Pulmonary Coagulopathy

Transcription

1 9th International Congress and Scientific Seminar 2009 Bangladesh Society of Medicine, Dhaka, Bangladesh Pulmonary Coagulopathy Pulmonary Coagulopathy as a New Therapeutic Target Marcus Schultz

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6 Disclosure Marcus Schultz has received speaker fees from Ely Lilly and Co, Leo Pharma, Sanofi Aventis, Hamilton Medical and Maquet Marcus Schultz participated in studies sponsored by Leo Pharma, Novartis, and Hamilton Medical Marcus Schultz is sponsored by grants from the Dutch Government (ZonMW) and the ESICM Marcus Schultz performs an Organon sponsored trial Marcus Schultz is, or has been an advisor of Novartis and Leo Pharma Marcus Schultz

7 Frame Work of this Presentation Systemic coagulation with systemic inflammation Local coagulation with pulmonary inflammation Rational for anticoagulant strategies for lung injury Presently performed preclinical studies Presently performed clinical studies Conclusions Marcus Schultz

8 Frame Work of this Presentation Systemic coagulation with systemic inflammation Local coagulation with pulmonary inflammation Rational for anticoagulant strategies for lung injury Presently performed preclinical studies Presently performed clinical studies Conclusions Marcus Schultz

9 Coagulopathy with SIRS, Sepsis and Septic Shock inflammation coagulation TFPI apc TF TF FVII thrombin AT PAI 1 tpa Matthay M. NEJM. 2001;344:759

10 Fibrinolysis Coagulation Coagulopathy with SIRS, Sepsis and Septic Shock coagulation TATc TF apc TFPI TF TF FVII PAI 1 PAI 1 thrombin AT PAA tpa Matthay M. NEJM. 2001;344:759

11 Survival (%) Anticoagulant Therapy in Sepsis Drotrecogin alfa (activated) 80 Placebo Days after start of infusion P =.006 Bernard GR. N Engl J Med. 2001;344:699

12 Take home Message 1 Systemic coagulopathy is intrinsic to systemic inflammation, e.g. sepsis Systemic coagulopathy can be attenuated by systemic treatment Attenuation of systemic coagulopathy (with APC) benefits patients with severe sepsis Marcus Schultz

13 Frame Work of this Presentation Systemic coagulation with systemic inflammation Local coagulation with pulmonary inflammation Rational for anticoagulant strategies for lung injury Presently performed preclinical studies Presently performed clinical studies Conclusions Marcus Schultz

14 FVIIa PAI-1 Coagulation TF PAA Fibrinolysis TATc Coagulopathy with VAP Schultz MJ. Thorax. 2004;59:130 Lavage Fluid

15 Coagulation Fibrinolysis Compartmentalized Coagulopathy Choi G. Eur Resp J 2004;24:786 Lavage Fluid

16 Natural inhibitors Compartmentalized Coagulopathy Choi G. Thorax. 2005;60:705 Lavage Fluid

17 Fibrinolysis Coagulation Coagulopathy with SIRS Van Till O. J Infect Dis. 2006;194:1331 Lavage Fluid

18 Fibrinolysis Coagulation Natural inhibitors Coagulopathy with Burns Hofstra JJH. Manuscript in preparation Lavage Fluid

19 Coagulopathy with ALI/ARDS Coagulation Fibrinolysis Gunther A. Am J Respir Crit Care Med. 2000;161:454 Lavage Fluid

20 Prognostic Significance of Altered Coagulation in ALI/ARDS Ware L. Crit Care Med 2007;35:1821 Blood Samples

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23 Ventilator Induced Lung Injury Control LVT lower V T HVT high V T Wolthuis EK. Crit Care 2009;13:R1

24 Ventilator Induced Lung Injury open boxes no correction of metabolic acidosis ///-hatched boxes correction of metabolic acidosis LV T lower tidal volumes HV T high tidal volumes Wolthuis EK. Crit Care 2009;13:R1 Lavage Fluid

