Download Block-A-Shock: The Use of Beta

Block-A-Shock:
The Use of Beta-Blockers in Septic Shock
Molly Curran, Pharm.D.
PGY2 Critical Care Pharmacy Resident
Department of Pharmacy, University Health System, San Antonio, TX
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center,
University of Texas Health Science Center at San Antonio
September 25, 2015
Learning Objectives
1.
2.
3.
4.
Discuss the pathophysiology of septic shock and sepsis-induced myocardial depression
Identify and recommend appropriate agents for hemodynamic management of septic shock
Describe the potential benefits and risks of using beta-blockers in septic shock
Devise an evidence-based recommendation for the appropriate use of beta-blockers in septic shock
Curran | 1
I.
Sepsis and septic shock
A. Definitions1-3
i.
Systemic inflammatory response syndrome (SIRS) is the presence of more than one of following clinical manifestations:
a. Body temperature > 38°C or < 36°C
b. Heart rate (HR) > 90 beats per minute (BPM)
c. Tachypnea with respiratory rate > 20 breaths per minute or hyperventilation with PaCO2 < 32 mmHg
d. White blood cell (WBC) count > 12,000 cu/mm or < 4,000 cu/mm or presence of > 10% immature
neutrophils (bands)
ii.
Sepsis: SIRS in response to infection
iii.
Severe sepsis: sepsis associated with organ dysfunction, hypoperfusion abnormality, or sepsis-induced hypotension
iv.
Septic shock: subset of severe sepsis defined as sepsis-induced hypotension persisting despite adequate fluid
resuscitation along with organ dysfunction and perfusion abnormalities
Sepsis
Infection (confirmed
or suspected)
Severe Sepsis
Sepsis
Septic Shock
+
Systemic response
(SIRS)
+
Organ dysfunction,
hypotension, or
hypoperfusion
Severe sepsis despite
adequate fluid
resuscitation
Figure 1: Progression of SIRS to septic shock
Figure 2: Relationship of SIRS, sepsis, and septic shock1
B. Incidence and epidemiology3-5
i.
750,000 cases annually in the US
ii.
Worldwide estimated 19 million cases per year
iii.
Significant health concern
a. Severe sepsis represents 10 % of all intensive care unit (ICU) admissions
b. Incidence of in-hospital mortality up to 50 %
1. Influenced by patient factors: comorbidities, pathogens, infection source, organ dysfunction
2. Introduction of guidelines is associated with decreased mortality during last 25 years
3. Severity of illness measured by several classification scales (Appendix A)
c. Annual US healthcare system cost of $24.3 billion
C. Pathophysiology2,3,7,8
i.
Infection triggers pro-inflammatory and anti-inflammatory response
a. Initial pro-inflammatory response cascade results in tissue injury
Curran | 2
Leukocyte
activation
Complement
activation
•Cytokines
•Proteases
•Reactive oxygen
species
Coagulation
activation
•Complement
products
Necrotic
cell death
•Coagulation
proteases
•Damage and
tissue injury
Figure 3: Pro-inflammatory response to host-pathogen interaction in sepsis3
b.
Subsequent anti-inflammatory response cascade results in immunosuppression with enhanced susceptibility to
secondary infections
Neuroendocrine
regulation
•Inhibit proinflammatory cytokine
production via hypothalamicpituitary-adrenal axis
Impaired function of
immune cells
•Apoptosis of T, B, and dendritic
cells
•Expansion of regulatory T and
myeloid suppressor cells
•Impaired phagocytosis
Inhibition of
proinflammatory gene
transcription
•Anti-inflammatory cytokines
•Soluble cytokine receptors
•Epigenetic regulation
Figure 4: Anti-inflammatory response host-pathogen interaction in sepsis3
ii.
Factors influencing response
a. Host: genetic characteristics and coexisting illnesses
b. Causative pathogen: load and virulence
iii.
Organ failure results from cumulative effect of decreased tissue oxygenation
a. Tissue hypoperfusion
1. Increased coagulation and decreased anticoagulation
2. Vasodilation and hypotension
b. Loss of barrier function
1. Cell shrinkage and cell death
2. Capillary leak and interstitial edema
iv.
Leads to distributive shock
a. Results from body’s attempts to compensate for vasodilation by increasing cardiac output (CO)
b. Compounds intravascular volume deficits
c. Induces myocardial depression
D. Treatment principles2,9-17
i.
Initial resuscitation of patients with sepsis-induced hypoperfusion
a. Initiate early, aggressive, quantitative resuscitation therapy when severe sepsis is identified
b. During first three hours (hr), initiate aggressive fluid resuscitation (30 mL/kg minimum)
1. Mean arterial pressure (MAP) ≥ 65 mm Hg
2. Urine output ≥ 0.5 mL/kg/hr
c. May consider other hemodynamic monitoring parameters (Appendix B)
d. Normalize elevated lactate levels to < 4 mmol/L
e. Fluid type
1. Crystalloids are preferred fluid
a) No benefit to use of colloids over crystalloids overall
b) Financial advantage
2. Colloids
a) Equally efficacious as crystalloid approach
b) Recommend when patients require substantial amounts of crystalloids for resuscitation
Curran | 3
ii.
Infection management and source control goals
a. Obtain cultures as soon as possible and prior to antibiotic therapy
1. At least two sets of blood cultures (in both aerobic and anaerobic bottles) with at least one culture
from all vascular access sites and at least one percutaneous culture
2. Culture other sites (urine, sputum, cerebrospinal fluid, etc.) as indicated
b. Initiate empiric antibiotic therapy within one hr of identifying severe sepsis
1. Association between each hr delay in antibiotic therapy and mortality in sepsis
2. Empiric therapy should be selected to cover all likely pathogens (bacterial ± fungal ± viral)
3. Reassess for de-escalation regularly to narrow coverage
Figure 5: Relationship of antibiotic timing and mortality after identification of septic shock 16
c.
d.
