Esmolol in Sepsis
Dr Pamela Eakin ST4
ICM Meeting Nov 2013
Altnagelvin Area Hospital
Beta-adrenoreceptors
•
•

Widespread

•

Immune cells, vessels, heart, airways, lungs, adipose tissues,
skeletal muscle, b...
Immune Modulation
•
•
•
•
•
•

Complex
Increased production of monocytes during sepsis
Increased pro-inflammatory cytokine...
Immune Modulation
• Beta 2 activation and beta 1

blockade down-regulates the
pro-inflammatory response

• Numerous studie...
Cardiovascular Modulation
•
•
•
•
•

Oxygen supply/demand imbalance
Adrenergic system stimulated

•

= positive inotropy +...
Cardiovascular Modulation
•
•

Energy demand > supply  risk of cell death

•

Cardiac dysfunction - mortality rates rise ...
Cardiovascular Modulation
•
•

The ability of cells to utilise oxygen is disrupted

•

Critical inflection point exists at...
Metabolic and Coagulation
Modulation
•
•

Adaptative catabolic response

•

Beta 2 signaling mediates the increase in prot...
Metabolic and Coagulation
Modulation
• Sepsis produces a procoagulant state
• Complex
• Beta 1 and beta 2 pathways appear ...
Questions
• Is an adrenergic antagonist beneficial?
• Which one?
• How?
• When?
• Who?
Evidence
•
•

2 recent studies

•

Aim - investigate effects of reducing heart rate to less than
95 bpm

Morelli et al. Mi...
Study Design
•
•

25 patients
Exclusion criteria

•
•
•
•
•
•

<18 y
use of an inotrope
CI < 2.2l/min/m2
PAOP >18mmHg
sign...
Observations
• Microcirculatory blood flow
• PAC
• Cardiac output monitoring
Outcomes
•
•
•
•
•
•

HR and cardiac index significantly reduced
Stroke volume maintained
Noradrenaline requirements were ...
Pitfalls
•
•
•
•
•
•
•

Small population
No controls
Unblinded
Pneumonia in majority
Male > female
Heart rate of 95bpm was...
Morelli et al. Effect of heart rate control with esmolol
on haemodynamic and clinical outcomes in patients
with septic sho...
Design
• Inclusion/exclusion criteria
• Esmolol commenced after 24 hours of
haemodynamic stabilisation

• 336 patients scr...
Design
•
•
•
•
•

Levosimendan added to improve systemic O2 delivery
Not in keeping with 2012 Surviving Sepsis Guidelines
...
Results
•

Esmolol increased stroke volume, maintained MAP, reduced
noradrenaline requirements

•
•

Improved 28 day morta...
Discussion
•
•
•
•
•

Many questions, more research is needed
How to determine optimal heart rate for each patient?
Is esm...
Conclusion
• Exciting concept in the management of sepsis
• Need to delineate optimal targets / agents /
cohorts

• More r...
References

•

Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Critical Care Medicine
2007; 35 (6)
...
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Esmolol in Sepsis

  1. 1. Esmolol in Sepsis Dr Pamela Eakin ST4 ICM Meeting Nov 2013 Altnagelvin Area Hospital
  2. 2. Beta-adrenoreceptors • • Widespread • Immune cells, vessels, heart, airways, lungs, adipose tissues, skeletal muscle, brain Excessive adrenergic stress has adverse effects • • • • • Myocardial damage Insulin resistance Thrombogenicity Immunosuppression Enhanced bacterial growth
  3. 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. 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. 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. 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. 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. 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. 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. 10. Questions • Is an adrenergic antagonist beneficial? • Which one? • How? • When? • Who?
  11. 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)
  12. 12. Study Design • • 25 patients Exclusion criteria • • • • • • <18 y use of an inotrope CI < 2.2l/min/m2 PAOP >18mmHg significant valve disease pregnancy
  13. 13. Observations • Microcirculatory blood flow • PAC • Cardiac output monitoring
  14. 14. Outcomes • • • • • • HR and cardiac index significantly reduced Stroke volume maintained Noradrenaline requirements were reduced Blood gas results improved Microvascular flow index improved MAP/lactate unchanged
  15. 15. Pitfalls • • • • • • • Small population No controls Unblinded Pneumonia in majority Male > female Heart rate of 95bpm was arbitrary Side stream dark field imaging open to artefact/bias
  16. 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. 17. Design • Inclusion/exclusion criteria • Esmolol commenced after 24 hours of haemodynamic stabilisation • 336 patients screened • 154 included (77 in each arm) • Unblinded
  18. 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. 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. 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. 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. 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)

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