25 Ventilator Induced Coagulopathy Coagulation open boxes no correction of metabolic acidosis ///-hatched boxes correction of metabolic acidosis LV T lower tidal volumes HV T high tidal volumes Fibrinolysis Wolthuis EK. Crit Care 2009;13:R1 Lavage Fluid

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27 PAI-1 activity Ventilator Induced Coagulopathy 8 6 Not-ventilated controls Ventilated after challenge Control Hit 6 ml/kg 15 ml/kg 25 ml/kg Dahlem P. Intensive Care Med. 2005;31:724 Lung Tissue

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29 Smaller V T Less Coagulopathy? tidal volume [ml/kg] Tidal volume - ALL - mean ± SEM V T 15 ml/kg V T 6ml/kg NAVA * * p<0.05 vs V T 15 ml/kg time [minutes] p<0.05 vs V T 6 ml/kg * p<0.05 vs V T 15 ml/kg p<0.05 vs V T 6 ml/kg * Respiratory rate - ALL - mean ± SEM respiratory rate [breaths per minute] * * * * * * * * * * * * * * * * * * * * 0 * * * Respiratory rate - ALL - mean ± SEM * respiratory rate [breaths per minute] * * * * * p<0.05 vs V T 15 ml/kg time [minutes] p<0.05 vs V T 6 ml/kg * * V T 15 ml/kg V T 6ml/kg NAVA * time [minutes] * V T 15 ml/kg V T 6ml/kg NAVA Brander L. Am J Resp Crit Care Med 2008; submitted

30 Fibrinolysis Coagulation NAVA Coagulopathy Lung wet to dry ratio - ALL - mean ± SE p = healthy control V T 15 ml/kg V T 6 ml/kg NAVA p = p = Plasma IL-8 concentration Mean ± SE time t-g group time t-g group V T 15 ml/kg V T 6 ml/kg NAVA Lung wet to dry ratio IL-8 concentration [pg/ml] time t-g group # p = p = dependent right lower lobe BAL PAI-1 concentration Mean ± SE non-dependent right lower lobe Healthy animals V T 15 ml/kg V T 6 ml/kg NAVA baseline 3 hours 6 hours BAL TF concentration Mean ± SE Wilcoxon signed rank test # p<0.05 vs baseline * p<0.05 vs 3 hours * Healthy animals V T 15 ml/kg V T 6 ml/kg NAVA p = p = <0.001 PAI-1 concentration [ng/ml] TF concentration [pg/ml] p = < Brander L. Am J Resp Crit Care Med 2008; submitted Lung Tissue

31 ng/ml % ng/ml S. pneumoniae Pneumonia Coagulation Fibrinolysis TATc BALF PAA BALF PAI-1 BALF Controls Injurious Protective 30 Controls Injurious Protective 20 Controls Injurious Protective Control: S. pneumoniae pneumonia, no MV Injurious: S. pneumoniae pneumonia, HV T ZEEP Protective: S. pneumoniae pneumonia, LV T 5 cm H 2 O PEEP Haitsma JJ. Europ Resp J 2008; in press Lavage Fluid

32 Fibrinolysis Coagulation Ventilator Associated Coagulopathy LV T /PEEP: lung protective Closed bars: T=0 hours HVT/ZEEP: lung injurious Open bars: T=5 hours Choi G. Anesthesiology. 2006;105:689 Lavage Fluid

33 Fibrinolysis Coagulation Ventilator Associated Coagulopathy Determann R. Manuscript in preparation Lavage Fluid

34 Take-home Message 2 Lung inflammation, whatever its cause (i.e., pneumonia, sepsis, inhalation trauma, mechanical ventilation) is characterized by local coagulopathy Local coagulopathy with lung inflammation resembles systemic coagulopathy with sepsis

35 Frame Work of this Presentation Systemic coagulation with systemic inflammation Local coagulation with pulmonary inflammation Rational for anticoagulant strategies for lung injury Presently performed preclinical studies Presently performed clinical studies Conclusions Marcus Schultz

