1. Is it really a shocking news?
Dr. S. Narayan
Prof Micheal Reade

2. Small study – 25 patients
Paediatric population
Did not look at mortality rate
Outcome focused on attenuation of hypermetabolism and muscle-protein catabolism
Propranolol associated with significant attenuation of hypercatabolism and muscle protein catabolism in burns patients

3. Journal of trauma in 2004
Retrospective cohort study – 1996 to 2001
Significant decrease in healing time and fatal outcome with oral beta blockers
Prospective, MC, RCT single blinded
Significant reduction in both short term(hospital mortality) and long term mortality (at 1 Yr)

4. Must read review article
Well explained about why beta blockers in sepsis
Evidence conflicting in regards to improvement in mortality but favours beta blockers with non significant trend towards improvement in mortality

5. Effect of Beta blockers in peri operative patients
RCT, MC, 8351 patients from 190 hospitals
Treatment group (with metoprolol) though had lower rate of MI, but the study did show increased risk of stroke and higher death rate

6. Retrospective cohort study Included 40 patients
Volume resuscitated, on NA and milrinone infusion
Metoprolol given orally (25 to 47.5mg/day )
After 96 hrs follow up:
HR, vasopressor requirement decreased
Cardiac OP stable
Lactate, pH, Creatinine, CRP improved
Many limitations in the paper – not assessed with control group

7. Retrospective analysis – Italian hospitals from 2003 to 2008
9,465 patients with chronic beta blocker therapy
Reduced mortality with beta blocker – 17% vs 24%

8. Phase II randomized clinical trial
Objective:
To investigate the effect of short acting β blockers in patients with septic shock
Open label
Phase II randomized clinical trial
Single centre, 18 bedded ICU – conducted in a University hospital
November 2010 to July 2012
Randomly assigned 154 patients with septic shock

9. Patient with septic shock After 24 hrs of optimization
Inclusion criteria:
Patient with septic shock
After 24 hrs of optimization
Still requiring high dose NA to maintain MAP > 65mmHg despite appropriate volume resuscitation
CVP ≥ 8mmHg
PAOP ≥ 12mmHg
SVO2 > 65%
HR ≥ 95/min
Exclusion criteria:
Age < 18yrs
β blocker therapy prior to randomization
Pronounced cardiac dysfunction
CI ≤ 2.2L/min/m2
PAOP > 18mmHg
Significant valvular heart disease
Pregnancy
Computer based randomization
Approved by local institutional ethic committee
Written informed consent obtained
Esmolol infusion titrated for HR < 95/min

10. Outcome: Primary: Reduce HR < than predefined threshold of 95/min
To maintain HR 80-94/min throughout the duration patient’s ICU stay
Secondary outcome:
Effect of esmolol on NA requirements
Cardio respiratory and oxygen indices
Safety endpoints
Markers of organ function and injury
Rescue therapy
28 day overall mortality

11. Esmolol infusion @ 25mg/hr
Increased Q 20 mins to > 50 mg/hr (median esmolol dose was 100mg/hr)
To reach predefined threshold < 12 hrs
Maintained infusion throughout ICU stay
Esmolol infusion max 2000mg/hr
Optimized volume status with boluses as required
Aimed for Hb target > 80g/L but transfused if < 70g/L
NA for MAP > 65
Hydrocortisone 300mg/d continuous infusion

12. Hemodynamic monitoring and investigations
Devices:
PA catheter
Radial artery catheter
Monitoring:
MAP
CVP
Mean PAP and occlusion pressure
Cardiac index – thermodilution technique
Arterial and mixed venous blood sampling
Laboratory investigations:
Biochemistry
Haematology
Coags profile
Cardiac troponin and CK-MB

13. Sample size and statistical analysis
64 patients per group required
To detect a 20% change in HR
Power of 80%
Type I error of 0.05
Statistical analysis:
Analysis performed for intention to treat principle
Wilcoxon-Mann or X2 test
28 day survival mortality using multivariable cox regression model

16. p < 0.001
p < 0.003
p < 0.03
Though Oxygen delivery was significantly reduced in esmolol group (100ml vs 32 ml/min/m2) the oxygen consumption was also significantly reduced ( -29ml vs -4ml/min/m2)

18. HCO3 was higher 0.8mmol/L vs 0.5mmol/L (p = 0.03)
pH was higher 0.28U (p = 0.003)
Lactate was lower (p = 0.006)
HCO3 was higher 0.8mmol/L vs 0.5mmol/L (p = 0.03)
P/F ratio was higher (p < 0.001)
CRP lower (p = 0.03)
Troponin / CK-MB was lower (p = 0.002)
No significant difference for pO2 and Sats % , LFT’s, RRT

21. Limitations:
Single centre study, Open label trial – difficult to blind the study
Septic shock patients with no tachycardia were excluded
? Effect of beta blockers in patient with no tachycardia
External validity:
In Australia - the mortality rate is way lower than the control group in this study
Odd primary outcome:
Control group – 80.5% Vs esmolol group 49.4%
NA requirement – no huge variation, and lactate was slightly higher in control group
Rather than reduction in the mortality in treatment group - the mortality rate in control group was exceptionally high (? Beneficial effect of esmolol)
Sub group analysis not done in patients who received levosimendan (> in esmolol group)
? Effect was influenced by levosimendan (50% of patient received levosimendan in esmolol group

22. Limitations:
Control group – SAPS II score was higher- ? Significant, ? Has lead to increased mortality
Fluid resuscitation:
Control group received more fluids
? Lead to increasing oxygen requirement / low P/F ratio
? Has significance in the mortality (evidence to support positive fluid balance associated with increased mortality)
Needs further RCT particularly looking into the improvement of sub clinical myocardial necrosis from septic shock
Role of beta blockers in sepsis:
Is it mechanistic effect?
Is it due to reduced inflammatory cytokine production (reduced CRP in esmolol group)
Burden of pathogens:
Control group higher number with peritonitis – more sicker
Cost effect analysis:
100mg of esmolol costs $ in Australia

23. Single centre trials: Rivers et al 2001:
Significant reduction in mortality rate 30.5% vs 46.5%
Steroids in ARDS: Phase I RCT
Significant improvement in mortality rate 76% vs 57%
Significant improvement in LIS 70% vs 35%
Intense insulin control therapy – 2001
Did not show increase in harm
NICE-SUGAR trial showed increased mortality with hypoglycaemia

24. Discussion
Sepsis is associated with increased mortality in ICU 25 to 40% throughout the world
Commonest cause of non-cardiogenic ICU death
Sepsis is associated with:
Extensive sympathetic outflow
High plasma catecholamine levels
Autonomic dysfunction
Sepsis patient present with:
Low SVR
High cardiac output
Arterial hypotension - may be non-responsive to exogenous vasopressors
Tachycardia

25. High adrenergic stress leads to
Myocardial depression, Takotsubo CMP
Tachyarrhythmia
High insulin resistance
Immune suppression
Increased thrombogenicity
Enhanced bacterial growth
Poor outcome with:
High plasma catecholamine level
Extend and duration of catecholamine therapy
Tachycardia

26. Effects of beta blockade:
Metabolic alterations
Reduces REE, decreased muscle catabolism
Prevents decompensated phase of cold sepsis
Glucose metabolism
Reduces gluconeogenesis
Glucose modulation
Increase peripheral utilisation of glucose
Reduces cytokine production
Improves myocardial function
Decrease in cardiac OP  decrease the demand
Decrease HR  increase in EDV  improves myocardial function
Shown to be in favour of improved mortality