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Ημερίδα Εντατικής Θεραπείας Προβλήματα χειρουργικών ασθενών στην Μονάδα Εντατικής Θεραπείας Β΄ ΧΕΙΡΟΥΡΓΙΚΗ ΚΛΙΝΙΚΗ ΙΑΤΡΙΚΗΣ ΣΧΟΛΗΣ ΕΚΠΑ Αμφιθέατρο Αρτεταίειου.

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Presentation on theme: "Ημερίδα Εντατικής Θεραπείας Προβλήματα χειρουργικών ασθενών στην Μονάδα Εντατικής Θεραπείας Β΄ ΧΕΙΡΟΥΡΓΙΚΗ ΚΛΙΝΙΚΗ ΙΑΤΡΙΚΗΣ ΣΧΟΛΗΣ ΕΚΠΑ Αμφιθέατρο Αρτεταίειου."— Presentation transcript:

1 Ημερίδα Εντατικής Θεραπείας Προβλήματα χειρουργικών ασθενών στην Μονάδα Εντατικής Θεραπείας Β΄ ΧΕΙΡΟΥΡΓΙΚΗ ΚΛΙΝΙΚΗ ΙΑΤΡΙΚΗΣ ΣΧΟΛΗΣ ΕΚΠΑ Αμφιθέατρο Αρτεταίειου Νοσοκομείου ΔΙΑΛΕΞΗ : Τι νεώτερο για τη σήψη Προεδρείο: κ. Γ. Ανδρουλάκης Εισηγητής: κ. Γ. Μπαλτόπουλος Σάββατο 2 Απριλίου 2011 G. J. Baltopoulos Professor of Critical Care, Athens University School of Nursing ICU at Agioi Anargyroi Hospital of Kifissia, Greece or.com

2 The net host immune response to infections depends on different factors pathogen virulence pathogen burden Immunostimulation /Inflammation Immunodepression age Genetic predisposition Comorbidities Nutritional status Type and severity of injury Trauma Stress-Surgery Drugs

3 Lewis Thomas said.. “the microorganisms that seem to have it in for us... turn out... to be rather more like bystanders.... It is our response to their presence that makes the disease. Our arsenals for fighting off bacteria are so powerful... that we are more in danger from them than the invaders.”

4 Pro-inflammatory Response Anti-inflammatory Response Time Simplified description of systemic pro- and anti-inflammatory immune responses over time after septic shock: Time matters!! Anti-inflammatory interventions Immunostimulation interventions /Pro-inflammatory drugs ? hours In some patients, CARS is pathologically exaggerated and prolonged (beyond 48 hours)→Immunoparalysis Early mortality ≈20% Late Mortality ≈80%

5 Keep the balance Nature reviews

6 Anti- inflammatory Sepsis Therapies Microbial products antagonists Anti-endotoxin antibodies LPS analogues Bactericidal/permeability- increasing protein Anticytokine strategies Anti-TNF antibodies TNF receptors IL-1ra Strategies against other mediators Nitric oxide—L-NMMA, L-NAME, methylene blue PAF acetylhydrolase Arachidonic acid metabolites Anti-HMGB1 Antioxidants Strategies against coagulation system Antithrombin III Tissue factor pathway inhibitor Activated protein C Enhanced elimination Hemofiltration Immune-stimulating strategies GM-CSF IFN-γ Immunonutrition Immunoglobulins? (replacement?) Vincent JL, Abraham E. AJRCCM 2006; 173: 256–263 Anti-antiinflammatory sepsis therapies

7 SepsisTrauma BurnsSurgery Systemic temporary immunosupression mild severe Prevents inflammation induced damage homeostasis Impairs antimicrobial defense High susceptibility to infections Drugs

8 Is /was the septic patient immunocompetent? Yes, if the patient finally survives !! But There is a period of marked immunosupression (1-7 days) necessary to brake down the initial pro-inflammatory response –most survivors of sepsis start spontaneously to recover immune functions 3-4 days post admission/septic episode The magnitude and the duration of immunosupression matters !!