36 Survival (%) Anticoagulant Therapy in Sepsis Drotrecogin alfa (activated) 80 Placebo Days after start of infusion P =.006 Bernard GR. N Engl J Med. 2001;344:699

37 Anticoagulant Therapy in Sepsis Laterre PF. Crit Care Med. 2005;33:952

38 Fibrinolysis Coagulation rh-apc and Alveolar Fibrin Turnover after Challenge with LPS * TATc (ng/ml) 15 Soluble TF (pg/ml) * * * 10 Challenge with: Endotoxin Control versus vehicle * versus control Infusion of 0.00 Vehicle rhapc 0 Vehicle rhapc PA activity (%) * * PAI-1 activity (ng/ml) * * 70 Vehicle rhapc 2.00 Vehicle rhapc van der Poll T. Am J Respir Crit Care Med. 2005:171:1125 Lavage Fluid

39 Take-home Message 3 Local coagulopathy with lung inflammation resembles systemic coagulopathy with sepsis Attenuation of local coagulopathy may be beneficial? Marcus Schultz

40 Frame Work of this Presentation Coagulopathy with systemic inflammation Coagulopathy with pulmonary inflammation Rational for anticoagulant strategies for lung injury Presently performed preclinical studies Presently performed clinical studies Conclusions Marcus Schultz

41 Systemic Anticoagulation in ALI Attenuates Pulmonary Coagulopathy Coagulation LPS Induced acute lung injury Choi G. Eur Resp J. 2007;30:423 Lavage Fluid

42 Systemic Anticoagulation in ALI Attenuates Pulmonary Coagulopathy Coagulation Fibrinolysis Pseudomonas aeruginosa pneumonia Choi G. Crit Care Med. 2007:35:1362 Lavage Fluid

43 Coagulation Fibrinolysis Systemic Anticoagulation in ALI Attenuates Pulmonary Coagulopathy Streptococcus pneumoniae pneumonia Choi G. Crit Care Med. 2008:36:204 Lavage Fluid

44 Risk of Anticoagulants Therapy Marcus Schultz

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47 Can Local Anticoagulation Therapy Attenuate Pulmonary Coagulopathy? Coagulation Fibrinolysis LPS Induced acute lung injury Hofstra JJH. Submitted Lavage Fluid

48 Can Local Anticoagulation Therapy Attenuate Pulmonary Coagulopathy? Coagulation Fibrinolysis Hofstra JJH. ATS annual meeting 2008 Streptococcus pneumoniae pneumonia Lavage Fluid

49 Take home Message 4 Local coagulopathy can be attenuated by systemic as well as local application of anticoagulants Attenuation of pulmonary coagulopathy attenuation of lung injury in humans? Marcus Schultz

50 Frame Work of this Presentation Systemic coagulation with systemic inflammation Local coagulation with pulmonary inflammation Rational for anticoagulant strategies for lung injury Presently performed preclinical studies Presently performed clinical studies Conclusions Marcus Schultz

51 Nebulized heparin in ALI Heparin cumulative daily dose Dixon B. Crit Care 2008:12:R64 Lavage Fluid

52 Nebulized heparin in acute lung injury Objective: to determine whether nebulized heparin will result in decrease of inflammation in BAL fluid (and in reduction of pulmonary vascular permeability) Study population: 50 intubated and mechanically ventilated patients with ALI/ARDS Intervention nebulized heparin IU every 8 hrs during 24 hrs versus placebo Main study parameters/endpoints: TATc and TNF/IL 6 levels in BAL fluid (and the PLI as a measure of pulmonary vascular permeability) Performed

53 Frame Work of this Presentation Systemic coagulation with systemic inflammation Local coagulation with pulmonary inflammation Rational for anticoagulant strategies for lung injury Presently performed preclinical studies Presently performed clinical studies Conclusions Marcus Schultz

54 Conclusions Pulmonary inflammation is characterized by local coagulopathy Local coagulopathy resembles systemic coagulopathy with sepsis Local coagulopathy can be attenuated by systemic or local application of anticoagulants Application of local anticoagulants may be beneficial Marcus Schultz