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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
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