9 Hotchkiss RS., Opal S. Immunotherapy for Sepsis. A New Approach against an Ancient Foe. NEJM 2010;363: Can we intervene ? Interleukin-15 (anti-apoptotic?) Interleukin-7 (anti-apoptotic?) Anti–PD-L1 antibody Anti–IL-10 Anti–regulatory T-cell therapy Blockade of negative costimulators (CTLA-4, BTLA, PD-1) GM-CSF/GC-SF/IFNg FLT-3L (DC growth factor)

10 Monitoring immune dysfunctions in septic patients: Toward tailored immunotherapy. Sepsis-induced immune dysfunction (lymphocyte and monocyte anergy) likely mediated by increased interleukin (IL)-10 and apoptosis might be treated by innovative and specific therapies administered based on measurements of selective biomarkers in patients before initiation of treatment. Venet F, Lepape A, Monneret G. Monitoring Immune Dysfunction in Septic Patients: Toward Tailored Immunotherapy. In: Yearbook of Intensive Care and Emergency Medicine pp: /GC-SF/IFN-γ

11 How we quantitate the immunosupression? IL-10 The higher the level of IL-10 the lower the level of HLA-DR HLA-DR –Reduced mHLA-DR expression has been proposed as a global biomarker of sepsis-associated immunosuppression. –Volk HD et al. Clin Transplant 1989;3:246–252 –Volk HD et al. Chem Immunol 2000;74:162–177 TNF-α Production post ex vivo peripheral blood stimulation with LPS The higher the level of HLA-DR the higher the level of ex vivo TNF-α production

12 Immunosupression monitoring and outcomes- available evidence 13/ 23 infected patients on ICU admission recovered the ex vivo TNF production and survived –Munoz C et al. J. Clin. Invest. 1991;88: pts with sepsis, decreasing serum levels of IL-10 indicates survival –van der Poll T et al. The Journal of Infectious Diseases 1997; 175: Septic shock pts. High IL-10 and low HLA-DR are associated with mortality –Monneret G et al. Immunology Letters 95 (2004) 193– Septic shock pts. Persisting low HLA-DR expression predicts mortality –Monneret G et al. Intensive Care Med 2006; 32:1175– burn pts. HLA-DR persistent decrease was associated with mortality and the development of septic shock –Tissot S et al. Crit Care Med 2007; 35:1910– /105 trauma pts. Low HLA-DR was correlated with infection –CheronA et al. Critical Care 2010, 14:R208 Low HLA-DR is independently associated with secondary nosocomial infections after septic shock. –Landelle C et al. Intensive Care Med 2010; 36:1859– pts HLA-DR does not predict mortality. In 70 ICU pts > 7 days in ICU the recovery slope predicts the secondary infections after 7 days. –Lukaszewicz A-C et al. Crit Care Med 2009; 37:2746–2752

13 What is the target of immune stimulation?? (1) to help bacterial killing at the primary focus of infection (2) to prevent the development of nosocomial infections (3) to prevent the reactivation of dormant viruses

14 HLA-DR in severely injured patients is markedly reduced can be increased significantly by IFN-γ HERSHMAN MJ, et al. Interferon-gamma treatment increases HLA-DR expression on monocytes in severely injured patients. Clin. exp. Immunol. 1989; 77: Ex vivo

15 Inflamm Res 2007; 56:38–44 The horizontal line shows the mean values of untreated samples of healthy controls with the two dotted lines indicating the standard deviation Ex Vivo

16 Inflamm Res 2007; 56:38–44 Conclusions: GM-CSF and IFN-γ may serve to support immune functions in severely injured patients. Ex Vivo

17 Cardiac arrest: The evolution of mHLA-DR expression in circulating monocytes pre & post interferon (100γ Sc) The evolution of mHLA-DR expression in circulating monocytes before, during, and after treatment with interferon-γ and BAL culture after cardiac arrest. Lukaszewicz A-C, et al. Monocytic HLA-DR expression in intensive care patients: Interest for prognosis and secondary infection prediction. Crit Care Med 2009; 37:2746–2752

