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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. Discuss the pathophysiology of septic shock and sepsis-induced myocardial depression2. Identify and recommend appropriate agents for hemodynamic management of septic shock3. Describe the potential benefits and risks of using beta-blockers in septic shock4. Devise an evidence-based recommendation for the appropriate use of beta-blockers in septic shock

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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

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

Sepsis

Infection (confirmed or suspected)

+

Systemic response (SIRS)

Severe Sepsis

Sepsis

+

Organ dysfunction, hypotension, or hypoperfusion

Septic Shock

Severe sepsis despite adequate fluid resuscitation

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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

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

Leukocyte activation

•Cytokines

•Proteases

•Reactive oxygen species

Complement activation

•Complement products

Coagulation activation

•Coagulation proteases

Necrotic cell death

•Damage and tissue injury

Neuroendocrine regulation

•Inhibit proinflammatory cytokine production via hypothalamic-pituitary-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

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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 shock16

c. Conduct imaging studies to assist with location of infection d. Establish source control when feasible

II. Cardiovascular management of septic shock

A. Role of adrenergic receptors in cardiovascular system18-20

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

Table 1. Adrenergic receptors and roles18-20

Type Location Role

α1 Smooth muscle of arteries and veins Contraction leading to vasoconstriction

α2 Central nervous system

Sympathetic nerve varicosities

Inhibition of catecholamine release

Inhibition of sympathetic nervous system

β1 Sinoatrial node

Atrial and ventricular muscle

Atrioventricular node and purkinje fibers

Increase HR

Increase conduction velocity and contractility

Increase conduction velocity

β2 Smooth muscle of arteries and veins Relaxation and vasodilation

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

Table 2. Vasopressor receptor binding18

α1 β1 β2 DA V1/V2

Norepinephrine (NE) +++++ +++ ++

Epinephrine (Epi) +++++ ++++ +++

Phenylephrine (PE) +++++

Isoproterenol (Iso) +++++ +++++

Dobutamine (Dobut) + +++++ +++

Dopamine (Dopa) +++ ++++ ++ +++++

Vasopressin (VASO) +

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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 support2,28-31 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

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ii. 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

iii. 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 surge32

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

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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) Dosing: continuous infusion Pharmacokinetics

Achieves steady-state level within 10–20 minutes

55 % protein bound

Elimination half-life: ~nine minutes

73-88 % renally eliminated

Undergoes esterase metabolism in blood Major adverse effects

Hypotension

Nausea

Injection site reaction

Formulations: IV, Oral Dosing: intermittent dosing Pharmacokinetics

Achieves peak ~90 minutes after oral dose

10 % protein bound

Elimination half-life: three to four hr

95 % renally eliminated

Undergoes hepatic metabolism via CYP2D6 Major adverse effects

Hypotension

Heart failure

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

•↑ Cardiac contractility

•↑ Heart rate

Elevated catecholamine levels

•Tissue hypoxia

•↓ ATP formation and energy supply

•Cell death

Circulatory derangement and mitochondrial dysfunction

•Hyporesponsiveness to catecholamines

•Inactivation of catecholamines

•↓ energy needs

Downregulate receptor response

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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

Table 4: Animal data for beta-blockade in septic shock50, 51

Study design Results Significance

Berk, et al 1969 Purpose: effect of beta-adrenergic blockers on endotoxin-induced shock in a dog model Treatment groups: 1. Propranolol 2.5 mcg/kg infusion or

doses ranging from 150 to 1500 mcg/kg over 3-minute period with fluid resuscitation

2. Fluid resuscitation treatment only 3. Untreated

Survival significantly improved in propranolol treated group v. 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)

1st study of beta-blockade in animal model Found improved survival

Aboab, et al 2011 Investigate cardiovascular tolerance of blockade of beta-adrenergic receptors in an endotoxin pig model Treatment groups: 1. Esmolol titrated to reduce HR by 20% 2. Placebo group

Esmolol infusion did not induce cardiovascular collapse in any of the septic animals Esmolol improved stroke index from 31 mL/min/m2 at 180 min to 47 mL/min/m2 at 300 min

Beta-blockade is well tolerated and offsets cardiac dysfunction in large septic animals

F. 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

Energy generation Energy expenditure

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2. MAP > 70 mm Hg in all patients c. Five hr after study enrollment, esmolol was given to obtain a target decrease in HR of 20 % for three hr d. 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

ii. 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

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

Primary diagnosis of septic shock

Myocardial depression (ScvO2 < 65 % despite adequate fluid resuscitation and/or cardiac index (CI) < 2.5 L/min/m2

requiring inotropic therapy)

Treated with enteral metoprolol within 48 hr after onset of shock or admission to the ICU

Exclusion criteria

< 18 years old

Any cause of low CO other than sepsis

Pre-existing decompensated heart failure

Did not require inotropic support

No measurement of CO

Received beta-blockers > 48 hr after shock onset/ICU admission

Outcomes Primary

Clinical course (ICU length of stay [LOS], 28-day mortality)

Reduction of HR to goal of 65–95 BPM

Hemodynamic effects measured by SVI, HR, central venous pressure (CVP)

Secondary

Vasopressor requirements (including NE, milrinone, vasopressin)

Surrogate markers: pH, arterial lactate, serum creatinine, C-reactive proteins

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

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Results

Baseline Characteristics

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

Primary Outcomes 97.5% of patients achieved target HR 65–95 BPM (n = 39)

Table 5: Change in hemodynamic monitoring parameters

Study initiation Study conclusion P-value

CVP, mean (± SD) 12 ± 3 9 ± 3 < 0.001

SVI, mean (± SD) 32 ± 12 44 ± 9 0.002

MAP, mean (± SD) 85 ± 23 90 ± 21 0.16

28-day mortality, n (%): 13 (33)