II.
Conduct imaging studies to assist with location of infection
Establish source control when feasible
Cardiovascular management of septic shock
A. Role of adrenergic receptors in cardiovascular system 18-20
i.
G-coupled protein receptors mediate effect via catecholamine release to exert excitatory/inhibitory effects on
vasculature
ii.
Act as target of pharmacological agents (vasopressors) aimed at improving CO and vascular tone
Type
α1
α2
Table 1. Adrenergic receptors and roles18-20
Location
Role
Smooth muscle of arteries and veins
Contraction leading to vasoconstriction
Central nervous system
Inhibition of catecholamine release
Sympathetic nerve varicosities
Sinoatrial node
Inhibition of sympathetic nervous system
Increase HR
Atrial and ventricular muscle
Increase conduction velocity and contractility
Atrioventricular node and purkinje fibers
Smooth muscle of arteries and veins
Increase conduction velocity
Relaxation and vasodilation
β1
β2
B. Vasopressor agents18,21-26
i.
Activity at adrenergic receptors is variable by agent
ii.
Agent selection based on properties of agents and goals of therapy or type of shock
iii.
Have rapid onset and are administered via continuous infusion for hemodynamic management
Norepinephrine (NE)
Epinephrine (Epi)
Phenylephrine (PE)
Isoproterenol (Iso)
Dobutamine (Dobut)
Dopamine (Dopa)
Vasopressin (VASO)
α1
+++++
+++++
+++++
+
+++
Table 2. Vasopressor receptor binding18
β1
β2
+++
++
++++
+++
+++++
+++++
++++
+++++
+++
++
DA
V1/V2
+++++
+
Curran | 4
Figure 6: Effects of vasoactive agents on pressure and blood flow22
C. Role of vasopressors in septic shock2,18,22-27
i.
Initiate vasopressor therapy for MAP ≤ 65 mm Hg to maintain adequate tissue perfusion
a. Below MAP goal, auto-regulation is lost and perfusion is dependent on pressure
1. May result in ischemic injuries of heart, brain, and kidney
2. Reduction in microcirculation
b. MAP goals should be individualized for each patient
1. Patients with chronic hypertension or atherosclerosis may require higher goals to maintain
perfusion
a) Higher goals associated with reduction in incidence of acute kidney injury
b) Reduction in need for renal-replacement therapy
2. Younger, normotensive patients may tolerate lower goals
ii.
Supplement MAP goals with other endpoints indicative of perfusion
a. Global markers: blood lactate concentrations, mental status
b. Local markers: urine output, skin perfusion
iii.
Agent selection
a. NE
1. Preferred vasopressor
2. Increases MAP due to vasoconstrictive properties with little effect on HR or stroke volume (SV)
b. Epi
1. Alternative to NE in patients with refractory hypotension
2. Effects at β2-receptors may increase lactate production
c. Dopa
1. Not recommended for majority of patients
a) Useful for absolute or relative bradycardia
b) Associated with higher relative risk of arrhythmias and mortality
2. Increases MAP and CO via increase in SV and HR
d. VASO
1. Endogenous vasopressin levels are lower in septic shock after 24-48 hr
2. Initiate at low rate 0.04 units/min
3. Higher doses of vasopressin are associated with cardiac, splanchnic, and digital ischemia
e. PE
1. Not recommended because decreases SV, CO, splanchnic, and renal perfusion
2. Only recommended for certain patients
a) Serious arrhythmias associated with NE use
b) CO is known to be high
c) Salvage therapy for patients who fail to achieve goal MAP with combination
vasopressor, inotrope, and vasopressin therapy
3. Unlikely to affect HR due to lack of β-activity
D. Alternative agents for additional hemodynamic support 2,28-31
i.
Addition of dobutamine
a. Recommended for select patients
1. Myocardial dysfunction (elevated cardiac filling pressure/low CO)
2. Evidence of hypoperfusion despite adequate intravascular volume and MAP
b. Clinical trials have failed to demonstrate benefit from increasing oxygen delivery with dobutamine
Curran | 5
ii.
iii.
Addition of stress dose corticosteroids (CCS)
a. Recommended for patients unable to maintain MAP goal despite adequate fluid resuscitation and vasopressor
therapy
b. Continue therapy until vasopressors no longer required and then initiate taper to withdraw CCS
Cardiovascular agents not included in Surviving Sepsis Campaign guidelines
a. Milrinone
1. Inhibits cAMP phosphodiesterase III in cardiac and vascular muscle to improve contractility
2. Increases CO, decreases PCWP and vascular resistance  improves left ventricular function
without increasing myocardial oxygen consumption
b. Levosimendan
1. Binds to cardiac troponin C to enhance the calcium sensitivity of contractile proteins and opens
ATP-sensitive potassium channels in vascular muscle to induce vasodilatation
2. In vitro acts like a PDE III inhibitor
3. Not available in the US
E. Complications from vasopressor use and ongoing septic shock8,32-34
i.
Vasopressor supplementation of already elevated endogenous catecholamines increases adrenergic stress
a. Excess catecholamines mediate injury over time
1. Induce hyper-metabolism by mediating insulin resistance  stress-induced muscle catabolism
2. Drives tachycardia and cardiac stress while preventing adequate cardiac perfusion
Figure 7: Deleterious effects of sustained catecholamine surge 32
ii.