18 Septic shock: The evolution of mHLA-DR expression in circulating monocytes pre & post interferon The evolution of mHLA- DR expression in circulating monocytes before, during, and after treatment with interferon-γ after initial septic shock. Lukaszewicz A-C, et al. Monocytic HLA-DR expression in intensive care patients: Interest for prognosis and secondary infection prediction. Crit Care Med 2009; 37:2746–2752

19 IFN-γ restored the deficient HLA-DR expression and ex vivo LPS-induced TNF- secretion post sepsis Höflich C, Döcke W-D, Meisel C, Volk H-D. Regulatory immunodeficiency and monocyte deactivation Assessment based on HLA-DR expression Clinical and Applied Immunology Reviews 2 (2002) 337–344 Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients

20 Interferon-γ (100 μg/m 2 sc ) on the 2 nd post postoperative day, increases monocyte HLA-DR expression IFN-γ exerts a favorable effect on cell-mediated immunity in patients after major surgery without effects on glucose and lipid metabolism. de Metz J, et al. Interferon-γ increases monocyte HLA-DR expression without effects on glucose and fat metabolism in postoperative patients. J Appl Physiol 96: 597–603, 2004 N=7N=6

21 Nakos G et al. Crit Care Med 2002;30: HLA-DR < 30 % (n = 21) Placebo (n = 10) Infection II : 5 50 % Interferon-gamma (n = 11) Infection II : 1 9 % p < 0.05 Immunoparalysis and 100 μg Interferon-γ inhalation x 3/day x 7 days in Trauma 52 pts with severe trauma (ISS>16) HLA-DR of alveolar macrophages at days 2 or 3 Immunoparalysis was detected in 21 pts (40%) who were older and sicker. ↑ PAF, phospholipase A2, IL-1β and AM HLA-DR ↓ IL-10

22 GM-CSF Reversed Sepsis-associated Immunosuppression in 9 severe sepsis patients HLA-DR < 150 mean fluorescence intensity (MFI) over a period of at least 48 h prior to intervention 5 µg/kg per day rhGM- CSF over a period of 3 days Mortality rate was 33% Nierhaus A, et al. Reversal of immunoparalysis by recombinant human GM-CSF in patients with severe sepsis. Intensive Care Med 2003; 29:646–651 Ex vivo stimulation

23 GM-CSF (72 hrs 125 μg/m 2 ) in Septic Patients Higher leukocyte count, increased mHLA- DR, and better resolution of infections Increased HLA-DR expression was associated with clearance of infection (p=0.02) No difference in mortality (14/14 vs. 9/15) GM-CSF elevated HLA-DR in all treated patients to a level not different from healthy controls (p= 0.27) Rosenbloom AJ, et al. Effect of granulocyte-monocyte colony-stimulating factor therapy on leukocyte function and clearance of serious infection in nonneutropenic patients. Chest 2005; 127: 2139–2150 Monocyte HLA-DR was significantly lower than healthy control subjects on all patients (p < 0.01). N=15 N=18

24 GM-CSF: Ten severe sepsis and respiratory dysfunction patients vs. 8 controls Presneill JJ, et al. A Randomized Phase II Trial of GM-CSF Therapy in Severe Sepsis with Respiratory Dysfunction Am J Respir Crit Care Med 2002;166:138–143 BAL ns p<0.02 PBlood ns p<0.08 BAL ns p<0.01 p < 0.12

25 GM-CSF: Ten severe sepsis and respiratory dysfunction patients vs 8 controls Presneill JJ, et al. A Randomized Phase II Trial of GM-CSF Therapy in Severe Sepsis with Respiratory Dysfunction Am J Respir Crit Care Med 2002;166:138–143 Blood Granulocytes H2O2 p ns 0.02 Blood granulocyte phagocytic function Alveolar cell phagocytic function p< 0.05 ns p ns ns GM-CSF : was associated with improved gas exchange without pulmonary neutrophil infiltration, despite circulating neutrophils functional activation was not associated with worsened ARDS or the MODS, homeostatic role for GM-CSF in sepsis-related pulmonary dysfunction?

