Dr Noryani Mohd Samat

Transcription

1 Dr Noryani Mohd Samat

2 CONTENT Sepsis pathophysiology revisit Rationale of beta blockers influencing sepsis s course Evidence so far Conclusion

3 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

4

5

6 Immune response in sepsis Beta blockade effect Hyperdynamic phase Decompensated phase Boomer et al. Virulence 2014

7 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

8 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!

9 Decreased cardiac dysfunction Normalization of cellular metabolism Beta blockade therapy in sepsis Cytokines effects Improves glucose hemeostatsis

10 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

11 Suppress L-type Ca channel Synergistic effect

12 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

13

14 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

15 Sepsis is catabolic state Characteried by Increase resting energy expenditure Extensive protein and fat metabolism Negative nitrogen balance Reduce lean body mass Mediated by beta 2 activation signaling Therefore, beta 2 antgonist ie, propanolol has potential to reverse these catabolic state

16

17 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

18 Investigated on 90 dogs, injected with endotoxin 3 groups : 1. Placebo 2. Endotoxin + propanolol 3. Endotoxin alone Landmark Paper!! 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)

19 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

20 Macchia et al. Crit Care 2012

21 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)

22 Favor beta blocker!

23 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

24 Usage of esmolol associates with lower usage of NA over times Morelli et al. JAMA 2013

25 Mean reduction of 18 beats/min Morelli et al. JAMA 2013

26 Morelli et al. JAMA 2013

27

28 Prospective cohort study Sample size: 151 septic patient Objectives: to look on esmolol tissue perfusion effect and clinical prognosis

29

30

31

32 Which beta blocker to use? When should it be used? How to administer it? What target is safe Who will be suitable to use beta blocker?

33 Prefer short acting Selective vs. Non Selective debatable

34

35 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

36 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.

37 Major aim to improve diastolic filling by slow down the heart rate By 20% Based on only RCT available beats/min seems to be safe

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

39 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

40

41