Statins_in_ARDS by xiaohuicaicai

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									         Statins in ARDS




            Danny McAuley
       Queen’s University of Belfast

Scottish Combined Critical Care Conference
            September 2010
Novel therapies for ARDS - What is on the horizon?
                    Conclusions
  • Beta agonists
    – Potential benefit in phase II study
    – Phase III multi-centre clinical trials awaited
  • Potential therapeutic interventions in phase II trials
    – APC
    – Statins
  • Novel potential future treatments
    – Modulation of renin-angiotensin system
    – Stem cell therapy

Scottish Critical Care Trials Group June 2007
                Statins in ARDS

•   Mechanism of action
•   Observational data
•   Statins and pulmonary inflammation
•   Phase 2 clinical trial (HARP)
•   HARP-2
   No pharmacological treatment for ALI
             Cecilia O’Kane

                              Ashbaugh et al.
                              described using “a clinical
                              trial of a variety of drugs,
                              respirators and fluid
                              regimens” with limited
                              success




Ashbaugh et al. Lancet 1967
      Step-wise approach to new therapies




McAuley et al. CCM (in press)
Cellular effects of statins
          Simvastatin reduces thrombin-induced
                    endothelial injury




Jacobson et al. AJRCMB 2004;30:662
Simvastatin attenuates LPS-induced
     experimental lung injury




                    Jacobson et al. AJP Lung 2005;288:L1026
   Observational data to support a role for
          novel therapies in ALI

                      40%

                                      34%                     OR 0.27 (0.06-1.21)
                                                              p=0.09
      Mortality (%)




                      30%


                                                                      21%
                      20%



                      10%
                                   No statin                         Statin
                                   n = 164                           n = 24

Irish Critical Care Trials Group. Critical Care 2008;12:R30
    Pre-treatment with simvastatin attenuates
  systemic inflammation following LPS challenge




Steiner et al. Circulation 2005; 111:1841
 Inhaled LPS as an in vivo model to study
pulmonary inflammation in healthy subjects

                                    FEV1            FEV1
                                     BAL           Plasma


                         6 hr              18 hr




                FEV1
               Plasma
        50 µg LPS inhalation
  E. Coli serotype O26:B6 (Sigma)
     Breath activated dosimeter
 Inhaled LPS induces inflammatory
cytokines in Cecilia O’Kane
             pulmonary compartment
     Simvastatin in the inhaled LPS model
                     of ALI
   Treatment with a clinically relevant dose of simvastatin
   will reduce pulmonary inflammation induced by LPS
   inhalation in humans




Shyamsundar et al. AJRCCM 2009 179:1107-1114
Schedule for patient safety monitoring
 Simvastatin decreases pulmonary
neutrophilia following LPS inhalation

                 Placebo   Simvastatin   P
                  (n=10)      (n=20)   value
 Total cells       15.2        10.7     0.2
 (x 105/ml)    (10.3-49.8) (4.6-17.4)
                    8.5         3.0    0.05
 Neutrophils
                (4.4-16.2)   (1.8-8.1)
                    7.0         5.1    0.48
 Macrophages
                (3.1-19.1)  (2.1-13.0)
                    1.1         0.9    0.37
 Lymphocytes
                 (0.6-3.2)   (0.2-1.6)
          Simvastatin increases neutrophil
         apoptosis following LPS inhalation




* p < 0.05 vs placebo
     Simvastatin decreases pulmonary
neutrophilic activity following LPS inhalation




 * p < 0.05 vs placebo
   Simvastatin decreases pulmonary TNF
         following LPS inhalation




* p < 0.05 vs placebo
Simvastatin pre-treatment reduces systemic
   inflammation following LPS inhalation


                80
                                      Placebo
   Plasma CRP                         Simvastatin
      (mg/L)    60
                          *
                40

                20

                0
                               * p < 0.05 vs placebo
Simvastatin decreases pulmonary MMP
   secretion following LPS inhalation




* p < 0.05 vs placebo
    Simvastatin pretreatment reduces nuclear NFκB
    translocation in monocyte-derived macrophages




p = 0.0001 for control vs. placebo BALF; ** p=0.03 for placebo BALF vs. simvastatin BALF;
# p=0.03 for placebo BALF vs. simvastatin + placebo BALF
 Lovastatin decreases pulmonary inflammation
measured by FDG PET following LPS instillation




Chen et al. AJRCCM 2009 180:533-539
FDG PET can detect pulmonary inflammation in
             patients with ALI




Bellani et al. Critical Care Medicine 2009 37:2216-2222
    HMGCoA reductase inhibition in ALI to
     Reduce Pulmonary oedema (HARP)

