Corticosteroids in Severe CAP. Mervyn Mer Department of Medicine & ICU Johannesburg Hospital University of the Witwatersrand

Transcription

1 Corticosteroids in Severe CAP Mervyn Mer Department of Medicine & ICU Johannesburg Hospital University of the Witwatersrand

2 Introduction Much controversy and debate regarding the use of corticosteroids (CS) in clinical medicine CS use in CAP controversial and unclear

3 Introduction Definition of Pneumonia Inflammatory condition of the lung parenchyma, caused by an infectious agent/s

4 Introduction Community-acquired pneumonia common Leading infectious cause of death 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: Alvarez-Lemma F, Torres A. Curr Opin Crit Care 2004; 10:

5

6 Introduction Mortality rates CAP relatively unchanged past half century Evans GM, Gainsford WF. Lancet 1938; 2: Landmark study: Austrian and Gold deaths occurring within 1st 5 days of r x not due to failure to eradicate micro-organism - suggested due to specific inflammatory response of host Austrian R, Gold J. Ann Intern Med 1964; 60 :

7 Introduction...inflammatory response of the host may be more important than the specific microorganism causing the infection or the type of antibiotic administered Rano A, Torres A, et al. Curr Opin Infect Dis 2006; 19:

8 Mechanism of Action CS modulate the inflammatory response Inhibit the production of key substances in the inflammatory pathway which contribute to vascular permeability, oedema, leucocyte migration and fibrin deposition

9 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: Marik P. Chest 2009

10 CS stimulate Histone deacetylation AP-1 CS/GR CBP / p300 HAT NF-KB STATs CS inhibit Histone acetylation

11 Feldman C, et al. SAMJ 2007; 97:

12 Severe CAP CURB-65 score

13 Treatment of Severe CAP Amoxicillin-clavulanate or 2 nd or 3 rd generation cephalosporin & Aminoglycoside & Macrolide / azalide Alternative : Flouroquinolone + another agent Management of CAP in Adults Guideline. Feldman C, et al. SAMJ 2007; 97:

14 ATS / IDSA Guideline on CAP Mandell LA, et al. Clin Infect Dis 2007; 44 Supp2: S27-72

15 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

16 History Initial description 1956 Effects of hydrocortisone upon course pneumococcal pneumonia treated with penicillin Wagner HNJ, et al. Bull John Hopkins Hosp 1956; 98:

17 Severe Community Acquired Pneumonia (CAP) Pneumonia leading cause of community-acquired infection requiring ICU admission Mortality remains high despite advances in antimicrobials & supportive measures

18 Severe CAP Randomized multicentre study in patients with severe CAP in ICU who received low-dose CS (HC) associated with - significant reduction length of hospital stay - significant reduction in mortality Confalonieri M, et al. AJRCCM 2005; 171:

19 Hydrocortisone in Severe CAP : Outcome Outcome variable Placebo Hydrocortisone p Value ICU mortality 7 (30%) 0 (0%) Hospital mortality 7 (30%) 0 (0%) d mortality 8 (38%) 0 (0%) Length of ICU stay, d Length of hospital stay, d 18 (3-45) 10 (4-33) (3-72) 13 (10-53) 0.03 Duration of MV 10 (2-44) 4 (1-27) Confalonieri M, et al. AJRCCM 2005; 171:

20 Hydrocortisone in Severe CAP Patients treated HC also showed significant improvements in - PaO 2 : FiO 2 ratio - chest radiograph score - MODS score - CRP reduction Dose : 200mg iv bolus followed by 10mg / hr x 7d Confalonieri M,et al. AJRCCM 2005; 171:

21 Recent Reviews Severe CAP : approach to therapy - CS promising adjunct Pineda L, et al. Expert Opin Pharmacother 2007; 8: CS infusion in patients with severe CAP - powerful immunomodulatory effects - seems to be associated with significant reduction in morbidity, mortality, hospitalisation Confalonieri M, Trevisan R. Recenti Prog Med 2006; 97: 32-36

