Beta-blockers:destressing the septic patient

UNSW

John MyburghMBBCh PhD FCICM FAICD

The George Institute for Global Health St George Clinical School, University of New South Wales

Arthur Guyton 1919-2003

Cardiac function

Right atrial pressure (mmHg)

0

10

Venous return

l/min

Cardiac function

Mean systemic pressure

Guyton: 1953

Cardiac failure

Right atrial pressure (mmHg)

0

10

Cardiac failure

Normal

Normal

l/min

Guyton: 1953

Cardiac failure

Right atrial pressure (mmHg)

0

10

Cardiac failure

Francis : Am Heart J 1982

l/min

Venoconstriction

Cardiac failure

Right atrial pressure (mmHg)

0

10

Catecholamines Catecholamines

l/min

Francis : Am Heart J 1982

Septic shock

Right atrial pressure (mmHg)

0

10 Normal

Normal

Jacobsohn: Can J Anes 1997

l/min

Septic shock

Right atrial pressure (mmHg)

0

10 Vasoplegia

l/min

Vasoplegia

Jacobsohn: Can J Anes 1997

Septic shock

Right atrial pressure (mmHg)

0

10

Cardiac depression

l/min

Jacobsohn: Can J Anes 1997

Septic shock

Right atrial pressure (mmHg)

0

10

l/min

Fluid / catecholamines

Catecholamines

Jacobsohn: Can J Anes 1997

Hein: Cell Tissue Research 2006

Neurohormonal vasoregulation

Neurohormonal vasoregulation

Sadowska : J Physiol Pharm 2006

VP

NoradrenalineAdrenaline

Cortisol

Cardiac failure

Spectrum of pathology

Compensated Decompensated

Acute

Chronic

Spectrum of treatment

Compensated Decompensated

Neurohormonal modulation

Acute

Chronic

Pharmacologicalaugmentation

Cardiac failure

Spectrum of treatment

Compensated Decompensated

Acute

Chronic

ACE inhibitorsAT-II inhibitors

Blockade

CatecholaminesDiuretics

Cardiac failure

Cardiac failure and β-blockade

Abraham: Arch Int Med 2001

Carvedilol: NYHA II-III

Bisoprolol: NYHA III-IV

β-blockade and outcomes in CHF

Shibata: Eur J Heart Failure 2001

Mortality and hospital admission

Pooled effect: 0.68, P<0.00001

ACS / PCI and β-blockade

ACS / PCI and β-blockade

Whole cohort: (n=3 692) Low LVEF: (n=450)

Bao: Cardiovasc Interv Ther 2013

Database registry 2005-2007PCI within 24h STEMI

Β-blockade at hospital dischage

Angus: NEJM 2013

β-blockade and sepsis

Ackland: Crit Care Med 2010

Hepatic

Myocardial

48h pre-LPS

6h post-LPS

Previous β-blockade and sepsis

Macchia: Crit Care Med 2012

Database linkage: 2003-20081061/ 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)

Rivers: NEJM 2001

MAP targets

MAP targets

Myburgh: ICM 2008

MAP targets

Asfar:NEJM 2014

Multicentre, pragmatic, POC, RCTCatecholamine-dependent sepsis65-70 vs 80-85mmHg x 5 days

MAP targets

Asfar:NEJM 2014

p=0.57 p=0.74

Multicentre, pragmatic, POC, RCTCatecholamine-dependent sepsis65-70 vs 80-85mmHg x 5 days

Lactate targets

James: Lancet 1999 Myburgh: ICM 2008

Heart rate target

Phase II, single centre, open-label prospective RCTΒ-blocker naïveCatecholamine dependent sepsis : MAP>65, CI > 2.2 l/m/m2

Esmolol 25mg/hr + 50 mg/h to HR 80-94

Morelli: JAMA 2013

The quest for meaningful outcomes

NICE-SUGAR: NEJM 2009 DECRA: NEJM 2011

Conclusions

Neurohormonal regulation is a complex biological process.

Neurohormonal modulation is a complex therapeutic intervention

β-blockade is a small component of modulatory therapy

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

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.

John F Kennedy1917-1963

“Too often we enjoy the comfort of opinion without the discomfort of thought”