A Cure for the Code Blues?

Vasopressin, Steroid and Epinephrine Cocktail for Use in Advanced

Cardiac Life Support

Hannah Davis, Pharm.D.

PGY2 Emergency Medicine Pharmacy Resident

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

August 28, 2015

Learning Objectives

1. Define therapeutic endpoints for basic life support and advanced cardiac life support (ACLS)

2. Describe the current level of evidence for vasopressor agents recommended by national ACLS

guidelines

3. Identify complications following return of spontaneous circulation which may decrease survival

4. Analyze evidence for role of combination vasopressin, steroids and epinephrine in ACLS

H. Davis | Page 2

I. Cardiac arrest (CA)

Figure 1. Introduction to CA

A. Incidence

1,2

i. Out-of-hospital cardiac arrests (OHCA): 94 per year per 100,000 people

ii. In-hospital cardiac arrests (IHCA): 1-5 per 1,000 patient admissions

a. Bias due to lack of official reporting and documenting

B. Survival rates1-7

i. Favorable determinants

a. Younger age

b. Fewer comorbidities

c. Ventricular fibrillation (VFib) or pulseless ventricular tachycardia (VTach)

d. Witnessed arrest

e. Shorter time to chest compressions and defibrillation

f. Shorter duration of code

g. IHCA

h. Occurrence during the day on a weekday

ii. National OHCA survival to hospital discharge: 3-16%

iii. National IHCA survival to hospital discharge: 23%

a. VFib or VTach: 18-64%

b. Pulseless electrical activity (PEA) or asystole arrests: 1-14%

iv. 60% of patients do not survive to discharge after return of spontaneous circulation

(ROSC)

a. Most deaths following ROSC occur within 24 hours

v. Neurologic function

a. Severe cerebral disability or vegetative state in 25-50%

b. Post-cardiac arrest brain injury manifests as coma, seizures, myoclonus,

neurocognitive dysfunction and brain death

c. Contributory factors: microcirculatory failure, impaired cerebral

autoregulation, hypercarbia, hyper/hypoxia, pyrexia, hyperglycemia and

seizures

Medical emergency

Sudden cessation of effective

blood circulation

Prevents delivery of oxygen and

nutrients

Results in loss of consciousness

and death

H. Davis | Page 3

C. Pathophysiology of CA8-11

i. Lack of effective cardiac contraction with minimal cardiac output (CO)

ii. Presenting rhythms

a. Shockable

1. VTach – organized electrical activity of ventricles

2. VFib – disorganized electrical activity of ventricles

b. Non-shockable

1. PEA – additional rhythms with lack of sufficient ventricular

activity to generate pulse

2. Asystole – absence of detectable ventricular electrical activity

aa. End-stage rhythm following prolonged VFib or PEA

ab. Worst prognosis

iii. Etiology

a. Underlying cause

1. Non-reversible causes

2. Reversible causes, “H’s and T’s” (see Appendix A)

iv. Physiologic response

a. Activation of sympathetic nervous system

1. Increases plasma catecholamines

2. Releases vasopressin (VASO) and activates renin-angiotensin-

aldosterone system

b. Hypothalamic-pituitary-adrenal (HPA) axis response

Figure 2. HPA axis

www.paleomom.com

Posterior

pituitary

VASO

H. Davis | Page 4

II. Basic Life Support (BLS) and Advanced Cardiac Life Support (ACLS)

A. Guidelines8,12

i. American Heart Association (AHA) ACLS 2010

ii. European Resuscitation Council (ERC) 2010

Figure 3. Chest compressions8

A. Defibrillation8

i. VFib or VTach rhythms following every cycle of chest compressions

a. Biphasic preferred, initial 120-200 J

ii. Increases survival

B. Ventilation8

i. Bag-mask-valve with 100% FiO2

a. 2 breaths every 30 seconds without advanced airway

b. 1 breath every 6-8 seconds with advanced airway

ii. Minimize excessive ventilation

a. Increases intrathoracic pressure, decreases blood flow to vital organs

b. Other complications: gastric inflation, regurgitation, aspiration

C. Medications in ACLS8,12,14,15

i. Administered by intravenous (IV) or intraosseous (IO) route

ii. Increase cardiac and cerebral perfusion pressure

iii. Facilitate restoration and maintenance of a perfusing spontaneous rhythm

iv. Guideline recommended drug therapy (See Appendix B)