22 Recent Reviews Associated inflammatory response in pneumonia: role of adjunctive corticosteroids - adjunctive treatment with CS probably indicated in severe CAP Rano A, Torres A, et al. Curr Opin Infect Dis 2006; 19: An update on the diagnosis of adrenal insufficiency & the use of corticotherapy in critical illness - possible role for CS in severe CAP Thomas Z, et al. Ann Pharmacother 2007; 41:

23 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

24 CS & CAP Requiring Hospitalisation Prospective randomized controlled Japanese study Aim : assess effectiveness CS as adjunctive therapy in CAP requiring hospitalization 31 adult patients Adrenal function evaluated Mikami K, et al. Lung (5):

25 CS & CAP Requiring Hospitalisation Results - shorter duration of iv antibiotics if received CS - vital signs stabilized earlier in steroid group - differences most prominent in moderate-severe subgp. - prevalence of relative adrenal insufficiency high : 43% Conclusion - in moderate-severe CAP, CS promote resolution of clinical symptoms & reduce duration iv antibiotic r x Mikami K, et al. Lung (5):

26 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 (77%) r x standard antimicrobial therapy - 70 (23%) received antibiotics & systemic steroids Clinical characteristics similar Garcia-Vidal C, et al. Eur Resp J 2007; 30:

27 CS and Severe CAP Median dose of CS : mg / 24 hours methylprednisolone Results - systemic steroids were independently associated with a decreased mortality ( odds ratio 0.287; 95% CI ) Conclusion - mortality decreased in patients with severe CAP who received simultaneous administration of systemic steroids along with antibiotic therapy Garcia-Vidal C, et al. Eur Resp J 2007; 30:

28 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:

29 Role of CS in Paediatrics Severe Mycoplasma Pneumoniae Pneumonia MP responsible for 10-40% 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

30 Role of CS in Paediatrics Severe Mycoplasma Pneumoniae Pneumonia Results - recipients afebrile within 24 hours - improvement in clinical status and radiographically Conclusion - CS r x temporally associated with clinical & radiographic improvement - may be helpful for reducing morbidity Lee KY, et al. Pediatr Pulmonol 2006; 41: 263-8

31 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: Cheng VCC, et al. J Infect 2004; 49: Mer M, et al. Chest 1998; 114:

32 Critical Determinants Timing Dose Duration

33 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 Initiation Dosage Duration of Treatment

34 Cortisol Levels and CAP Cortisol levels predictors of severity and outcome 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:

35 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:

36 Limitations New Data 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 with either shock or ALI Snijders D, et al. Am J Respir Crit Care Med 2010; 181: Meduri GU, Confalonieri M. Am J Respir Crit Care Med 2010; 181:

37 Recent Meta-analyses Corticosteroid treatment Patients with severe sepsis (n = 1228) Acute lung injury-acute respiratory distress syndrome (n = 648) Conclusions - CS of benefit Annane D, et al. JAMA 2009; 301: Tang B, et al. Crit Care Med 2009; 37:

38 Aggregate Data Randomised Trials CS in patients with pneumonia requiring ICU Many with septic shock & / or acute 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: Nawab Q, et al. Am J Respir Crit Care Med 2007;175: A594 Annane D, et al. JAMA 2002; 288: Meduri GU, et al. Chest 2007; 131:

39 Consensus Guidelines Patients admitted to ICU with severe CAP with either shock or acute lung injury - CS indicated Marik PE, et al. Crit Care Med 2008; 36:

40 Corticosteroids for Pneumonia Cochrane Database Systems Review 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

41 Future ESCAPe Trial Extended Steroid (in) CAP(e) Patients admitted to ICU with severe CAP Randomised trial; 1400 patients Prolonged use low dose MP

42 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

43 Never underestimate the power of steroids Umberto Meduri

44 In the ICU People Die, Steroids Never Do

45

46

47