Dr Noryani Mohd Samat

Sepsis pathophysiology –revisit

Rationale of beta blockers influencing sepsis’s course

Evidence so far…

Conclusion

CONTENT

Sepsis still contributes to high morbidity & mortality

Efforts has been made to understand sepsis and to find the proper strategy to combat sepsis

One of sepsis’s complex pathophysiology associates with hyperadrenergic condition that leads to overwhelming haemodynamic instability

Promising role of beta blocker has been explored and the answer is still out there…

Beta blockade

effect

Hyperdynamic

phase Decompensated

phase

Boomer et al. Virulence 2014

Immune response in sepsis

The autonomic nervous system and immune system are closely related in the inflammatory response

The main connecting pathway is the hypothalamus-pituitary-adrenergic axis and the autonomic nervous system.

Catecholamines play a role in immune regulation through the α-and β-adrenergic receptors expressed by immune cells

Vagus nerve stimulation and α 7-cholinergic receptor activation can reduce macrophage intracellular cytokine synthesis and lower the inflammatory response

Sepsis involve multitude of pathophysiological changes in terms of cardiovascular alterations, metabolic derangements and immunomodulation

Hyperadrenergic state due to sepsis results in

Cardiac: increased contractility, heart rate and myocardial energy demand

Extra cardiac: catabolic state, hyperglycemia, hypercoagulability, release modulation of systemic inflammatory cytokines effects

Prolong exposure to catecholamine is toxic!

Beta blockade therapy in

sepsis

Decreased cardiac dysfunction

Cytokines effects

Improves glucose hemeostatsis

Normalization of cellular

metabolism

Occur in 50%, described as diminution of right and left ventricular function

Mechanisms of myocardial depression are multiple

Beta blockers may improve endothelium dependent relaxation by exerting anti-inflammatory effects and could reduce arterial elastance(Ea), help the LV to generate a higher SV with less contractility and lower energetic cost and indirectly will cause reduction in vasopressor requirements

Morelli et al. ICM 2016

Suppress L-type Ca

channel

Synergistic effect

Lymphoid organs such as the spleen, thymus, lymph nodes and bone marrow are predominantly innervated by the sympathetic system

The majority of lymphoid cells except T helper type 2 (Th2) express β-adrenergic receptors (beta 2) on their surface

Catecholamines, via a β2-mediated pathway

downregulate the synthesis of proinflammatory cytokines :

TNFα, IL-6 and IL-1

upregulate synthesis of anti inflammatory cytokines : IL-10 Muthu et al. J Neuro- immunol 2005

Deng et al. Am J Physiol Cell Physiol 2004

• One study done by Suzuki et al. in mice

noted decreased the levels of circulating cytokines

-TNF- α, IL-6, and high-mobility group box 1 by using

landiolol

• A study by Jeschke et al found a significant decrease

in IL-1 production after the administration of propranolol

in 250 burns patient

Sepsis is catabolic state

Characteried by

Increase resting energy expenditure

Extensive protein and fat metabolism

Negative nitrogen balance

Reduce lean body mass

Therefore, beta 2 antgonist ie, propanolol has potential to reverse these catabolic state

Mediated by beta 2 activation signaling

1969

Berk et al

Propanolol

2005

Gore et al

Esmolol

2011

Aboab et al

Esmolol

2008

Schmittinger et al

Metoprolol (en)

2012

Balik et al

Esmolol

2013

Morelli et al

Esmolol

Observation , RCT

Investigated on 90 dogs, injected with endotoxin

3 groups :

1. Placebo

2. Endotoxin + propanolol

3. Endotoxin alone

Result:

• Survival significantly improved in propranolol

treated group vs. untreated or fluid resuscitation

group (25/32 v. 7/36 v. 6/22, P < 0.001)

• treated group required more fluid than propranolol

group (80 mL/kg v 40 mL/kg)

Landmark

Paper !!

Retrospective study , Italy ICUs

Sample size: 9465 patients in sepsis

Primary end point: to look at 28 day mortality in patient who had beta blocker

presciption pre ICU admission

Macchia et al. Crit Care 2012

Patients previously on β-blockers had a lower mortality of 17.7% compared to 22.1% in patients not previously exposed (odds ratio 0.78; 95% confidence)

Favor beta blocker!

Conducted in Italy, single center

Randomised control trial

Sample size =154

Intervention : control versus esmolol infusion

End point:

primary: reduction in heart rate

secondary: haemodynamic changes and organ function measures

Usage of esmolol associates with lower usage of NA over times

Morelli et al. JAMA 2013

Mean reduction of 18 beats/min

Morelli et al. JAMA 2013

Morelli et al. JAMA 2013

Prospective cohort study

Sample size: 151 septic patient

Objectives: to look on esmolol tissue perfusion effect and clinical prognosis

Which beta blocker to use? When should it be

used?

How to administer it?

Who will be suitable

to use beta blocker?

What target is safe

Prefer short acting

Selective vs. Non Selective…debatable

• Preferably after optimising circulating blood volume

adequately, at least after 24 h

• According to Morelli et al., the optimise condition noted

by pulmonary arterial occlusion pressure of ≥12 mm Hg

and central venous pressures of ≥8 mm Hg, a mixed

venous oxygen saturation higher than 65% and a MAP of

65 mm Hg or higher

Intravenous most practical

Infusion, in titrating mannner

a fixed dose is not a good choice

physiological titration to heart rate or oxygen delivery in relation to oxygen demand seems more advisable.

Major aim to improve diastolic filling by slow down the heart rate

By 20%

Based on only RCT available 94-80 beats/min seems to be safe

Best candidate will be those with hyperdynamic state provided preserved and good left ventricle function

At current rate, β-blockers could improve outcome

decreased myocardial oxygen demand,

improved myocardial oxygen utilization

immunomodulation of hypercatecholaminemia

So far, proper recommendation on it’s clinical practice use are pending, more and further concrete evidence to be implemented.

Looking forward to see more trials