3. Immune Modulation
•
•
•
•
•
•
Complex
Increased production of monocytes during sepsis
Increased pro-inflammatory cytokines
Simultaneous counter-inflammatory response
Excessive inflammation favours organ failure
Understimulation/over-production of antiinflammatory mediators reduces response to infection
4. Immune Modulation
• Beta 2 activation and beta 1
blockade down-regulates the
pro-inflammatory response
• Numerous studies, primarily
animal based
• Results are conflicting
5. Cardiovascular Modulation
•
•
•
•
•
Oxygen supply/demand imbalance
Adrenergic system stimulated
•
= positive inotropy + positive chronotropy
Initial benefit but long term harm
Tachycardia increased myocardial oxygen consumption,
shortened diastolic relaxation time, reduced coronary
perfusion, depleted ATP
Increased heart rate at presentation and following
haemodynamic stabilisation is associated with nonsurvivor status
6. Cardiovascular Modulation
•
•
Energy demand > supply risk of cell death
•
Cardiac dysfunction - mortality rates rise by up to 70% in
sepsis
•
Postmortem studies have shown increased inflammatory
infiltration but minimal myocardial cell death
Heart failure and aggravated microcirculatory
disturbance/tissue hypoxia
7. Cardiovascular Modulation
•
•
The ability of cells to utilise oxygen is disrupted
•
Critical inflection point exists at which further
reduction of cardiac work will lead to harmful
reduction of cardiac output
Is the answer to reduce cell oxygen demand, vs drive
more oxygen to the cell unable to use it?
8. Metabolic and Coagulation
Modulation
•
•
Adaptative catabolic response
•
Beta 2 signaling mediates the increase in protein and lipid
catabolism and hyperglycaemia
•
Herndon et al
Increased basal metabolic rate, extensive protein and fat
catabolism, negative nitrogen balance, hyperglycaemia,
progressive loss of lean body mass
9. Metabolic and Coagulation
Modulation
• Sepsis produces a procoagulant state
• Complex
• Beta 1 and beta 2 pathways appear to have
opposite effects
• Beat 2 blockade may be detrimental
• Beta 1 blockade could be beneficial
10. Questions
• Is an adrenergic antagonist beneficial?
• Which one?
• How?
• When?
• Who?
11. Evidence
•
•
2 recent studies
•
Aim - investigate effects of reducing heart rate to less than
95 bpm
Morelli et al. Microvascular effects of heart rate control
with esmolol in patients with septic shock: a pilot study.
Critical Care Medicine 2013; 41 (9)
16. Morelli et al. Effect of heart rate control with esmolol
on haemodynamic and clinical outcomes in patients
with septic shock. A randomized clinical trial. JAMA
2013; 310 (16)
•
•
Single centre, open-label, randomized
•
Secondary aim - effects on noradrenaline requirements,
cardiorespiratory and oxygenations indices, safety end
points, 28 day survival
Aim - determine if esmolol could reduce heart rates to
lower than 95bpm and maintain heart rates between 8090bpm
17. Design
• Inclusion/exclusion criteria
• Esmolol commenced after 24 hours of
haemodynamic stabilisation
• 336 patients screened
• 154 included (77 in each arm)
• Unblinded
18. Design
•
•
•
•
•
Levosimendan added to improve systemic O2 delivery
Not in keeping with 2012 Surviving Sepsis Guidelines
Confounder?
Results applicable to our own ICU patients?
No breakdown data to compare patients in esmolol vs nonesmolol group who did or did not receive levosimendan
19. Results
•
Esmolol increased stroke volume, maintained MAP, reduced
noradrenaline requirements
•
•
Improved 28 day mortality (80.5 vs 49.4%)
•
High mortality rates - is the mortality benefit a chance
finding?
•
Unblinded
Mortality rates are higher than would be predicted from
SAPS II scores does this skew the results?
20. Discussion
•
•
•
•
•
Many questions, more research is needed
How to determine optimal heart rate for each patient?
Is esmolol the most appropriate beta blocker?
Other effects of esmolol?
Timeframe for intervention?
21. Conclusion
• Exciting concept in the management of sepsis
• Need to delineate optimal targets / agents /
cohorts
• More research needed
• Reassurance provided with respect to the safety of
further studies
22. References
•
Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Critical Care Medicine
2007; 35 (6)
•
Montmollin et al. Bench to beside review: Beta adrenergic modulation in sepsis. Critical Care
2009;13:230
•
Sander O et al: Impact of prolonged elevated heart rate on incidence of major cardiac events in
critically ill patients with a high risk of cardiac complications. Critical Care Medicine 2005; 33:
81-88
•
Parker et al: Serial cardiovascular variables in survivors and non-survivors of human septic
shock: Heart rate as an early predictor of prognosis. Critical Care Medicine 1987; 15:923-929
•
Blanco et al. Incidence, organ dysfunction and mortality in severe sepsis: A Spanish Multicentre
study. Critical Care 2008; 12:R158
•
•
Herndon et al. Reversal of catabolism by beta-blockade after severe burns. NEJM 2001; 345
•
Morelli et al. Effect of heart rate control with esmolol on haemodynamic and clinical outcomes
in patients with septic shock. A randomised clinical trial. JAMA 2013; 310 (16)
Morelli et al. Microvascular effects of heart rate control with esmolol in patients with septic
shock: A pilot study. Critical Care Medicine 2013; 41(9)
