1. Influence of complement C5a antagonist (AcPepA) treatment on the hemodynamic complications of cardiac tamponade (Critical Care Med. in press 2013)
Dániel Érces1, József Kaszaki1, Ildikó László1, Miklós Nógrády1, Enikő Nagy1, Hidechika Okada2, Mihály Boros1
Institute of Surgical Research1, University of Szeged, Hungary
Department of Immunology2, Nagoya City University, Nagoya, Japan

2. Intrapericardial fluid
Cardiac Tamponade
Impaired cardial pump function, which may lead to cardiogenic shock due to fluid accumulation in the pericardial sack.
Ethiology:
Trauma
Iatrogenic
Systemic diseases (tumors, renal failure, SLE, carditis)
Rupture of postinfarct heart-wall and aortic aneurysm
Intrapericardial fluid
Pericardium

3. Splanchnic hypoperfusion
Importance of splanchnic hypoperfusion as a complication of cardiogenic shock
Cardiac tamponade
Circulatory redistribution
Therapy :
Fluid replacement
Pericardiocentesis
Heart surgery
Reperfusion injury
Inflammation
Splanchnic hypoperfusion
Cell- and plasma derived inflammatory mediators:
Production of reactive oxygen species
Activation of the complement system
LOCAL EFFECTS
SYSTEMIC EFFECT
Tissue damage
Microcirculatory damage
General circulatory impairment

4. Effects of complement C5a Induction of histamine release
Chemoattraction
  Activation of COX and lipoxygenase
Induction of histamine release
Inflammation

5. High mobility group box protein 1 (HMGB1)
Nuclear protein:
active secration from cells of the congenital immunity
passively released from necrotic cells
‘Alarm’ – signal:
very potent proinflammatoric signal
able to aggravate inflammation to SIRS/sepsis

6. Objective
To examine the effects of complement C5a inhibition on the circulatory and inflammatory complications of cardiac tamponade:
Macrohemodynamics
Superoxide production;
Leukocyte (myeloperoxidase) activity;
HMGB1 concentration.

7. The complement C5a antagonist
Synthetic antisense peptide, developed by the Department of Immunology, Nagoya City University, Japan. (Acetilated version of the Peptid-A)*
Binds to the central region of C5a.
Half-life is less than 30 minutes.
Improved the survival rate of endotoxic shock in macaques -„Anaphylatoxin Blocker”** c
* Emiko Fujita, Imre Farkas, William Campbell, Lajos Baranyi, Hidechika Okada, Noriko Okada: Inactivation of C5a anaphylatoxin by a peptide that is complementary to a region of C5a J. Immunol. 2004; 172;
** Hidechika Okada, Fumiko Ono, Keiji Terao, Alan Okada, Suzuka Asai, William Campbell, Yuka Mizue, Kazuo Suzuki, Noriko Okada: C5a anaphylatoxin inhibitor suppresses a lethal cytokine storm in monkeys injected with LPS
XXII International Complement Workshop 2008.

8. Methods I. PiCCO reference thermistor pressure sensor thermistor
Sublingual- and gastric tonometer
pressure
sensor
Flow probe:
Superior mesenteric artery
thermistor
Ventilation
VT=10ml*kg-1
FiO2=0,21
EtCO2=35 mmHg
Anaesthesia:
Induction: Ketamine+Xylazine
Maintenance: Propofol 2% (50 μl*kg-1*min-1)

9. Methods II. CO2 gap = pgiCO2 – paCO2
Tonometry: The pCO2 gap value is an indirect index of the mucosal microcirculation (Boda D; Eur J Anaesthesiol 2006)
pgiCO2= local, tissue pCO2 in the small intestine
paCO2= systemic arterial pCO2
CO2 gap = pgiCO2 – paCO2
Chemiluminometry
Measurement of whole blood superoxide production
lucigenin h
Superoxide
O2*- +
lucigenin-O2
Detection
Myeloperoxidase (MPO) aktivity Photometry
HMGB1 plasma concentration
ELISA kit /HMGB1 ELISA Kit II/

10. Tissue biopsy at 240 min for biochemical measurements
Protocol
hemodynamics
blood gas
tonometry
Blood samples for superoxide and HMGB1 measurements
1. Sham-operated (n=6)
-60 min
2. Cardiac Tamponade (n=5)
Cardiac
tamponade
-60 min
3. Cardiac Tamponade + C5a antagonist (n=5)
Cardiac
tamponade
-60 min
C5a antagonist
(Anablock; iv. 4 mg*kg-1)
Tissue biopsy at 240 min for biochemical measurements

11. Statistical analysis Non-parametric methods - Inside groups:
Friedman & Dunn test;
* p< 0,05 vs 0 min
- Between groups:
Kruskal-Wallis & Dunn test;
x p<0,05 Sham-operated vs Tamponade
# p<0,05 Tamponade vs Tamponade + C5 antagonist

12. Mean Arterial Pressure
TAMPONADE
C5a antagonist

13. Cardiac Index
TAMPONADE
C5a antagonist

14. Central Venous Pressure
TAMPONADE
C5a antagonist

15. Influence of complement C5a antagonist (AcPepA) treatment on the hemodynamic complications of cardiac tamponade Superior Mesenteric Artery Blood Flow
TAMPONADE
C5a antagonist

16. Sublingual pCO2 gap
TAMPONADE
C5a antagonist

17. Gastric pCO2 gap
TAMPONADE
C5a antagonist

18. Influence of complement C5a antagonist (AcPepA) treatment on the hemodynamic complications of cardiac tamponade (Crit. Care Med. 2013) Whole Blood Superoxide Production
TAMPONADE
C5a antagonist AcPepA

19. Influence of complement C5a antagonist (AcPepA) treatment on the hemodynamic complications of cardiac tamponade Superior Mesenteric Artery Blood Flow
TAMPONADE
C5a antagonist

20. HMGB1 plasma concentration
TAMPONADE
C5a antagonist AcPepA

21. Small Intestinal Tissue MPO Activity

22. Summary PT C5a ant Mean arterial pressure SMA blood flow
SMA blood flow
Central venous pressure
Cardiac index
Gastric CO2 gap
Superoxide production
HMGB1 plasma concentration
Small intestinal MPO activity

23. Conclusion c
Administration of C5aA has been able to influence the hemodynamic complications of Cardiac Tamponade (CT), beside moderation of its inflammatory consequences.
These results refer to the importance of complement activation in the circulatory changes following cardiogenic shock.

24. THANK YOU FOR YOUR ATTENTION !
TÁMOP /

26. Szívfrekvencia c

27. A szív végdiasztolés térfogata (GEDVi)c

28. Plazma big-endothelin szint
C5a A

30. Állatok instrumentálása ( anesztézia, erek preparálása és a katéterek behelyezése, tonomitorok behelyezése, has és a mellkas megnyitása, ultrahangos áramlásmérő felhelyezése, pericardiális kanül behelyezése majd kolloid befecskendezés.
Vérminták levétele és elemzése,