John Myburgh on the emerging evidence for the use of beta-blockade in sepsis. Direction for future research.

1. Beta-blockers:
destressing the septic patient
UNSW
John Myburgh
MBBCh PhD FCICM FAICD
The George Institute for Global Health
St George Clinical School, University of New South Wales

2. Arthur Guyton
1919-2003

3. Cardiac function
Right atrial pressure (mmHg)
0
10
Venous return
l/min
Cardiac function
Mean systemic pressure
Guyton: 1953

4. Cardiac failure
Right atrial pressure (mmHg)
0
10
Cardiac failure
Normal
Normal
l/min
Guyton: 1953

5. Cardiac failure
Right atrial pressure (mmHg)
0
10
Cardiac failure
Francis : Am Heart J 1982
l/min
Venoconstriction

6. Cardiac failure
Right atrial pressure (mmHg)
0
10
Catecholamines Catecholamines
l/min
Francis : Am Heart J 1982

7. Septic shock
Right atrial pressure (mmHg)
0
10
Normal
Normal
Jacobsohn: Can J Anes 1997
l/min

8. Septic shock
Right atrial pressure (mmHg)
0
10 Vasoplegia
l/min
Vasoplegia
Jacobsohn: Can J Anes 1997

9. Septic shock
Right atrial pressure (mmHg)
0
10
Cardiac
depression
l/min
Jacobsohn: Can J Anes 1997

10. Septic shock
Right atrial pressure (mmHg)
0
10
l/min
Fluid / catecholamines
Catecholamines
Jacobsohn: Can J Anes 1997

11. Hein: Cell Tissue Research 2006
Neurohormonal vasoregulation

12. Neurohormonal vasoregulation
Sadowska : J Physiol Pharm 2006
VP
Noradrenaline
Adrenaline
Cortisol

13. Cardiac failure
Spectrum of pathology
Compensated Decompensated
Acute
Chronic

14. Spectrum of treatment
Compensated Decompensated
Neurohormonal
modulation
Acute
Chronic
Pharmacological
augmentation
Cardiac failure

15. Spectrum of treatment
Compensated Decompensated
Acute
Chronic
ACE inhibitors
AT-II inhibitors
βBlockade
Catecholamines
Diuretics
Cardiac failure

16. Cardiac failure and β-blockade
Abraham: Arch Int Med 2001
Carvedilol: NYHA II-III
Bisoprolol: NYHA III-IV

17. β-blockade and outcomes in CHF
Shibata: Eur J Heart Failure 2001
Mortality and hospital admission
Pooled effect: 0.68, P<0.00001

18. ACS / PCI and β-blockade

19. ACS / PCI and β-blockade
Whole cohort: (n=3 692) Low LVEF: (n=450)
Bao: Cardiovasc Interv Ther 2013
Database registry 2005-2007
PCI within 24h STEMI
Β-blockade at hospital dischage

20. Angus: NEJM 2013

21. β-blockade and sepsis
Ackland: Crit Care Med 2010
Hepatic
Myocardial
48h pre-LPS
6h post-LPS

22. Previous β-blockade and sepsis
Macchia: Crit Care Med 2012
Database linkage: 2003-2008
1061/ 8404 patients with sepsis
28-day mortality:
β-blocker: 188/1061 (17.7%)
No β-blocker: 1857/ 8404 (22.1%)
OR 0.78 (0.66 to 0.93)

24. Rivers: NEJM 2001
MAP targets

25. MAP targets
Myburgh: ICM 2008

26. MAP targets
Asfar:NEJM 2014
Multicentre, pragmatic, POC, RCT
Catecholamine-dependent sepsis
65-70 vs 80-85mmHg x 5 days

27. MAP targets
Asfar:NEJM 2014
p=0.57 p=0.74
Multicentre, pragmatic, POC, RCT
Catecholamine-dependent sepsis
65-70 vs 80-85mmHg x 5 days

28. Lactate targets
James: Lancet 1999 Myburgh: ICM 2008

29. Heart rate target

30. Phase II, single centre, open-label prospective RCT
Β-blocker naïve
Catecholamine dependent sepsis : MAP>65, CI > 2.2 l/m/m2
Esmolol 25mg/hr + 50 mg/h to HR 80-94
Morelli: JAMA 2013

31. The quest for meaningful outcomes
NICE-SUGAR: NEJM 2009 DECRA: NEJM 2011

32. Conclusions
Neurohormonal regulation is a complex biological process.
Neurohormonal modulation is a complex therapeutic intervention
β-blockade is a small component of modulatory therapy

33. Conclusions
The efficacy of β-blockade in chronic heart failure has been
determined in large RCTs.
The efficacy of β-blockade after ACS remains uncertain
The biological effects of β-blockade in inflammatory states are
complex, but tantalising based on animal and observational
studies

34. Conclusions
Caution is required with neuroendocrine intervention in
critically ill patients.
A pragmatic RCT to test the effects of β-blockade on patient-
centred outcomes in sepsis is required.

35. John F Kennedy
1917-1963
“Too often we enjoy the
comfort of opinion
without the discomfort of
thought”