26 Prospective, randomized, placebo-controlled, double-blind clinical trial Adults with severe sepsis/septic shock underwent immune monitoring. Those with monocyte HLA-DR expression < 8,000 molecules/cell for 2 days were randomized to get SQ GM-CSF or placebo for 8 days (Biomarker-guided GM-CSF therapy) Monocyte HLA-DR expression, ex vivo LPS-induced TNF-α production, cytokines, and outcomes were measured

27 n = 19 patients per limp

28 Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence There was no increase either in IL-6 or IL-10 systemic levels in the GM-CSF-treated group. There were no GM-CSF-related adverse events reported. Underpowered to address mortality. Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay.

29 28-day mortality of G-CSF or GM-CSF therapy versus placebo Bo L, et al. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Critical Care 2011, 15:R58

30 In-hospital mortality of G-CSF or GM-CSF therapy versus placebo Bo L, et al. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Critical Care 2011, 15:R58

31 Reversal rate from infection of G-CSF or GM-CSF therapy versus placebo Bo L, et. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM- CSF) for sepsis: a meta-analysis. Critical Care 2011, 15:R58

32 Adverse events of G-CSF or GM-CSF therapy versus placebo. Bo L, et al. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM- CSF) for sepsis: a meta-analysis. Critical Care 2011, 15:R58 Conclusions: There is no current evidence supporting the routine use of G-CSF or GM-CSF in patients with sepsis.

33 Tapering of Immunosuppression HLA-DR+ Monocytes Rapid Tapering of Immunosuppression Patient Survival Graft Survival <30%No0/12 (0%)1/12 (8%) <30%Yes30/33 (90%)*29/30% (98%) Tapering of exogenous immunosuppression in the face of immunoparalysis is associated with improved outcomes in adult transplant patients with sepsis- induced MODS. (Volk, 1996)

34 The Journal of Immunology, 2002, 169: 384–392. Just one animal study !!!! The benefit was observed only if AS101 was injected post the hyperinflammatory state The increased survival was due, mostly, to the prompt inhibition of IL-10 The timeThe dose

35 Anti- inflammatory Sepsis Therapies Microbial products antagonists Anti-endotoxin antibodies LPS analogues Bactericidal/permeability- increasing protein Anticytokine strategies Anti-TNF antibodies TNF receptors IL-1ra Strategies against other mediators Nitric oxide—L-NMMA, L-NAME, methylene blue PAF acetylhydrolase Arachidonic acid metabolites Anti-HMGB1 Antioxidants Strategies against coagulation system Antithrombin III Tissue factor pathway inhibitor Activated protein C Enhanced elimination Hemofiltration Immune-stimulating strategies GM-CSF IFN-γ Immunonutrition Immunoglobulins? (replacement?) Vincent JL, Abraham E. AJRCCM 2006; 173: 256–263

36 Zeni F et al. Anti-inflammatory therapies to treat sepsis and septic shock: A reassessment. Critical Care Medicine (7): Sepsis/Septic shock non corticosteroid antiinflamamtory drugs Survival  No benefit

37 Figure 3 Zeni F et al. Anti-inflammatory therapies to treat sepsis and septic shock: A reassessment. Critical Care Medicine (7): Sepsis /septic Shock: High corticosteroid dose Survival  No benefit

38 Corticosteroid mortality effect (OR), stratified by high (upper panel) or low (lower panel) dose steroid regimen Moran et al. Critical Care 2010, 14:R134

39 Corticosteroid shock- reversal effect (OR), stratified by high (upper panel) or low (lower panel) dose steroid regimen Further large-scale trials appear mandated Moran et al. Critical Care 2010, 14:R134

40 APC- Drotrecogin Alfa PROWESS trial 19.4 mortality reduction aPC mediates antiinflammatory effects in the context of lethal sepsis in mice Wolfram R. New players in the sepsis-protective activated protein C pathway. J Clin Invest. 2010;120(9):3084–3087

41 All cause mortality Lutz HU, Späth P J. Anti-Inflammatory Effect of Intravenous Immunoglobulin Mediated Through Modulation of Complement Activation. Clinical Reviews in Allergy and Immunology. 2005:29: Nimmerjahn F, Ravetch JV. Anti-Inflammatory Actions of Intravenous Immunoglobulin. Annual Review of Immunology 2008; 26:

42 Fish oil is good!!! ↓ Mortality, infections and LOS Marik P, Zaloga G. Intens Care Med 2008; 34: No effect on mortality. Effect on acquisition of new infection Immunonutrition in: ICU (12), burn (5) and trauma (7) pts.