Myocardial depression may develop in septic shock
a. Occurs in about 50 % of patients with septic shock within first 48 hr
b. Decreased left ventricular ejection fraction
c. Confers poor prognosis
d. Mechanism similar to process of chronic heart failure
e. Autonomic system unable to adjust cardiovascular response to the intensity of inflammatory stress
1. Complex process resulting from interaction between genetic, molecular, metabolic, structural,
and hemodynamic alterations
2. Occurs due to sustained reductions in preload, afterload, and the microcirculation
Curran | 6
Circulatory derangement
and mitochondrial
dysfunction
•↑ Cardiac contractility
•↑ Heart rate
•Tissue hypoxia
•↓ ATP formation and
energy supply
•Cell death
Elevated catecholamine
levels
•Hyporesponsiveness to
catecholamines
•Inactivation of
catecholamines
•↓ energy needs
Downregulate receptor
response
Figure 8: Septic mechanism of cardiac depression8
III.
Potential role of beta-blockers in septic shock
A. Beta-blocker agents35
i.
Block the action of endogenous catecholamines on adrenergic β receptors
ii.
Classified based on receptor activity
a. Nonselective: work on all β-receptors
1. Early studies evaluated propranolol, a nonselective agent in septic shock
2. Some nonselective agents also have α-adrenergic antagonism
b. Selective: preferentially block the action of one distinct subtype of β-receptor
B. Review of cardioselective β-blocker pharmacology36-42
i.
Mechanism of action
a. Selectively antagonize the β1-receptor to counteract the catecholamine effect by competing for receptor sites
Table 3: Properties of cardioselective beta-blockers studied in septic shock41, 42
Esmolol
Metoprolol
Formulation: intravenous (IV)
Formulations: IV, Oral
Dosing: continuous infusion
Dosing: intermittent dosing
Pharmacokinetics
Pharmacokinetics
 Achieves steady-state level within 10–20 minutes
 Achieves peak ~90 minutes after oral dose
 55 % protein bound
 10 % protein bound
 Elimination half-life: ~nine minutes
 Elimination half-life: three to four hr
 73-88 % renally eliminated
 95 % renally eliminated
 Undergoes esterase metabolism in blood
 Undergoes hepatic metabolism via CYP2D6
Major adverse effects
Major adverse effects
 Hypotension
 Hypotension
 Nausea
 Heart failure
 Injection site reaction
 Bradyarrhythmia
 Dizziness/fatigue
C. Beta-blocker theory43-47
i.
External stimulation of β1-receptors may further promote cell death via increased cardiac stimulation and demand
ii.
Blocking catecholamine effects may reduce exogenous stress on the heart and preserve cardiac myocytes
a. Decrease HR
b. Decrease contractility
iii.
The use of beta-blocker agents in other states associated with reduced left ventricular function (i.e., chronic heart failure)
has resulted in decreased ventricular arrhythmias, cardiac hypertrophy, and mortality
Curran | 7
Energy generation
Energy expenditure
Figure 9: Imbalance between energy generation and expenditure47
iv.
Macchia, et al (2012) attempted to determine effect of preadmission beta-blocker therapy in septic shock
a. Record linkage analysis of an Italian administrative database reviewing sepsis hospitalizations between 2003 and
2008 to determine if there was a difference in mortality between patients who had been taking beta-blockers
versus those who had not
b. 1061 of 9465 patients reviewed were on beta-blocker therapy preadmission
c. Patients with previous beta-blocker therapy found to have lower 28-day mortality (188/1061, 17.7 %) versus
those previously untreated (1857/8404, 22.1 %), P = 0.005 for unadjusted analysis and P = 0.025 for adjusted
analysis
D. Potential dangers of beta-blockade in septic shock48,49
i.
Excessive beta-blocker dosages may cause negative inotropic effect and cardiac decompensation
a. Generate pulmonary edema
b. Excessively low CO
ii.
May result in higher rates of hemodynamic instability
E. Using beta-blockers in animal models (Appendix C for overview of all trials)50,51
i.
Initial trials experimented in septic animal models in 1960s
ii.
Data explored effects of beta-blockade in rat, dog, and pig models
Berk, et al 1969
Aboab, et al 2011
Table 4: Animal data for beta-blockade in septic shock50, 51
Study design
Results
Purpose: effect of beta-adrenergic blockers
Survival significantly improved in
on endotoxin-induced shock in a dog model propranolol treated group v.
untreated or fluid resuscitation
Treatment groups:
group (25/32 v. 7/36 v. 6/22,
1. Propranolol 2.5 mcg/kg infusion or
P < 0.001)
doses ranging from 150 to 1500 mcg/kg
over 3-minute period with fluid
Treated group required more fluid
resuscitation
than propranolol group
2. Fluid resuscitation treatment only
(80 mL/kg v 40 mL/kg)
3. Untreated
Investigate cardiovascular tolerance of
Esmolol infusion did not induce
blockade of beta-adrenergic receptors in an
cardiovascular collapse in any of
endotoxin pig model
the septic animals
Treatment groups:
1. Esmolol titrated to reduce HR by 20%
2. Placebo group
F.
Esmolol improved stroke index
from 31 mL/min/m2 at 180 min
to 47 mL/min/m2 at 300 min
Significance
1st study of betablockade in
animal model
Found improved
survival
Beta-blockade is
well tolerated and
offsets cardiac
dysfunction in
large septic
animals
Preliminary data exploring beta-blockade in septic human patients52,53
i.