Mean ICU LOS, days (± SD): 15 ± 11

Secondary Outcomes

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

Author’s 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

Strengths 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

Limitations 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

Take Home Points 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

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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

Septic shock requiring NE to maintain MAP ≥ 65 mm Hg despite adequate fluid resuscitation after 24 hr

HR ≥ 95 BPM

Exclusion criteria

< 18 years old

Need for inotropic agent

Cardiac dysfunction (CI ≤ 2.2 L/min/m2 with pulmonary capillary wedge pressure (PCWP) > 18 mm Hg)

Valvular disease

Pregnancy

Outcomes Primary

Change in sublingual microvascular flow index (MFI) to measure microvascular circulation

Secondary

Pulmonary artery monitoring (MAP, PCWP, right 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 Characteristics

Age in years, median (IQR): 62 (43–76)

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)

Figure 10: Change in microcirculatory flow index of small vessels after 24 hr of esmolol administration

MFI Flow

0 Absent

1 Intermittent

2 Sluggish

3 Normal

Secondary Outcomes

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)

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Conclusions

Author’s 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

Strengths 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

Limitations 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

Take Home Points 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

Septic shock requiring NE to maintain MAP ≥ 65 mm Hg after 24 hr

Appropriate volume resuscitation indicated by pulmonary arterial occlusion pressure (PCWP) ≥ 12 mm Hg and CVP ≥ 8 mm Hg

HR ≥ 95 BPM

Exclusion criteria

< 18 years old

Beta-blocker therapy prior to randomization

Cardiac dysfunction (CI ≤ 2.2 L/min/m2 with PCWP > 18 mm Hg)

Significant valvular disease

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

Reduction in HR below 95 BPM and maintenance of HR between 80–94 BPM for duration of ICU stay

Secondary

Mortality within 28 days after randomization and adverse events

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

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Results

Baseline Characteristics

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 co-morbidities between groups

SAPS II score, median (IQR): 52 (47–60) in esmolol group v. 57 (49–62) in control group

Primary Outcome 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 Figure 15: Change in CI Figure 16: Change in MAP

Acid-base and metabolic Organ function 28-day mortality

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)

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

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

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Conclusions

Author’s 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

Strengths 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

Limitations 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

Take Home Points 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

V. 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

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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

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X. Appendices Appendix A. ICU Severity Scores59-61

Scoring system Mortality interpretation Background

Simplified Acute Physiology Score (SAPS II)

Score range 0 to 163 points

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 Every 24 hr assess:

Coagulation and respiratory, nervous, cardiovascular, hepatic, and renal function every 24 hr

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 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 Normal Description

Mean Arterial Pressure MAP 60–100 mm Hg Average BP value derived from systolic and diastolic BP

Central Venous Pressure CVP 2–6 mm Hg Indicator of volume status and preload

Stroke Volume SV 50–100 mL Amount of blood ejected from left ventricle with each heart contraction

Stroke Volume Index SVI 25–45 mL/m2 SV adjusted for body surface area (BSA)

Superior Vena Cava Oxygen Saturation ScvO2 ≥ 60% Represents oxygen delivery

Pulmonary Artery Occlusion Pressure (Wedge)

PAOP/PCWP 8–12 mm Hg Elevations may indicated left ventricular failure or acute pulmonary edema

Systemic Vascular Resistance Index SVRI 1600-2400 dyne∙ sec∙cm

Vascular resistance across the whole systemic circulation

Cardiac Output CO 4-7 L/min Amount of blood the heart pumps through vasculature in one minute

Stroke Volume Variation SVV < 13% Variation in arterial pulsations during positive-pressure ventilation

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Appendix C. Evidence Table of Beta-Blockers in Septic Animal Models50, 51, 63-66

Trial Year Model Intervention Results of beta-blocker treatment arms

Limitations

Berk, et al. 1969 Dogs Propranolol 0.15 to 1.5 mg/kg given 5 to 60 min after endotoxin injection

Survival increased from 27 % to 72 % In vivo: Increased BP and PaO2; Decreased fluid requirements Post-mortem: Decreased lung injury

Only study using non-selective beta-blocker Co-administered calcium chloride for contractility and atropine for bradycardia

Suzuki, et al. 2005 Rats Esmolol infusion of 10 to 20 mg/kg/hr for 24 hr

In vivo: Decreased HR, BP, TNF-alpha Ex vivo: Increased SV, CO, cardiac efficiency

No outcome data Dosing of esmolol higher than typical human dosing

Hagiwara, et al. 2009 Rats Landiolol infusion of 0.1 mg/kg/min for 24 hr

In vivo: Decreased HR, TNFα, IL-6 Ex vivo: Left ventricular end diastolic pressure decreased Post mortem: Decreased lung injury

No outcome data Landiolol is an ultra-short acting, cardioselective beta-blocker not available in the US

Ackland, et al. 2010 Rats Metoprolol pre- and post-treatment (various doses)

In vivo: Decreased HR, CO, IL-6 Increased survival in pre-treatment arm

Survival benefits were not conferred to post-treatment arm Clinical endpoint improvements occurred in both arms

Aboab, et al. 2011 Pigs Esmolol infusion titrated to reduce HR by 20%

In vivo: Decreased HR with increase in SVI

No outcome data Selective β1-blockade appears to be well tolerated in larger animal models to offset septic dysfunction

Kimmoun, et al. 2015 Rats 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 Increased survival

Dosing was fixed All rats received 10 mg/kg imipenem for treatment of infection