43 Crit Care Med 2010; 38:72– pts per limp Placebo vs 105 mg

44 Crit Care Med 2010; 38:1685–1694 n=93n=92 IL-6 levels were significantly higher in patients randomly assigned to placebo. IL-6 levels decreased over time in all three treatment groups. The trial was terminated because of a lack of effect of TAK-242 in suppressing serum interleukin-6 levels. Transient, dose-related methemoglobinemia (31%) NS

45 500mg/kg Zymozan IP + EP (1 & 6 hrs post) ↓ TNF-a, IL-1β, nitrotyrosine, inducible nitric oxide synthase, poly (ADP-ribose) in tissue sections staining ↓ 7 day mortality (20% vs 60%), body weight loss ↓ lung, liver, renal and pancreatic injury and renal dysfunction Crit Care Med 2009; 37:270 –282 One more animal study !!!!

46 Blood purification therapies Rimmelι and Kellum Critical Care 2011, 15:205

47 Human studies: high-volume hemofiltration Rimmelι and Kellum Critical Care 2011, 15:205

48 30 pts with severe sepsis /septic shock were randomized to hemoperfusion (2 sessions) and 34 to conventional therapy In the intervention group at 72 hours –MAP ↑ vasopressor requirement ↓ –PaO2/FIO2 ratio ↑ (slightly) –SOFA scores improved 28-day mortality was 32% (11/34 patients) in the polymyxin B group and 53% (16/30 patients) in the conventional therapy group Cruz et al. JAMA 2009;301: Reducing circulating LPS levels with polymyxin B hemoperfusion

49 33 pts, 11 in the experimental group (5days, 7.5 hrs/day Extracorporeal Immunoadsorption for IL-6, LPS and C5a) Ventilator days, ICU days ↓ Renal replacement therapy ↓ (NS) Norepinephrine need ↓ Mean APACHE II, SOFA, HLA- DR and MOF  improved SHOCK 2007; 28 (4): , IL-10 pg/ml C5a ng/ml TNF-α pg/ml PCT μg/L LBPmg/ml IL-6 pg/mL ± vs 38.2 ± 15.2 P = 0.02

50 ClinicalTrials.gov 747 studies recruiting, terminated, completed Clarithromycin as Immunomodulator for the Management of Sepsis A Safety and Efficacy Study of Intravenous E5564 in Patients With Severe Sepsis ACCESS: A Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients With Severe Sepsis A Study to Assess Safety,and Tolerability of 2 Doses of AZD9773 (CytoFab™) in Japanese With Severe Sepsis/Septic Shock Effect of APC and Epo on the Inflammatory Response During Sepsis Hydrocortisone for Prevention of Septic Shock (HYPRESS) Statin Therapy in the Treatment of Sepsis

51 Conclusion I Keeping the Balance: Keep Walking…… Either control early hyper-inflammatory states to prevent early mortality of septic shock –Steroids, APC, HVH, Immunoadsorption, Immunoglobulins, Immunonutrition –How to detect? Serum markers/cutoff points? Cytokine ratios? –Which is the right time and How to intervene? –Better definition of targets and patient population Or to boost immune response on early stages of immune suppression/paralysis to prevent secondary infections –Better defined and monitored –More specific reasoning –INF-γ and GM-CSF, promising results, more studies needed

52 Conclusion II Reduced HLA-DR (and /or the ex vivo LPS stimulation TNFα production) has been proposed as a global biomarker of immunosuppression Any immunostimulating intervention should be relied on patient immune status evaluation Consider immunostimulation within the first week post ICU admission/ sepsis Most likely GM-CSF and IFN-γ are useful treatment modalities Large prospective multicenter clinical trials investigating mHLA-DR-guided immunostimulating therapy in patients with sepsis are warranted to investigate clinical parameters and mortality as primary endpoints


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