Gore, et al (2005)
a. Purpose: to examine hemodynamic and metabolic effects of selective beta-blockade in patients
b. Six septic subjects (three burn patients and three trauma patients) with pneumonia
1. None required vasopressor therapy
Curran | 8
2. MAP > 70 mm Hg in all patients
Five hr after study enrollment, esmolol was given to obtain a target decrease in HR of 20 % for three hr
Use of esmolol was associated with a decrease in CO, but did not affect blood pressure (BP), systemic vascular
resistance index (SVRI), or stroke volume index (SVI)
e. Reduction of CO was not associated with significant hemodynamic deviation
Balik, et al (2012)
a. Purpose: to examine effects of beta-blockade in septic shock patients who require NE administration
b. 10 septic shock patients with HR > 120 BPM, NE infusion < 0.5 mcg/kg/min, MAP > 80 mm Hg, and no
known history of coronary artery disease
c. Esmolol was administered to obtain target decrease in HR of 20 % for 24 hr
1. Mean HR reduced from 142 to 116 BPM (P < 0.001)
2. No other evaluated endpoints including MAP found to be statistically significant
d. Combination of esmolol and NE did not decrease MAP while significantly decreasing HR
c.
d.
ii.
IV.
Literature review: beta-blockade in septic shock
Schmittinger CA, Dunser MW, Haller M, et al. Combined milrinone and enteral metoprolol therapy in patients with septic
myocardial depression. Critical Care 2008;12(9):R99.54
Overview
Objective
To summarize clinical experience with combined use of milrinone and enteral metoprolol therapy in 40 patients
with septic shock and cardiac depression
Trial Design
Retrospective study design in Austria
Patients
Inclusion criteria
Exclusion criteria
 Primary diagnosis of septic shock
 < 18 years old
 Myocardial depression (ScvO2 < 65 %
 Any cause of low CO other than sepsis
despite adequate fluid resuscitation and/or
 Pre-existing decompensated heart failure
cardiac index (CI) < 2.5 L/min/m2
 Did not require inotropic support
requiring inotropic therapy)
 No measurement of CO
 Treated with enteral metoprolol within 48 hr  Received beta-blockers > 48 hr after shock onset/ICU
after onset of shock or admission to the
admission
ICU
Outcomes
Primary
Secondary
 Clinical course (ICU length of stay [LOS],
 Vasopressor requirements (including NE, milrinone,
28-day mortality)
vasopressin)
 Reduction of HR to goal of 65–95 BPM
 Surrogate markers: pH, arterial lactate, serum
creatinine, C-reactive proteins
 Hemodynamic effects measured by SVI,
HR, central venous pressure (CVP)
 Adverse events: decrease in BP (> 20 % reduction in
MAP, MAP < 65 mm Hg, decrease in CI, SVI, or
ScvO2, bradycardia < 60 BPM)
Interventions
 All patients monitored with an arterial, a central venous catheter, and a transpulmonary thermodilution
device to assess CO
 Mechanical ventilation and sedation with midazolam/fentanyl initiated in all patients
 Continuous veno-venous hemofiltration (35 mL/min) was used for renal indications
 Parenteral nutrition was initiated on ICU day 2 and substituted with enteral nutrition on ICU day 3 or when
CV function was established
 Hemodynamic protocol added NE plus hydrocortisone (HCT) for MAP < 65-70 (if persisted, added
vasopressin) and milrinone for myocardial depression
 Metoprolol therapy with an extended release formulation was started as considered indicated by charge MD
between 25 to 47.5 mg via enteral route and gradually increased to reach a targeted HR of 65-95 BPM
o Initially, restricted to patients with chronic beta-blocker therapy to attenuate rebound
tachycardia/decrease risk of perioperative myocardial ischemia
o After 1/3 observation period, may use in patients without chronic beta-blocker therapy to treat
tachycardia and economize cardiac function
o All patients had stable cardiovascular function before initiating and held if HR < 60 BPM
Statistics
 Descriptive statistics to report demographic and clinical data
 Linear mixed-effects model to assess changes in hemodynamic or laboratory parameters
 Bonferroni correction used to verify significant changes over time
 P-values < 0.05 indicate statistical significance
Curran | 9
Baseline
Characteristics
Primary Outcomes




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



Results
Of 174 patient reviewed, 40 received milrinone infusion plus metoprolol
Age in years, mean (± standard deviation, SD): 71 ± 13
Chronic beta-blocker therapy, n (%): 15 (38)
Simplified Acute Physiology Score II (SAPS II), mean (± SD): 53 ± 16
CVVH, n (%): 28 (70)
Pre-morbidities, n (%):
o Compensated heart failure: 12 (30)
o Obstructive coronary artery disease: 10 (25)
Baseline milrinone dose mcg/kg/min, mean: 0.31
Baseline NE dose mcg/kg/min, mean: 0.17
97.5% of patients achieved target HR 65–95 BPM (n = 39)
CVP, mean (± SD)
SVI, mean (± SD)
MAP, mean (± SD)
Secondary
Outcomes

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
Author’s
Conclusions
Strengths
Limitations
Take Home Points

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
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









Table 5: Change in hemodynamic monitoring parameters
Study initiation
Study conclusion
P-value
12 ± 3
9±3
< 0.001
32 ± 12
44 ± 9
0.002
