33) 0.01
Length ofhospital stay, d
21 (3-72) 13 (10-53) 0.03
Duration of MV 10 (2-44) 4 (1-27) 0.007
Confalonieri M , et al. AJRCCM 2005; 171: 242-48
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Hydrocortisone in Severe CAP
Patients treated HC alsoshowed significantimprovements in
- PaO2
: FiO2
ratio
- chest radiograph score
- MODS score
- CRP reduction
Dose : 200mg iv bolusfollowed by 10mg / hr x 7d
Confalonieri M ,et al. AJRCCM 2005; 171: 242-248
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Recent Reviews
Severe CAP : approach to therapy
- CS promising adjunct
CS infusion in patients with severe CAP
- powerful immunomodulatory effects
- seems to be associated with significantreduction in morbidity, mortality, hospitalisation
Confalonieri M, Trevisan R. Recenti Prog Med 2006; 97: 32-36
Pineda L, et al. Expert Opin Pharmacother 2007; 8: 593-606
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Recent Reviews
Associated inflammatory response in pneumonia: role ofadjunctive corticosteroids
- adjunctive treatment with CS probably indicated
in severe CAP
An update on the diagnosis of adrenal insufficiency & theuse of corticotherapy in critical illness
- possible role for CS in severe CAP
Thomas Z, et al. Ann Pharmacother 2007; 41: 1456-65
Rano A, Torres A, et al. Curr Opin Infect Dis 2006; 19: 179-184
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CS and Severe CAP
Systematic review 2008
No evidence adverse outcomes or harm
Moderate doses of CS safe
Consider particularly in patients with COPD
or asthma receiving antimicrobials
Salluh JIF, et al. Critical Care 2008; 12: R76
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CS & CAP Requiring Hospitalisation
Prospective randomized controlled Japanesestudy
Aim : assess effectiveness CS as adjunctivetherapy in CAP requiring hospitalization
31 adult patients
Adrenal function evaluated
Mikami K, et al. Lung 2007 185 (5): 249-55
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CS & CAP Requiring Hospitalisation
Results
- shorter duration ofiv antibiotics if received CS
- vital signs stabilized earlierin steroid group
- differences most prominent in moderate-severe subgp.- prevalence ofrelative adrenal insufficiency high : 43%
Conclusion
- in moderate-severe CAP, CS promote resolution ofclinical symptoms & reduce duration iv antibiotic rx
Mikami K, et al. Lung 2007 185 (5): 249-55
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CS and Severe CAP
Spanish retrospective observational study
Cohort of patients hospitalised with severe CAP
(classes IV & V Prognostic Severity Index score)
308 patients evaluated- 238 (77%) rx standard antimicrobial therapy
- 70 (23%) received antibiotics & systemic steroids
Clinical characteristics similar
Garcia-Vidal C, et al. Eur Resp J 2007; 30: 951-956
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CS and Severe CAP
Median dose of CS :- 45.7mg / 24 hours methylprednisolone
Results
- systemic steroids were independentlyassociated
with a decreased mortality
( odds ratio 0.287; 95% CI 0.113-0.732 )
Conclusion
- mortality decreased in patients with severe CAPwho received simultaneous administration of systemic
steroids along with antibiotic therapy
Garcia-Vidal C, et al. Eur Resp J 2007; 30: 951-956
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CS and Severe CAP
Severe sepsis
Adrenal insufficiency
- common
- up to 2/3rds of patients with severe CAP
admitted to ICU
Salluh J, et al. Intensive Care Med 2006; 32: 595-598
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Role of CS in Paediatrics
Severe Mycoplasma Pneumoniae Pneumonia
MP responsible for10-40% cases paediatric CAP
Occasionally progression to severe pneumonia despite
appropriate antibiotic therapy
Retrospective evaluation effect prednisolone
Dose : 1mg/kg x 3-7 days, tapered over 7 days
Lee KY, et al. Pediatr Pulmonol 2006; 41: 263-8
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Role of CS in Paediatrics
Severe Mycoplasma Pneumoniae Pneumonia
Results
- recipients afebrile within 24 hours
- improvement in clinical status and radiographically Conclusion