a. All rhythms

1. Epinephrine (EPI)

2. VASO

b. Refractory VFib/VTach

1. Amiodarone

aa. α, β, Na+

, K+

, Ca++

channel antagonist

ab. After 1st

defibrillation attempt, following 2 minutes of

chest compressions

ac. Increases ROSC and survival to hospital admission

•Compression= systole

•Recoil = diastole

Generates CO

•≥ 2 inches deep

•Good recoil

•≥ 100 per min

•1 cycle = 2 min

Push hard and fast

•Increases odds of defibrillation success

Improves survival

H. Davis | Page 5

v. Clinically evaluated endpoints

a. ROSC

b. Short term survival/survival to hospital admission

c. Survival to hospital discharge

d. Survival to hospital discharge with favorable neurologic recovery

1. Cerebral Performance Category (CPC) (See Appendix C)

e. Long term survival

vi. Evidence for medications

a. Increase ROSC and survival to hospital admission when compared to no

medications

b. Every 1 minute delay in vasopressor administration is a 4% decrease in

ROSC

c. None for long-term survival or favorable neurologic outcomes

vii. Consider reversible causes and treat underlying pathophysiology (See Appendix A)

II. EPI

A. Background13,16

i. Catecholamine hormone and neurotransmitter

ii. Chemical mediator conveying nerve impulses to organs (heart, lung, etc.)

iii. First used in 1906 to treat CA

iv. Integral part of CPR recommendations since 1974

Figure 4. EPI plasma concentrations10

B. Dosing

8,

i. 1 mg every 3-5 minutes IV/IO

C. Mechanism of action8,12,17,19-24

i. α- and β-adrenergic receptor stimulation

ii. α1/α2 – vasoconstriction

a. Most potent catecholamine for α stimulation

b. Increases coronary and cerebral perfusion pressures

1. Increases ROSC

c. Decreases microcirculatory cerebral blood flow

1. Increases severity of cerebral ischemia during CPR

2. Impairs neurologic function

14

145

23 10

25

201

0

50

100

150

200

250

Before EPI After EPI After ROSC 1 Hr After

ROSC

(ng/

mL

)

ROSC Achieved No ROSC

H. Davis | Page 6

iii. β1 – inotropic, chronotropic

a. No evidence of benefit from β-stimulation

1. β-agonism has demonstrated harm over BLS alone

2. Decreases survival vs. phenylephrine or EPI + esmolol

3. Increases defibrillation attempts required to attain ROSC

b. Detrimental effects

1. Increases myocardial work, oxygen consumption and utilization of

scarce energy reserves

aa. Lactic acid production

ab. Ectopic ventricular arrhythmias

ac. Secondary VFib

2. Transient hypoxemia due to pulmonary arteriovenous shunting

3. Post-ROSC tachycardia and hypertension

aa. Precipitates recurrence of VFib

4. Post-cardiac arrest myocardial dysfunction

aa. Greater incidence of post-resuscitation shock

iv. β2 – vasodilation

a. Increases blood flow to skeletal muscles

b. Predominantly masked by α1 effects

D. Efficacy data14,25-28

Table 1. EPI vs. Placebo

Author (n) Patients Intervention Results

Woodhouse et al. 1995

339

OHCA/IHCA

Asystole or resistant VFib

Prospective RCT

HDE= 10 mg x 2 vs.

SDE= 1 mg x 2 or

placebo (not randomized) x 2

Followed by open label 1 mg EPI

No difference in:

Immediate survival

Hospital discharge

Herlitz et al. 1995 1203

OHCA

VFib

Retrospective

EPI after ≥3 rounds defibrillation vs.

no EPI regardless of defibrillation

attempts

↑ ROSC

↑ hospital admission

No difference in:

Hospital discharge

Ong et al. 2007 1296 OHCA

Prospective observational

Before vs. after protocol:

EPI 1 mg x 1 prior to transport with 1

mg dose x 1 in ED

No difference in:

ROSC

Hospital admission

Hospital discharge

Olsveengen et al. 2010 851 OHCA

Prospective RCT

ACLS with vs. without IV access and

standard drugs

↑ ROSC

↑ hospital admission

↑ CPR time

No difference in:

Hospital discharge

Favorable neurologic outcome

Jacobs et al. 2011 534 OHCA Prospective, DB, RCT

EPI 1 mg vs. placebo every 3 min

↑ ROSC

↑ hospital admission

No difference in:

Hospital discharge

*All differences demonstrated statistical significance

OHCA: out-of-hospital cardiac arrest; IHCA: in-hospital cardiac arrest; RCT: randomized controlled trial; HDE: high dose epinephrine; SDE:

standard dose epinephrine; EPI: epinephrine; VFib: ventricular fibrillation; ROSC: return of spontaneous circulation; ED: emergency

department; ACLS: advanced cardiac life support; IV: intravenous; CPR: cardiopulmonary resuscitation; DB: double blind

H. Davis | Page 7

E. Bottom line19,29

i. EPI increases likelihood of achieving ROSC and survival to hospital admission

ii. Effects on long-term survival remain uncertain

iii. No role for higher doses

a. No improvement in survival with EPI doses > 1 mg

iv. Dose-dependent adverse effects

a. Unfavorable neurologic outcomes

III. VASO

A. Background8,12

i. Endogenous peptide and antidiuretic hormone

ii. Regulates water retention and electrolyte homeostasis

iii. Increases peripheral vascular resistance

iv. Guideline recommendations

a. AHA: alternative to EPI since 2000

b. ERC: not enough evidence to recommend or refute use

Figure 5. VASO plasma concentrations10

B. Dosing

8

i. 40 units once IV/IO

a. May replace first or second dose of EPI

C. Mechanism of action12

i. Non-adrenergic peripheral vasoconstrictor

a. Stimulates smooth muscle V1 receptors

D. Physiologic effects31-35

i. Increases coronary perfusion pressure

ii. Causes cerebral vasodilation

iii. Minimal effect on pulmonary vasculature

iv. Longer t1/2 and duration of effect than EPI

a. Increases mean arterial pressure (MAP) post-resuscitation

v. Potentiates release of ACTH and cortisol

vi. Greater stability in acidic environment compared to catecholamines

193 177

117

24

70 58

0

50

100

150

200

250

Before EPI After EPI After ROSC 1 Hr After

ROSC

(pg/

mL

)

ROSC Achieved No ROSC

H. Davis | Page 8

E. Efficacy data35-38

Table 2. VASO vs. EPI

Author (n) Patients Intervention Results

Linder et al. 1997 40 OHCA

Resistant VFib

Prospective, DB, RCT, VASO 40

units x 1 vs. EPI 1 mg x 1

Followed by standard ACLS

medication

↑ ROSC

↑ hospital admission

↑ 24 hr survival

No difference in:

Hospital discharge

Good neurological outcome

Stiell et al. 2001 200 IHCA

Prospective, RCT, triple blind

VASO 40 units x 1 vs. EPI 1 mg x 1

Followed by open label EPI

No difference in:

ROSC

Hospital discharge

Neurologic outcome

Survival

Wenzel et al. 2004 1186 OHCA

Prospective MC, DB, RCT

VASO 40 units every 3 min x 2 vs.

EPI 1 mg every 3 min x 2

Followed by open label EPI

(↑ hospital admission,

↑ hospital discharge in asystolic patients)

No difference in:

Hospital admission

Hospital discharge

Cerebral performance

Grmec et al. 2005 109 OHCA

VFib/VTach

Prospective observational cohort

(retrospective control)

VASO 40 units x 1 then EPI every 3-5

min vs.

EPI every 3-5 min x 3 then VASO 40

units x 1

vs. EPI every 3-5 min

Results include both combo arms vs. only EPI:

↑ ROSC

↑ hospital admission

↑ 24 hr survival

No difference in:

Hospital discharge

Neurologic outcomes

*All differences demonstrated statistical significance

OHCA: out-of-hospital cardiac arrest; VFib: ventricular fibrillation; DB: double blind; RCT: randomized controlled trial; EPI: epinephrine;