• Proof of concept single centre trial
• Prospective double blind
• Within 48 hours of onset of ALI
• Randomised to simvastatin 80mg or placebo for up
  to 14 days
• Outcomes:
   – Extra-vascular lung water
   – Pulmonary function and systemic organ failure
   – Safety
   – Biological markers in plasma and BAL
Craig et al. AJRCCM 2010 (in press)
                Exclusion criteria
               Cecilia O’Kane

•   Age < 18 years             • Current treatment
•   Pregnancy                    with statins
•   Drug interactions          • Creatinine kinase
•   Declined consent             (CK) > 10 times
                                 upper limit
•   Participation in a
    clinical trial within 30   • Transaminases > 3
    days                         times upper limit
               Patient demographics

                          Simvastatin    Placebo
                                                      p value
                             n=30         n=30
Age (years)               52.5 (17.1)   52.8 (20.0)    0.95
Gender (% male)               73            73         1.00
APACHE II                 25.1 (6.5)    23.3 (6.8)     0.30
APACHE II
                          45.6 (25.0)   46.1 (24.7)    0.93
predicted mortality (%)
SAPS II                   53.4 (14.4)   54.2 (14.3)    0.83
SAPS II
                          51.2 (25.2)   53.6 (24.9)    0.72
predicted mortality (%)

Sepsis n (%)                15 (50)      15 (50)       1.00
Simvastatin improves oxygenation index
                 Cecilia O’Kane




         n =30    n=30   n=10   n=9
Simvastatin reduces plateau pressure
               Cecilia O’Kane




        n=30    n=30   n=10   n=9
Simvastatin improves sequential organ
             Cecilia O’Kane
  failure assessment (SOFA) score




         n=30   n=30   n=10   n=9
                          Safety profile
                          Cecilia O’Kane

                              Simvastatin   Placebo
                                                      p value

  CK > 10 times ULN (%)           4.5         8.7      0.58

  ALT > 3 times ULN (%)           4.4         8        0.60

  AST > 3 times ULN (%)           8.3        16.7      0.34

  Adverse events (%)              47          43       0.79
  Serious adverse
                                  20          23       0.75
  events (%)


• No serious adverse events due to study drug occurred
                           Outcome data
                           Cecilia O’Kane


                             Simvastatin     Placebo      p value
Ventilator free days           8.2 (8.1)     9.1 (8.7)     0.7
ICU free days                 7.20(7.47)     8.4 (8.4)     0.6
ICU survival n (%)            21 (70%)      21 (70%)       1.0
Hospital LOS (days)           51.2 (39.3)   48.0 (37.4)    0.8
Hospital survival (days)      19 (63%)      19 (63%)       1.0
      Simvastatin decreases
          Cecilia O’Kane
    bronchoalveolar lavage IL-8

                    p=0.89
                    p = NS           *p = 0.05
  IL-8 10000
(pg/ml)                                                 Placebo
        8000                                            Simvastatin

       6000

       4000

       2000

          0
               D0            D3     D0           D3
               n=17          n=10   n=23         n=17
     Simvastatin decreases
   bronchoalveolar lavage IL-6


                     p=0.43
                     p = NS         p = 0.07
  IL-6 5000
(pg/ml)                                               Placebo
        4000                                          Simvastatin

       3000

       2000

       1000

          0
                D0            D3   D0          D3
               n=17       n=10     n=23        n=17
      Simvastatin decreases systemic
inflammation as measured by plasma CRP
              Cecilia O’Kane


                     p=0.06
                     p = NS           *p = 0.0004
    CRP     400
   (mg/L)                                            Placebo
                                                     Simvastatin
            300


            200


            100


             0
                  D0          D14     D0       D14
                  n=30        n=9   n=29      n=8
                  Conclusions

• In a human LPS model of ALI simvastatin reduces
  pulmonary and systemic inflammation
• In patients with ALI simvastatin
   – Improves pulmonary and non-pulmonary organ
     dysfunction
   – Well tolerated
   – Reduces inflammation
• Study now needed to determine if simvastatin
  improves clinical outcome in large clinical trials
  HARP-2
Cecilia O’Kane
Acknowledgements
HMGCoA reductase inhibition in prevention of
        ALI (HARP-prevention)
    (http://www.controlled-trials.com/ISRCTN56543987)

• Proof of concept, double blind, placebo controlled,
  single centre study
• Study population
   – Patients undergoing oesphagectomy
   – N=30 of planned sample size 36
• Simvastatin 80mg or placebo
• Endpoints:
   – Pulmonary dead space
   – Respiratory compliance, oxygenation index
   – Biological markers in plasma and EBC

								
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