- CS rx temporally associated with clinical & radiographic
improvement- may be helpful for reducing morbidity
Lee KY, et al. Pediatr Pulmonol 2006; 41: 263-8
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CS in Other Pulmonary Infections
Data indicating benefit Pneumocystis Jirovecii pneumonia
Tuberculosis
Varicella-zoster virus
Hantavirus
Influenza virus
Severe acute respiratory syndrome (SARS)Rano A, et al. Curr Opin Infect Dis 2006; 19: 179-184
Cheng VCC, et al. J Infect 2004; 49: 262-273
Mer M, et al. Chest 1998; 114: 426-31
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Critical Determinants
Timing
Dose
Duration
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Factors Affecting Response to CS Treatment
Factors Affecting
Treatment Response
Prevention of
Potential Complications
Corticosteroid
Treatment
Infection
Surveillance
Avoidance of
Paralysis
Avoidance of
Rebound Inflammation
Timing of
InitiationDosage
Duration of
Treatment
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Cortisol Levels and CAP
Cortisol levels predictors of severity andoutcome in CAP
Similar to PSI
Better than routinely measured laboratory
parameters ( CRP, procalcitonin, leukocytes)
Free cortisol not superior to total cortisol wrt
prognostic accuracy in CAP
Christ-Crain M. Am J Respir Crit Care Med 2007; 176: 913-20
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New Data
Corticosteroids not effective in CAP
RDBP trial, 213 hospitalised patients
7 days of adjunctive prednisolone (40mg dly)
- did not improve outcome
- increased late failure in nonsevere CAP
Snijders D, et al. Am J Respir Crit Care Med 2010; 181: 975-82
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New Data
Limitations
73% patients CURB-65 2
Abrupt cessation of CS (rebound)
Benefit in more severely ill patients cannot be
excluded
Underpowered
No assessment of adrenal function
Editorial: CS if admitted ICU with severe CAP witheither shock or ALI
Snijders D, et al. Am J Respir Crit Care Med 2010; 181: 975-82
Meduri GU, Confalonieri M. Am J Respir Crit Care Med 2010; 181: 880-82
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Recent Meta-analyses
Corticosteroid treatment
Patients with severe sepsis (n = 1228)
Acute lung injury-acute respiratory distresssyndrome (n = 648)
Conclusions
- CS of benefitAnnane D, et al. JAMA 2009; 301: 2362-2375
Tang B, et al. Crit Care Med 2009; 37: 1594-1603
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Aggregate Data Randomised Trials
CS in patients with pneumonia requiring ICU Many with septic shock& / oracute lung injury
Significant reduction in short term mortality
- relative risk 0.40; p=0.03
Small size of trials
Confalonieri M, et al. Am J Respir Crit Care Med 2005; 171:242-248
Nawab Q, et al. Am J Respir Crit Care Med 2007;175: A594
Annane D, et al. JAMA 2002; 288: 862-871
Meduri GU, et al. Chest 2007; 131:954-963
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Consensus Guidelines
Patients admitted to ICU with severe CAP
with eithershockoracute lung injury
- CS indicated
Marik PE, et al. Crit Care Med 2008; 36:1937-1949
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Corticosteroids for Pneumonia
Cochrane Database Systems Review 2011
6 studies, 437 participants
CS improve oxygenation and reduce need for
mechanical ventilation in severe pneumonia
Hastened resolution of symptoms
Adverse events related to CS infrequent
Chen Y, et al. Cochrane Database Syst Rev 2011: CD007720
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Future
ESCAPe Trial
Extended Steroid (in) CAP(e)
Patients admitted to ICU with severe CAP Randomised trial; 1400 patients
Prolonged use low dose MP
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Conclusion
Encouraging data regarding use of CS in
severe CAP
They should be used in this setting Dose
Avoid in non-severe CAP
Timing, dose, duration are critical variables
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Never underestimate
the power of steroids
Umberto Meduri
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In the ICU
People Die,
Steroids Never Do
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