VASO: vasopressin; ROSC: return of spontaneous circulation; hr: hour(s); IHCA: in-hospital cardiac arrest; MC: multi-centered; min:

minute(s); CPR: cardiopulmonary arrest; ER: emergency room

F. Bottom line35,37,38

i. Many studies included EPI administration in VASO arm

ii. Conflicting results on benefit of VASO over EPI

a. Some reports of increasing ROSC and hospital admission

1. Small studies

2. Predominantly with repeat dosing of VASO

3. Predominantly in asystolic patients

G. EPI + VASO vs. EPI1,20,37,39,40

i. Stimulates both catecholamine and VASO receptors

a. Improves perfusion of vital organs

b. Decreases vasopressor-mediated adverse effects

ii. EPI + VASO diminishes cerebral microvascular blood flow

iii. Subgroup analysis suggests benefit in those requiring > 2 doses of initial

vasopressor when VASO is combined with EPI

iv. Subgroup analysis suggests benefit of EPI + VASO in patients with pH < 7.2

H. Davis | Page 9

H. Efficacy data1,32,39,41-44

Table 3. EPI +VASO vs. EPI

Author (n) Patients Intervention Results

Guyette et al. 2004 298 OHCA

Retrospective

VASO administration determined by

physician on scene

EPI 1 mg every 3-5 min + VASO 40 units x 1

vs. EPI 1 mg every 3-5 min

↑ ROSC

↑ ER arrival

Callaway et al. 2006 325 OHCA

Prospective, DB, RCT

VASO 40 units x 1 vs. placebo x 1

after ≥ 1 EPI

Followed by open label EPI

No difference in:

ROSC

Hospital arrival

Mally et al. 2006

598

OHCA

Resistant to

defibrillation

Prospective observational

VASO 40 units then EPI 1 mg every 3 min

vs. EPI 1 mg every 3 min

↑ petCO2; MAP

↑ ROSC

↑ 24 hr survival

↑ neurologic outcome upon

discharge

(↑ hospital discharge in asystole

subgroup)

No difference:

Hospital discharge

Gueugniaud et al. 2008 2894 OHCA

resistant VFib/VTach

Prospective DB, MC, RCT

VASO 40 units + EPI 1 mg

every 3 minutes x 2

Followed by open label EPI

vs. EPI 1 mg + placebo

every 3 minutes x 2

Followed by open label EPI

(↓ hospital discharge in PEA

subgroup analysis)

No difference in:

ROSC

Hospital admission

Hospital discharge

Neurologic recovery

1 year survival

Cody et al. 2010 191 OHCA

Retrospective cohort evaluating protocols

VASO 40 units + EPI 1 mg

Followed by EPI 1 mg every 3-5min

vs. EPI 1 mg every 3 min

No difference in:

Hospital admission

Hospital discharge

Ducros et al. 2010 44 OHCA

Prospective, DB, RCT

EPI 1 mg every + VASO 40 units every 5 min

vs. EPI 1 mg every 5 min

vs. EPI 1 mg + VASO 40 units + nitroglycerin

300 mcg every 5 min

No difference in:

Diastolic BP

ROSC

Ong et al. 2012 727 OHCA/IHCA

(ED patients)

Prospective MC, DB, parallel, RCT

VASO 40 units x 1 vs. EPI 1 mg x 1

Followed by open label EPI

↑ hospital admission (when

variables accounted for)

No difference in:

Hospital discharge

*All differences demonstrated statistical significance

OHCA: out-of-hospital cardiac arrest; EPI: epinephrine; mg: milligram; min: minute(s); VASO: vasopressin; ROSC: return of spontaneous

circulation; ER: emergency room; DB: double blind; RCT: randomized controlled trial; petCO2: end-tidal carbon dioxide; hr: hour; MC: multi-

centered; mcg: micrograms; BP: blood pressure; IHCA: in-hospital cardiac arrest

I. Bottom line40,45-48

i. Systematic reviews and meta-analyses failed to demonstrate benefit of VASO over

EPI or in combination with EPI

a. Secondary analysis suggests dose dependent increases in survival rates

when treated with VASO vs. EPI in asystolic patients

b. Largest OHCA study associated with mean time to medications > 20

minutes

ii. Meta-analysis 2014, reviewing 10 RCTs

a. No improvement in ROSC, survival to hospital admission or discharge

H. Davis | Page 10

b. IHCA subgroup analysis

1. Higher ROSC

2. Higher survival to hospital admission and discharge

3. Favorable neurologic outcomes

4. Non-traditional, repeated dosing of vasopressin

5. All vasopressin, steroid, epinephrine (VSE) data

IV. Complications after ROSC

A. Adrenal insufficiency (AI) of CA11,49-52

i. Inability to adequately increase cortisol secretion in response to ACTH during and