85 ± 23
90 ± 21
0.16
28-day mortality, n (%): 13 (33)
Mean ICU LOS, days (± SD): 15 ± 11
Lower mean NE, vasopressin, and milrinone requirements from initiation through conclusion; P < 0.001
for all values
Table 6: Change in surrogate markers
Study initiation
Study conclusion
P-value
pH, mean (± SD)
7.36 ± 0.09
7.42 ± 0.07
< 0.001
Arterial lactate (mg/dL), mean (± SD)
22 ± 15
10 ± 5
< 0.001
Serum creatinine (mg/dL), mean (± SD) 2.3 ± 1.3
1.6 ± 0.7
0.02
Other organ function measurements remained unchanged
Adverse events observed, n (%): asymptomatic bradycardia, 2 (5); increase in NE
requirements, 9 (22.5); decrease in CI, 7 (17.5); increase in milrinone dose, 6 (15); decrease in SVI, 2 (5)
Conclusions
Enteral metoprolol has no major adverse effects on cardiovascular or organ function
MAP increased despite decreasing NE, vasopressin, and milrinone dosages
Cardiac function was economized, resulting in a maintained CI with a lower HR and higher SVI
Used cardioselective beta-blocker
Assessed hemodynamic and markers of organ function to assess effect of beta-blockade
Found mean increase in SVI and relatively unchanged CI demonstrating a potential economization of
cardiac work and oxygen consumption
Retrospective study design
Initial administration of beta-blockers aimed at reducing rebound tachycardia in chronic beta-blocker users
Time to metoprolol initiation varied 17.7 ± 15.5 hr after onset of shock and initiation of standard therapy
Management differed from guidelines because milrinone was used as inotropic agent in all patients
Enrollment at MD discretion
Used enteral route in patients on vasoactive agents
Gave extended-release formulation metoprolol via enteral route
Small population size
Lacks external validity due to institutional practice model versus current guidelines
Beta-blocker use associated with decrease in cardiac work without affecting organ function
Use of beta-blocker in resuscitated septic shock patients may allow decrease in vasopressor requirements
Curran | 10
Morelli A, Donati A, Ertmer C, et al. Microvascular effects of heart rate control with esmolol in patients with septic shock.
Crit Care Med 2013;41:2162-8.55
Overview
Trial Design
Single-center, observational, prospective study
Objectives
To investigate microcirculatory and macrocirculatory effects of reducing HR in septic shock below a predefined
threshold using esmolol
Enrollment
25 ICU patients with septic shock diagnosis
Patients
Inclusion criteria
Exclusion criteria
 Septic shock requiring NE to maintain
 < 18 years old
MAP ≥ 65 mm Hg despite adequate fluid
 Need for inotropic agent
resuscitation after 24 hr
 Cardiac dysfunction (CI ≤ 2.2 L/min/m2 with
 HR ≥ 95 BPM
pulmonary capillary wedge pressure (PCWP)
> 18 mm Hg)
 Valvular disease
 Pregnancy
Outcomes
Primary
Secondary
 Change in sublingual microvascular flow index  Pulmonary artery monitoring (MAP, PCWP, right
(MFI) to measure microvascular circulation
atrial pressure) to measure macrovascular circulation
 Differences in surrogate markers: arterial pH, lactate
Interventions
 All treated with esmolol infusion to maintain HR between 80–94 BPM
o Initiated at 25 mg/hr and increased by 50 mg/hr every 20 minutes or as needed to reach target HR
o Continued for 24 hr with upper dose limit of 2000 mg/hr
 Standard therapy: IV fluids, red blood cell transfusion if hemoglobin < 7 g/dL, NE titrated to MAP ≥ 65
mm Hg, sedation with midazolam and sufentanil, IV HCT 200 mg/d
 Recorded hemodynamic variables, microcirculatory flow variables, blood gas, NE requirements at baseline
and after 24 hr of esmolol
Statistics
 Correlation of 0.99, standard deviation for MFI of 0.6
 90% power to detect a minimum difference of 0.4 units before and after esmolol infusion
 Wilcoxon signed-rank test for continuous variables
 Expressed data as median (IQR)
 P-value < 0.05 was considered statistically significant
Results
Baseline
 Age in years, median (IQR): 62 (43–76)
Characteristics
 SAPS II score: median (IQR): 55 (48–62)
 Hr of NE prior to esmolol infusion, median (IQR): 26 (24; 29)
 NE dose at baseline in mcg/kg/min, median (IQR): 0.53 (0.29; 0.96)
 Causes of septic shock (n): peritonitis (5), pneumonia (18), pyelonephritis (1), endocarditis (1)
Primary Outcome  Sublingual MFI significantly increased after 24 hr of esmolol infusion from median 2.8 to 3.0 (P = 0.002)
 Heterogeneity index decreased from 0.06 to 0 (P = 0.002)
MFI
Secondary
Outcomes






Flow
0
Absent
1
Intermittent
2
Sluggish
3
Normal
Figure 10: Change in microcirculatory flow index of small vessels after 24 hr of esmolol administration
HR decreased from 117 BPM to 86 BPM (P < 0.001)
CI decreased after 24 hr esmolol therapy from 4 L/min/m2 to 3.1 L/min/m2 (P = < 0.001)
NE requirements reduced from 0.53 mcg/kg/min to 0.41 mcg/kg/min (P = 0.03)
Median esmolol dose used 250 mg/hr (IQR 100;1050)
Oxygen delivery and consumption were decreased (P < 0.05)
No significant change in median MAP from 71 mm Hg to 72 mm Hg (P = 0.67)
Curran | 11
Author’s
Conclusions
Strengths
Limitations
Take Home Points

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
Conclusions
Use of esmolol associated with maintenance of SV and preservation of microvascular blood flow
