Jong-Hau Hsu, MD, PhD Kaohsiung Medical University Hospital, Kaohsiung Taiwan

1. Early elevated BNP are associated with cardiac dysfunction and poor clinical outcome in pediatric septic patients Jong-Hau Hsu, MD, PhD Kaohsiung Medical University Hospital, Kaohsiung Taiwan

3. Sepsis • Sepsis: High mortality • Adult ICU: 30-60% • PICU: 10% • Incidence of sepsis: increase by 1.5% per yr. -- Annane D et al, 2003, AJRCCM

4. Cardiovascular dysfunction in sepsis • Presence of CV dysfunction in sepsis • mortality rate of 20%  70- 90% ---Ann Intern Med. 1990

5. Early cardiac dysfunction in sepsis • Associated with mortality -- Kumar 2001 Crit Care Med • Early cardiac echo changes in sepsis • LV enlargement • EF decreases transiently • returning to baseline within 7–10 days -- Parker 1984 Ann Intern Med

6. Challenges in assessing cardiac function in PICU • Direct monitoring CO: not feasible • Drawbacks of current tool • subjective • late • nonspecific

7. Objective, early, specific Biomarker ?

8. Endocrinefunction of the heart • Secretory granules found in atria -1964 • ANP (atrial natriuretic peptide) -1983 • BNP found in porcine Brain -1988, sudoh et al,

9. The family of natriuretic peptides

10. ABC of Natriuretic Peptide

11. Physiologic effects of NP --NEJM 1998

12. Signaling and clearance -- NEJM 1998

13. Why BNP ? • ANP • Mainly stored in granules in the atria • CNP • low plasma level, less hemodynamic effect • BNP • Secreted by ventricle • Little can be stored • Rapid synthesis in response to ventricular wall stress, even when global hemodynamics unchanged

14. Stimulation of BNP synthesis • Ventricular wall stretch • Endothelin-1 • Angiotensin-II • Catecholamine • Corticosteroid • Inflammatory cytokines

16. BNP A “distress hormone” specific to cardiac ventricles

17. BNP as a cardiac biomarker • Adult • Diagnostic and prognostic indicator for • Congestive heart failure • Coronary artery disease • Pediatric • Prognostic marker of CHD for surgery • Sepsis ?

18. BNP as a HF indicator in adults Maisel et al. NEJM, 2002

19. Our previous work of BNP in PICU • Neonatal CHD • Hsu et al, JTCVS 2007 • ECMO • Chikovani andHsu et al, JTCVS 2008 • Patent ductus arteriosus • Hsu et al, J Peds 2010 • Single Ventricle CHD • Hsu et al, JTCVS 2008

20. BNP: A valuable biomarker in PICU • CHD • Neonatal cardiac surgery -- Hsu et al, JTCVS 2007 • Single ventricle surgery -- Hsu et al, JTCVS 2008 • ECMO -- Chikovani & Hsu et al, JTCVS 2008 • Premature neonates with PDA - Response to Indomethacin -- Hsu et al, J Pediatrics 2010 • Sepsis?

21. Hypothesis of this study SEPSIS ?

22. Questions of this study • BNP levels in early pediatric sepsis • clinical associations • Cardiac function • Disease severity • Clinical outcome

23. Patients Inclusion Criteria: Sepsis or Septic shock (International Pediatric Consensus Conference, 2005, Ped Critical Care Med) Sepsis:SIRS + Infection • SIRS: >2/4 • fever or hypothermia • tachycardia • tachypnea • WBC abnormality Septic shock: Sepsis + hypoperfusion despite fluid challenge • Hypoperfusion: • lactic acidosis • decreased peripheral pulses • prolonged capillary refill • oliguria (urine output 1 mL/kg/hr) • acute alteration in mental status. • For this study, all patients required inotropic agent. Exclusion Criteria: • < 1 month, or > 18y • CHD

24. Methods • Day 1 of PICU admission • Paired plasma BNP and Echo • Study outcomes: • Mortality • Sepsis or septic shock • PRISM III scores • Inflammatory status • Cardiac function • Inotropic support

25. Quantification of inotropic support • Inotropic score = (Dopamine + dobutamine) x 1 + epinephrine x 100 + norepinephrine x 100 + milrinone x 10

26. Results

27. Question 1 of this study: BNP levels ? in infants and children with sepsis

28. Patients demographics • Patient number 94 • Mean age, yr (range) 5.7(0.2-16) • Male, n (%) 43 (46%) • PRISM III score 5 (0-32) • Need for mechanical ventilation, n 25 (26%) • ICU length of stay, day 9 (2-169) • Sites of infection • Lung 58% • Blood/Catheter 14% • Urine 10% • Abdomen 9% • Skin 6% • CNS 3% • Admission BNP 139 pg/ml(5 to 11563)

29. Normal range of BNP • Peak at birth • Decline with age (pg/ml) Costello et al , 2006, Ped Crit Care Med

30. Answer of question 1 BNP levels increase in infants and children with sepsis

31. Questions of this study: 2 Associations with Clinical Outcome?

32. Clinical outcome of patients • Mortality • Non-survivor: 13 (14%) • Survivor: 81 (86%) • CV dysfunction • Septic shock: 36 (39%) • Sepsis: 58 (61%)

33. BNP correlated with severityat ICU admission PRISM III

34. BNP correlated with inflammation CRP

35. BNP correlated with cardiac function and inotrope support

36. BNP and systolic function (FS)

37. BNP and survival

38. BNP and shock

39. Summary of Results • Early elevated BNP associated with: • Mortality • Septic shock • CRP • PRISM III • LV FS • Inotropic score

40. BNP increase in sepss Cardiac dysfunction SIRS

41. Discussions • High BNP associated with • Cardiac function and support • Inflammation status and mortality • Causes of BNP release • Cardiac dysfunction • Inflammation

42. Similar results in adult sepsis Survival Cardiac function

43. Conclusions BNP is a prognostic biomarker in early pediatric sepsis

44. Clinical Implications • BNP may identify those requiring • Myocardial support • Meticulous intensive care

45. Thank you