after ACLS

ii. Etiology

a. Adrenal gland ischemia

b. Inflammatory response to ischemia results in further damage

iii. Increases mortality

iv. Diminishes response to catecholamines

v. Leads to hemodynamic instability and circulatory collapse

B. Inflammatory mediated ischemic/reperfusion injury50,52-54

i. Activation of cytokines, endotoxins, and reactive species after CA

ii. Inflammatory response further damages ischemic organs

a. Compounds neurologic damage

b. Cytokines associated with mortality and unfavorable neurologic outcomes

iii. Normal physiologic response to cytokines is stimulation of cortisol release

a. Unable to adequately respond due to AI

C. Post-resuscitation shock6,51,55-60

i. Precise definitions of hemodynamic instability/shock are lacking

ii. Impaired contractile function and diastolic function that reverses several hours to

days after resuscitation

iii. Hyperdynamic phase, lasting minutes

a. Tachycardia and hypertension

iv. Post-resuscitation cardiovascular collapse phase

a. Cardiac index (CI) and filling pressures are low

1. Lactic acid produced

2. Myocardial stunning results in left ventricular dysfunction

3. Pro-inflammatory response resulting in loss of vascular tone

b. Occurs several hours after CA

c. Results in multi-system organ dysfunction which may progress to mortality

1. Decreases cerebral blood flow

H. Davis | Page 11

d. CI increases approximately 24 hours after arrest

1. Independent of filling pressures or inotropic agents

e. Vasodilation continues and requires vasoactive drugs

1. Recovery often seen within 3 days

v. Risk factors for development of post-resuscitation shock

a. Fifteen minute time interval between onset of arrest and ROSC

b. More frequent doses of EPI

c. Greater number of defibrillation attempts

vi. Treatment

a. Avoid hypotension

b. AHA recommends maintaining systolic blood pressure ≥ 90 mmHg and

MAP ≥ 65 mmHg

c. Other authors advocate for more aggressive goals

1. American Academy of Neurology and the Rocky Mountain

Critical Care Conference recommend MAP goal of 80-100

mmHg

aa. Based on expert opinion

ab. Theoretical improvement in neurologic outcomes

d. Hemodynamic instability was not associated with worse neurologic

outcomes when aggressively treated

1. MAP goal ≥ 75 mmHg

2. Volume expansion based on left ventricle end diastolic pressure

3. Vasoactive drugs: epinephrine or dobutamine with advanced

hemodynamic monitoring

V. Steroids

A. Background8,12

i. Decrease inflammatory response and regulate homeostasis

ii. No role for steroids in AHA or ERC guidelines

B. Cortisol plasma concentrations10,49,50,53

i. Normal range

a. Without stress: 5-20 mcg/dL

b. Under stress: 50-90 mcg/dL

ii. Low levels during or after CA indicate lack of appropriate response

a. Associated with early post-resuscitation mortality

iii. Higher cortisol levels have been associated with neurologically intact survival and

survival > 1 month

C. Mechanism of action11

i. Regulates gene expression

a. Decreases production of kinins, histamines, liposomal enzymes,

prostaglandins, leukotrienes

b. Inhibits cell migration to area of injury

c. Decreases vessel permeability

H. Davis | Page 12

D. Physiologic effects11,49,50,61,62

i. Homeostasis

a. Fluid and electrolyte balance

1. Decreases cell apoptosis and provides positive inotropy through

calcium homeostasis

b. Maintains integrity of membrane structures

ii. Anti-inflammatory

a. Decreases ischemia/reperfusion injury

iii. Vascular

a. Decreases permeability, increases SVR

b. Decreases production of vasodilators

c. Increases vascular reactivity to catecholamines and angiotensin II

iv. Cardiac

a. Increases coronary perfusion pressure

i. Increases production of coronary vasodilators

b. Increases contractility

v. Endocrine

a. Supplements cortisol not produced during AI

E. Detrimental effects62

i. Electrolyte disturbances, sodium or glucose

ii. Infections

iii. Negative regulation on HPA axis, may result in AI

F. Dosing5,52,61

i. ACLS

a. Hydrocortisone (HCT) 100 mg IV push once

b. Methylprednisolone 40 mg IV push once

ii. Stress dose steroids

a. HCT 300 mg IV per day

H. Davis | Page 13

G. Efficacy data49,52,63-66

i. Animal data demonstrates increase ROSC with corticosteroids

Table 4. Steroids

Author (n) Patients Intervention Results

White et al. 1976 5 IHCA

Refractory VFib or asystole

Retrospective case series

DEX 100 mg once after conventional

therapy failed

Plus: EPI, atropine, bicarbonate, isuprel

Compared to historical control

Corrected rhythm**

White et al. 1979 25 IHCA

VFib or asystole

Retrospective case series

DEX 100 mg once

Plus: atropine, isoproterenol, EPI,

calcium

Compared to historical control

↑ ROSC**

↑ long term survival**

Paris et al. 1984 86 OHCA

PEA

Prospective, RCT, DB

Pre-hospital DEX 100 mg vs. placebo

Plus: bicarbonate, EPI, and atropine

No difference in:

ROSC

Long term survival

Grafton et al. 1988 458 After OHCA

VFib or asystole

Retrospective

Steroid use following ROSC for brain

ischemia or lung injury

Predominantly low dose DEX

No difference in:

Regaining consciousness

Hospital discharge

Tsai et al. 2006 97 OHCA

Prospective, non-randomized (required

family member pre-approval)

HCT 100 mg vs. placebo

Plus: EPI, VASO in ~1/3

↑ ROSC

No difference in:

Adverse effects

Survival

Neurologic function

*Unless specified, results demonstrated statistical significance

**Statistical significance not evaluated

IHCA: in-hospital cardiac arrest; VFib: ventricular fibrillation; DEX: dexamethasone, EPI: epinephrine; CO: cardiac output; PEA:

pulseless electrical activity; ROSC: return of spontaneous circulation; OHCA: out-of-hospital cardiac arrest; RCT: randomized

controlled trial; HCT: hydrocortisone; VASO: vasopressin; min: minutes

H. Bottom line52,66,67

i. Weakly associated with increases in ROSC

a. Time dependent

b. Driven by subgroup receiving hydrocortisone within 6 min of ED arrival

or 22 min from collapse

ii. No role for steroid administration following ROSC to treat brain ischemia

iii. No increases in adverse effects

VI. VSE data

A. Is a cocktail of stress hormones the solution?

i. EPI has been the mainstay of ACLS drug therapy but is associated with

consequences linked to worse outcomes after ROSC

ii. VASO alone or in combination has not shown to be superior to EPI

iii. VASO administration increases serum ACTH but does not result in an adequate

physiologic response of cortisol

iv. Evidence of relative AI and inflammatory mediated ischemia/reperfusion injury of

CA linked to post-resuscitation shock which is known to increase mortality

H. Davis | Page 14

B. Efficacy data61

Table 5. Mentzelopoulos S, Zakynthinos S, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest.

Arch Intern Med. 2009;169:15-24.

Objective Determine if VSE supplementation during and after resuscitation improves survival in refractory IHCA

Study Design

Prospective, single-center, double blind, placebo-controlled, parallel group, randomized controlled trial

Intervention:

Methylprednisolone 40 mg x 1

EPI 1 mg + VASO 20 units (per resuscitation cycle)

Following ROSC, HCT 300 mg/day continuous

infusion x 3-7 days, followed by taper, if post-

resuscitation shock present

Control:

Placebo x 1

EPI 1 mg + placebo (per resuscitation cycle)

Following ROSC, placebo x 3-7 days, followed by

taper, if post-resuscitation shock present

Post-resuscitation shock – sustained > 4 hours, MAP ≤ 70 mmHg despite appropriate fluid resuscitation, or doubling of peri-arrest

vasopressor requirements

Patients Inclusion: IHCA with PEA/asystole or VFib/VTach after 2 defibrillation attempts

Exclusion: pediatric, terminal illness, do not resuscitate order, arrest due to exsanguination, recent treatment with IV corticosteroids

Statistics

ITT analysis

Dichotomous variables: χ2

or Fisher exact test

Continuous variables: independent t test or Mann-Whitney exact test

Linear mixed-model analysis for post-resuscitation shock

Kaplan-Meier for survival

Multivariate analysis for independent predictors of death

Results

VSE:

n=100

↑ ROSC: 39/48 (81%) vs. 27/52 (52%) p=0.003

↑ survival to discharge: 9/48 (19%) vs. 2/52 (4%) p=0.02

Following ROSC: ↑ MAP, ↓ vasopressor requirements, ↓ cytokine levels, ↑ central venous oxygen saturation, ↓ in lactate,

↑ renal-failure free days

Stress dose steroids:

↑ hospital discharge 8/27 (30%) vs. 0/15 (0%) p=0.02

↑ organ failure free days

Authors’