NE requirements decreased
SV, MAP, and lactate levels remained unchanged
HR reduction preserves myocardial function in septic shock by decreasing cardiac workload
Defined HR goal (< 95 BPM) based on previous literature evaluating cardiac events in critically ill patients
Ensured adequate fluid resuscitation prior to enrollment in the trial
Patients managed similarly to Surviving Sepsis Campaign guidelines
Small patient size
Patient population crossover with other esmolol sepsis data (four patients included in the phase II trial)
No control group utilized for comparison
Primary endpoint (sublingual MFI) may not be clinically significant endpoint
Titrating esmolol to predefined HR threshold did not cause significant cardiovascular rearrangement
Vasopressor requirements were decreased
Microvascular blood flow is unaffected by beta-blockade although CO is reduced
Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in
patients with septic shock. JAMA 2013;310(16):1683-91.56
Overview
Trial Design
Single-center, open-label, randomized two-group phase II trial
Objectives
To determine whether esmolol could reduce HR to predefined threshold and measured subsequent effects on
systemic hemodynamics, organ function, adverse events, 28-day mortality
Enrollment
154 ICU patients with severe septic shock were randomized to 2 study groups in 1:1 ratio
Methods
Patients
Inclusion criteria
Exclusion criteria
 Septic shock requiring NE to maintain
 < 18 years old
MAP ≥ 65 mm Hg after 24 hr
 Beta-blocker therapy prior to randomization
 Appropriate volume resuscitation indicated by
 Cardiac dysfunction (CI ≤ 2.2 L/min/m2 with
pulmonary arterial occlusion pressure (PCWP)
PCWP > 18 mm Hg)
≥ 12 mm Hg and CVP ≥ 8 mm Hg
 Significant valvular disease
 HR ≥ 95 BPM
 Pregnancy
Interventions
Assigned in 1:1 ratio by computer-based random number generator to receive:
 Standard therapy: fluid resuscitation, red blood cell transfusion if hemoglobin < 7g/dL, NE titrated to MAP
≥ 65 mm Hg, 300 mg continuous infusion of IV HCT daily
 Standard therapy with esmolol infusion to maintain HR between 80-94 BPM
o Initiated at 25 mg/hr and increased by 50 mg/hr every 20 min or as needed to reach target HR
within 12 hr
o Continued until ICU discharge or death with upper dose limit of 2000 mg/hr
 Adjunctive therapy: if mixed venous O2 saturation < 65% with hemoglobin ≥ 8g/dL and increased lactate,
patients also received levosimendan at 0.2 mcg/kg/min for 24 hr
Outcomes
Primary
Secondary
 Reduction in HR below 95 BPM and maintenance  Mortality within 28 days after randomization and
of HR between 80–94 BPM for duration of ICU
adverse events
stay
 Hemodynamic and organ function measures
 NE dosages at 24, 48, 72, and 96 hr
Statistics
 Pre-hoc sample size calculation found 64 patients per group were required to detect 20% change in HR with
80% power and α = 0.05 by using 2-sided t test; increased to 75 patients per group to account for
nonparametric distribution of sample
 Intention-to-treat analyses were used for all statistics
 Wilcoxon-Mann-Whitney or χ2 were used to compare baseline/demographic data and 28-day mortality
 Areas under the curve (AUC) were calculated for continuous variables with repeated measurements and
analyzed with Wilcoxon-Mann-Whitney test
 Log-rank test using multivariable Cox regression model to compare 28-day overall survival  accounted for
multi-drug resistant infection, sex, group assignment, levosimendan infusion, age, BMI, SAPS II score, NE
dosage, lactate concentration, platelet counts
 Primary outcome was confirmatory tested at 2-sided significance level of α = 0.05
Curran | 12
Baseline
Characteristics
Primary Outcome
Results
 77 patients enrolled in esmolol group and 77 patients enrolled in control group
 No significant differences in age, gender, BMI, NE dosage, arterial lactate, platelet count, pathogens, or comorbidities between groups
 SAPS II score, median (IQR): 52 (47–60) in esmolol group v. 57 (49–62) in control group
 HR in the esmolol group was significantly lower than control group
 Median AUC for HR in esmolol group -28/min (IQR, -37 to -21) v. -6/min (IQR, -14 to 0) for control group
(P < 0.001)
Figure 11: Change in HR over time
Secondary
Outcomes
 Esmolol group required less NE over time during the study period
Figure 12: Esmolol infusion in study patients
Figure 13: NE infusion in study patients
 AUC were reported for other hemodynamic parameters (MAP, SVI, and CI)
Figure 14: Change in SVI


Acid-base and metabolic
AUC for pH were higher
for esmolol (0.28 units) v.
control (-0.02 units)
Lower median AUC lactate
concentration for esmolol
(-0.1 mmol/L) v. control
(0.1mmol/L)
Figure 15: Change in CI



Organ function
AUC of kidney function (based
on MDRD) was better in
esmolol group
(14 mL/min/m2) v. control
group (2 mL/min/m2)
No difference in liver function,
need for RRT
CK-MB and troponin lower in
esmolol group
Figure 16: Change in MAP



28-day mortality
49.4% in esmolol group versus
80.5% in control group
(P < 0.001)
Overall survival higher in
esmolol group
Esmolol group allocation and
SAPS II predicted survival
Curran | 13
Author’s
Conclusions
Strengths
Limitations
Take Home Points
V.