Conclusions VSE during resuscitation and stress-dose HCT in post-resuscitation shock improves survival by a factor of 4.5 in refractory IHCA

Critique

Examined IHCA, did not exclude trauma patients

Examined physiologic endpoints potentially associated with improvements in survival

Predominantly asystole patients (75-80%)

More reversible causes of CA in study group

Use of multiple interventions; unclear if individual interventions are beneficial

Used a previously unstudied dose of VASO

Administered EPI and VASO every 2-3 minutes vs. 3-5 minutes

Feasibility of administering VASO and EPI at the same time when not prepared ahead of time by study personnel

C. Bottom line

i. Combination VSE demonstrates improvement in ROSC and survival to hospital

discharge compared to EPI alone

ii. Benefits in ROSC likely from EPI + VASO

iii. Benefits in survival likely from methylprednisolone

iv. Neurologically favorable survival not demonstrated in this study

H. Davis | Page 15

D. Efficacy data5

Table 6. Mentzelopoulos S, Malachias S, Charnos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival

after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310:270-279.

Objective Determine if combination VSE improves outcomes compared to standard of care for IHCA

Study Design

Prospective, multi-centered, double blind, placebo-controlled, parallel-group, randomized controlled trial

Intervention

Methylprednisolone 40 mg x 1

EPI 1 mg + VASO 20 units (per resuscitation cycle)

Following ROSC, HCT 300 mg/day continuous

infusion x 3-7 days followed by taper, if post-

resuscitation shock present

Control

Placebo x 1

EPI 1 mg + placebo (per resuscitation cycle)

Following ROSC, placebo x 3-7 days followed by

taper, if post-resuscitation shock present

Post-resuscitation shock – sustained > 4 hours, MAP ≤ 70 mmHg despite appropriate fluid resuscitation, or doubling of peri-arrest

vasopressor requirements

Patients Inclusion: IHCA, requiring EPI

Exclusion: pediatric, terminally ill, do not resuscitate orders, arrests due to exsanguination, current treatment with steroids

Statistics

ITT analysis

Kolmogorov-Smirnov for normality

Dichotomous variables: 2-sided χ2

, Fishers exact test

Continuous variables: 2-sided t test, Mann-Whitney exact U test

Bonferroni correction

Linear mixed model analysis to determine effect of groups

Logistical regression for ORs with 95% Cis

Multivariable Cox regression for HRs with 95% CIs

Results

VSE:

n=268

↑ ROSC: 109/130 (84%) vs. 91/138 (66%) p=0.005

↑ discharge with CPC score 1 or 2: 18/130 (14%) vs. 7/138 (5%) p=0.02

↓ duration ACLS, ↓ total EPI dose, ↑ hemodynamics, ↑ central venous oxygen saturation, ↑ cerebral perfusion pressure,

↑ renal-, neurologic-, ventilator-failure free days, ↓ organ dysfunction, similar adverse effects

Stress dose steroids:

↑ discharge with CPC score of 1 or 2: 16/76 (21%) vs. 6/73 (8%) p=0.02

15 EPI patients received HCT, ↑ circulatory-, renal-, hepatic-, coagulation-, respiratory-failure free days

No difference in incidence of adverse effects due to steroids

Authors’

Conclusions

VSE and stress-dose HCT vs. EPI results in ↑ survival to hospital discharge with favorable neurologic outcomes

Post-arrest HCT may decrease poor outcomes, but requires further investigation

Critique

Examined IHCA, large sample, did not exclude all trauma patients

CPR quality assessed with diastolic blood pressures

Utilized CPC score to evaluate neurologically favorable survival

Detailed protocol for treatment of underlying conditions, therapeutic hypothermia, sedation/analgesia, etc

Predominantly asystolic medicine patients

Chest compression cycles lasted approximately 3-4 minutes

Frequent use of atropine and bicarbonate

E. Bottom line

i. VSE increases ROSC and neurologically favorable survival

a. ROSC, number needed to treat (NNT)= 6

b. Neurologically favorable survival, NNT = 12

ii. Overall reduction in EPI doses, length of ACLS, improved peri-arrest

hemodynamics and perfusion which results in improved long-term outcomes

iii. No increase in complications from steroids

iv. Medications administered approximately every 3-4 minutes

H. Davis | Page 16

VII. Summary of evidence

A. Majority of studies are in OHCA vs. IHCA of non-traumatic origin and are powered for

detecting differences in hospital admission

B. Many variables throughout studies over the years

i. Time to initiation of BLS/ACLS

ii. Variation in protocols of emergency responders

iii. Unknown quality of chest compressions and approach to ventilatory support

iv. Change in availability of AEDs and defibrillators

v. Change in standard medications and doses

C. Many of the principles of therapy are based on data from previously healthy animals

D. Prior to VSE, no ACLS medication or combination of medications has improved survival

to discharge or neurologically favorable survival

E. VSE demonstrated neurologically favorable survival

VIII. Conclusions

A. Addition of methylprednisolone complements EPI + VASO in improving ROSC rates

i. Improves hemodynamic stability

ii. Decreases ischemia/reperfusion injury

iii. Reduces end-organ damage

B. Improves neurologic outcomes and overall survival in IHCA requiring vasopressors

IX. Recommendations

A. IHCA

i. Administer methylprednisolone 40 mg IV x 1 during first compression cycle

requiring medications

ii. Alternate every compression cycle (2 minutes) between

a. EPI 1 mg IV every 4 minutes

b. VASO 20 units IV every 4 minutes

1. Maximum of 5 doses

iii. Continue standard use of other adjunctive treatments during ACLS when indicated

based on clinical scenario

B. If ROSC is obtained, observe for post-resuscitation shock

i. At minimum maintain a MAP of ≥ 65 mmHg consider goals of ≥ 75 mmHg

a. After appropriate volume resuscitation

b. After appropriate vasopressors are initiated

i. If norepinephrine requirements ≥ 0.2-0.5 mcg/kg/min, consider

additional stress dose steroids

ii. Avoid inotropes

H. Davis | Page 17

Appendices

Appendix A. “H’s & T’s” of Cardiac Arrest8

Cause Indications Treatment

Hypovolemia

Distributive shock

Anaphylactic shock

Hemorrhagic shock

Crystalloids

Crystalloids, EPI, H1RA, H2RA, steroids

Blood products

Hypoxia ↓ oxygen saturation, cyanosis, PEA Oxygen

Hydrogen ion (acidosis) ↓ pH, ↓ CO2 Sodium bicarbonate

Treat underlying condition

Hypokalemia ↓ K+ ↓ Mg

++

K+

, Mg++

replacement

Hyperkalemia

EKG progressing from peaked T waves to

absent P waves to prolonged PR and QRS

to sine-wave prior to loss of pulse

Shift K+

:

Calcium, insulin, dextrose

Sodium bicarbonate

Hypothermia Core temp ≤ 30°C Prevent additional heat loss

Rewarm

Tension pneumothorax

Tracheal deviation away from tension,

tachycardia, tachypnea, hypoxia resulting in

CA associated with PEA

Needle decompression initially

Chest tube for definitive management

Cardiac tamponade ↓ ventricular filling and cardiac output

causing hypotension and ultimately CA

Pericardiocentesis – needle aspiration

Pericardial window –hole in pericardium

Toxins Toxidrome presentations, patient history,

UDS or other laboratory indicators

CCB/β blockers: calcium, glucagon, high dose

insulin/D50, fat emulsions

Digoxin: antidigoxin Fab antibodies

Cyanide: hydroxocobalamine or sodium nitrite/sodium

thiosulfate

Local anesthetics: fat emulsion

Thrombosis (pulmonary)

Tachycardia, tachypnea prior to arrest, right

heart strain, PEA with rapid/narrow QRS,

evidence of DVT

Fibrinolytics and prolonged chest compressions

Thrombosis (cardiac) Chest pain, diaphoretic, EKG findings prior

to arrest, troponin elevation, cardiac history

Early coronary revascularization

Fibrinolytics as a less favorable alternative

Appendix B. Guideline Concordant ACLS Medication Dosing8

Medication Dose Indication

Epinephrine 1 mg every 3-5 minutes All rhythms

Vasopressin 40 units x 1

To replace the 1st

or 2nd

dose of epinephrine per

AHA guidelines

All rhythms

Amiodarone

1st

dose: 300 mg x 1

Refractory VFib or VTach After 3-5 minutes

2nd

dose: 150 mg x 1

After 3-5 minutes

Per ERC guidelines: 900 mg IV drip over 24 hours

All medications may be administered by IV or IO routes

H. Davis | Page 18

Appendix C. Cerebral-preformance Category5,61

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