Conclusions
 Open-label use of esmolol allowed patients to achieve target HR goals without an increase in adverse events
 The use of esmolol increased SV, maintained MAP, and reduced NE requirements without need for inotropic
support or causing adverse effects on organ function
 Esmolol was also associated with improvement in 28-day survival
 Accounted for worst-case scenario when conducting pre-hoc power analysis  recruited enough patients to
meet power
 Use of AUC to evaluate continuous variables minimized outliers  limit confounder effect
 Achieved 80 % power to detect 20 % change in HR
 Assessed organ function via clinically meaningful surrogate markers  GFR
 SAPS II score did not accurately predict observed mortality in control arm
 Numerous variables used in Cox proportion model for sample size of 154 patients
 Standard care differed from current US guidelines  levosimendan use, Swan-Ganz catheter to measure
CVP, PCWP, duration of goal-directed therapy
 Large population of multi-drug resistant pathogens (Klebsiella and Acinetobacter)  may have influenced results,
multivariate analysis attempted to account for differences
 No data on appropriateness of concurrent antibiotic therapy administered during study
 Potential investigator bias  two authors have conflicts of interest, investigators unblinded
 External validity questionable  larger patient population (n = 166) were excluded due to HR < 95 BPM
 Not designed to detect difference in secondary outcomes
 Excluded patients on chronic beta-blocker therapy
 Unable to assess weight-based esmolol dosing to determine range of therapy
 Initial SAPS II score did not accurately predict observed mortality rate in control arm
 Esmolol was associated with significant mortality benefit in septic shock patients with poor prognosis with
HR sustained > 95 BPM after initial 24 hr resuscitation period
 Unreported data would be important for determining the external validity of these results: anti-microbial
therapy appropriateness, and MDR pathogen coverage
 Standard protocol differed from US approach to severe sepsis
Future directions
A. Esmolol to treat the hemodynamic effects of septic shock57
i.
Randomized open label efficacy study sponsored by Beth Israel Deaconess Medical Center in collaboration with
American Heart Association enrolling patients between March 2015 to January 2019
ii.
Primary outcome: determine if esmolol reduces need for vasopressor support six hr after initiation
iii.
Secondary outcomes: time to shock reversal, change in lactate levels, difference in HR, need for vasopressor support at
24 hrs
iv.
Clinicaltrials.gov identifier: NCT02369900
B. Esmolol effects on heart and inflammation in septic shock (ESMOSEPSIS)58
i.
Open-label study sponsored by Central Hospital (Nancy, France) in collaboration with Baxter Healthcare Corporation
enrolling patients between December 2013 and January 2016
ii.
Primary outcome: compare mean CI before and after esmolol administration
iii.
Secondary outcomes: effect of esmolol on vasopressor requirements, microcirculatory effects of esmolol, changes in
cytokine patterns in esmolol patients, echocardiography assessment of ventricular function during esmolol
administration
iv.
Clinicaltrials.gov identifier: NCT02068287
VI.
Summary of evidence
A. Variety of studies examining role of beta-blockade in septic shock models
i.
Animal data using different beta-blocking agents in small and large mammals
ii.
Human data originally reported in retrospective, observational studies with metoprolol and esmolol
iii.
Prospective data has been published looking at hemodynamic effects of septic shock
B. Patients studied
i.
Mean SAPS II scores ranged from 50-60, indicating predicted mortality up to 50%
a. Results do not match predicted mortality
b. Morelli et al. had significantly sicker population than predicted by SAPS II score
ii.
Beta-blockade to be administered to patients who had persistent tachycardia > 95 BPM
Curran | 14
a. Cardiac ICU patient threshold above which there were greater occurrences of major cardiac events including
nonfatal MI, cardiac arrest, and cardiac death
b. Ensured underwent adequate volume resuscitation prior to enrollment to prevent deleterious effect on CO
iii.
Treated with protocols that varied from Surviving Sepsis Campaign recommendations
a. Concomitant inotrope therapy with milrinone in one study
b. Italian studies included levosimendan use
iv.
No data on appropriateness of antimicrobial therapy known to reduce mortality in septic shock
C. Efficacy outcomes
i.
Beta-blocker therapy resulted in majority of patients achieving desired HR goals
ii.
Mean vasopressor requirements (NE) were lowered across all studies for duration of esmolol therapy
iii.
Surrogate markers were also positively impacted by addition of esmolol in larger studies
a. Lowering in arterial lactate levels
b. pH increased to physiologic levels
c. No evidence of developing organ dysfunction (MDRD, troponins, myoglobin)
iv.
Largest study associated esmolol with possible mortality benefit
D. Safety outcomes
i.
Concerns reducing CO due to use of beta-blocker not found to be clinically significant
ii.
Relatively few adverse events occurred resulting in the need to stop beta-blocker therapy
E. Limitations of current data
i.
No study designed to evaluate clinical outcome or mortality endpoint
ii.
Variable patient populations limit external validity of current studies
VII.
Conclusions
A. Use of esmolol in persistently tachycardic, septic shock patients requiring vasopressors after adequate resuscitation mitigates
development of myocardial depression
i.
Lowers HR to allow for better ventricular filling during diastole  improves SV
ii.
More efficient myocardial work and energy consumption via beta-adrenergic mitigation of catecholamine mediated
pathways  reduce risk of arrhythmias and myocardial infarction
a. Lower vasopressor requirements
b. No changes in cardiac enzymes
B. Data lacking
i.
Optimal timing of esmolol administration from presentation
ii.
Esmolol dosing strategy: duration and weight-based dose
iii.
HR target (20 % reduction versus goal of 80-94 BPM)
iv.
Safety and efficacy in a large patient population
VIII.
Recommendations
A. Further studies are warranted before beta-blockers should be broadly introduced into the Surviving Sepsis Campaign guidelines
B. IV cardioselective beta-blockade with esmolol may be considered in septic shock patients with SAPS II score > 55
i.
Criteria for use:
a. HR > 95 BPM
b. MAP ≥ 65 mmHg
c. Undergoing close cardiac monitoring
d. Requiring vasopressor therapy with NE in combination with VASO/HCT
ii.
Titrate esmolol to target HR of 80–94 BPM
iii.
Continue until patient does not require vasopressors, ICU discharge, or death
iv.
Considerations for discontinuing esmolol
a. HR < 80 BPM despite dose titration
b. Sustained increase in NE requirements to maintain MAP > 65 mmHg
c. Signs of progressive multi-organ failure
Curran | 15
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Curran | 17
X.
Appendices
Appendix A. ICU Severity Scores59-61
Scoring system
Mortality interpretation
Simplified Acute
Score range 0 to 163 points
Physiology Score
(SAPS II)
Background
Measure severity of disease for patients (> 15 years) admitted to
ICU
Based on 12 measurements during first 24 hr including:
 Age, HR, SBP, temperature, GCS, mechanical
ventilation, FiO2, PaO2, urine output, BUN, Na, K,
bicarbonate, bilirubin, WBC, chronic diseases, type of
admission
Predicts mortality of a patient
Sequential Organ
Failure
Assessment Score
(SOFA)
Score range 0 to 24 points
SOFA score
Mortality
0–6
< 10 %
7–9
15–20 %
10–12
40–50%
13–14
50–60%
15
> 80%
15–24
> 90%
Determine extent of a person’s organ function or rate of failure
Acute Physiology
and Chronic
Health
Evaluation II
Score
(APACHE)
Score range 0 to 71 points
Classifies severity of disease based on worst physiologic value
during initial 24 hr after ICU admission
Every 24 hr assess:
 Coagulation and respiratory, nervous, cardiovascular,
hepatic, and renal function every 24 hr
Based on age, chronic health conditions, and an acute
physiological score (composite of):
 Temperature, MAP, HR, RR, oxygenation, arterial pH,
serum sodium, serum potassium, serum creatinine,
hematocrit, WBC, GCS
Appendix B. Hemodynamic Monitoring Parameters62
Parameter
Abbreviation
Mean Arterial Pressure
MAP
Normal
60–100 mm Hg
Central Venous Pressure
Stroke Volume
CVP
SV
2–6 mm Hg
50–100 mL
Stroke Volume Index
Superior Vena Cava Oxygen Saturation
Pulmonary Artery Occlusion Pressure
(Wedge)
Systemic Vascular Resistance Index
SVI
ScvO2
PAOP/PCWP
25–45 mL/m2
≥ 60%
8–12 mm Hg
SVRI
Cardiac Output
CO
1600-2400 dyne∙
sec∙cm
4-7 L/min
Stroke Volume Variation
SVV
< 13%
Description
Average BP value derived from systolic and
diastolic BP
Indicator of volume status and preload
Amount of blood ejected from left ventricle with
each heart contraction
SV adjusted for body surface area (BSA)
Represents oxygen delivery
Elevations may indicated left ventricular failure or
acute pulmonary edema
Vascular resistance across the whole systemic
circulation
Amount of blood the heart pumps through
vasculature in one minute
Variation in arterial pulsations during positivepressure ventilation
Curran | 18
Appendix C. Evidence Table of Beta-Blockers in Septic Animal Models50, 51, 63-66
Trial
Year Model Intervention
Results of beta-blocker treatment
arms
Berk, et al.
1969 Dogs
Propranolol 0.15 to
Survival increased from 27 % to
1.5 mg/kg given 5 to
72 %
60 min after
endotoxin injection
In vivo: Increased BP and PaO2;
Decreased fluid requirements
Suzuki, et al.
Hagiwara, et al.
Ackland, et al.
Aboab, et al.
Kimmoun, et al.
2005
2009
2010
2011
2015
Rats
Rats
Rats
Pigs
Rats
Esmolol infusion of
10 to 20 mg/kg/hr
for 24 hr
Landiolol infusion of
0.1 mg/kg/min for
24 hr
Metoprolol pre- and
post-treatment
(various doses)
Post-mortem: Decreased lung injury
In vivo: Decreased HR, BP, TNFalpha
Ex vivo: Increased SV, CO, cardiac
efficiency
Limitations
Only study using non-selective betablocker
Co-administered calcium chloride
for contractility and atropine for
bradycardia
No outcome data
Dosing of esmolol higher than
typical human dosing
In vivo: Decreased HR, TNFα, IL-6
No outcome data
Ex vivo: Left ventricular end
diastolic pressure decreased
Landiolol is an ultra-short acting,
cardioselective beta-blocker not
available in the US
Post mortem: Decreased lung injury
In vivo: Decreased HR, CO, IL-6
Increased survival in pre-treatment
arm
Esmolol infusion
titrated to reduce HR
by 20%
In vivo: Decreased HR with increase
in SVI
Esmolol infusion of
300 mcg/kg/min
In vivo: Decreased HR, lactate, EF;
No significant change in CO
Increased median time to death by
10 hr
Survival benefits were not conferred
to post-treatment arm
Clinical endpoint improvements
occurred in both arms
No outcome data
Selective β1-blockade appears to be
well tolerated in larger animal
models to offset septic dysfunction
Dosing was fixed
All rats received 10 mg/kg
imipenem for treatment of infection
Increased survival
Curran | 19