Is it time to abandon epinephrine in out-of-hospital cardiac arrest?

Ellen Robinson, Pharm.D. PGY-1 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

February 5, 2016

Learning Objectives

1. Discuss epidemiology, pathophysiology, and treatment for out-of-hospital cardiac arrest2. Describe positive and negative effects of epinephrine during advanced cardiac life support and post

return of spontaneous circulation3. Analyze evidence for epinephrine use in out-of-hospital cardiac arrest

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I. Incidence and survival1,2

a. Out-of-hospital cardiac arrest (OHCA) occurs in approximately 420,000 individuals each year b. Pooled survival rate to hospital admission is 23.8% and survival to hospital discharge is 7.6% c. Most deaths occur within 24 hours despite return of spontaneous circulation (ROSC)

II. Survival predictors a. Survival to hospital discharge outcomes2

i. Five prehospital factors improve survival to discharge ii. Do not address neurological outcomes

b. Neurological outcomes3

i. Nine prehospital factors were independently associated with increased odds of favorable neurological outcomes at one month

1. Initial non-asystole rhythm a. Ventricular fibrillation (VF), pulseless ventricular tachycardia (pVT), or

pulseless electrical activity (PEA) 2. Age < 65 years 3. Arrest witnessed by emergency medical services (EMS) personnel 4. Call-to-hospital arrival time < 24 minutes 5. Arrest witnessed by bystander 6. Physician-staffed ambulance 7. Call-to-response time < 5 minutes 8. Prehospital shock delivery 9. Presumed cardiac cause

ii. When four of the nine factors were present, more patients achieve a cerebral performance category (CPC) score of 1-2 at one month [Refer to Appendix A]

1. Initial VF (16.1% vs 23.2%) 2. Initial pVT (8.3% vs 16.7%) 3. PEA (3.8% vs 9.4%)

III. Bottom-line

a. OHCA is associated with an extremely high mortality rate

Bystander witnessed

arrest (6.4% vs. 13.5%)

EMS witnessed arrest

(4.9% vs. 18.2%)

Bystander CPR(3.9% vs. 16.1%)

Initial shockable

rhythm(14.8% vs. 23.%)

ROSC in field(15.5% vs. 34%)

Initial non-asystole rhythm < 65 years EMS witnessed

arrestCall-to-hospital

arrival < 24 minutes

Epidemiology

Figure 1. Improvement in survival to hospital discharge based on prehospital factors

Figure 2. Prehospital factors influencing neurological outcomes

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b. Patients who experience an OHCA: i. Will likely not survive to hospital admission ii. If patient survives to admission, chance of survival to hospital discharge is minimal iii. Survivors commonly have poor neurological outcomes and quality of life

I. Cardiac arrest (CA) 1,4-6 a. Cardiac mechanical activity cessation and absence of circulatory signs

b. Etiology1,5-6

i. Coronary artery disease (CAD) accounts for > 70% of OHCA ii. Underlying reversible etiologies can be assessed using the H’s & T’s as a tool

Table 1: Common reversible etiologies of cardiac arrest

H’s T’s Hypovolemia Tension pneumothorax

Hypoxia Tamponade, cardiac Hydrogen ion (acidosis) Toxins

Hypo/hyperkalemia Thrombosis, pulmonary Hypothermia Thrombosis, coronary

c. Cardiac rhythms5-6 i. Shockable

1. VF: disorganized rhythm in ventricles 2. pVT: organized rhythm in ventricles

ii. Non-shockable 1. PEA: ventricular activity is not adequate to generate pulse 2. Asystole: no detectable ventricular electrical activity

II. Post cardiac arrest syndrome (PCAS)7,8 a. Characterized by brain injury, myocardial dysfunction, systemic ischemia/reperfusion response

i. Brain injury 1. Ischemic degeneration and impaired autoregulation 2. Leads to cerebral edema

Cardiac Arrest

Pathophysiology

Figure 3. Pathophysiological process of cardiac arrest

• Cessation of heart's mechanical activity

• Loss of circulation signs • Reduced oxygen and nutrient

delivery to vital organs • Loss of consciousness and

death

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3. Reperfusion exacerbates neuronal injury by activating apoptotic cellular pathways and introducing free radicals to tissue

4. Presents clinically as neurologic deficits including neurocognitive dysfunction, seizures, myoclonus, coma, and brain death

ii. Myocardial dysfunction 1. Largely characterized by global hyperkinesis 2. Typically reversible 3. Catecholamine excess/surge in combination with myocardial stunning causes

hemodynamically instability 4. Results in tachycardia, hypotension, decreased ejection fraction, elevated left

ventricular end-diastolic pressure, decreased cardiac output, and diastolic dysfunction

iii. Systemic ischemia/reperfusion response 1. Results in a systemic inflammatory immune response, impaired vasoregulation,

increased coagulation, adrenal suppression, impaired oxygen delivery, and immunosuppression

I. Basic life support (BLS) and advanced cardiac life support (ACLS) can be provided in emergent situations

a. Goal i. Restore perfusing rhythm and circulation ii. Minimize ischemic injury

II. Immediate high-quality cardiopulmonary resuscitation (CPR)5,6 a. Chest compressions are associated with increased survival to hospital discharge b. Do not interrupt for vascular access, drug delivery, or advanced airway placement c. Compression – ventilation ratio

i. In absence of advanced airway: 30:2 at a compression rate of at least 100 per minute ii. After airway placement: 100-120 compressions per minute without pauses for ventilation

d. Technique i. Push hard and fast ii. > 2 inches (5 cm) deep iii. Allow for complete chest recoil

Figure 4: Out-of-hospital chain of survival

OHCA Treatment

http://cpr.heart.org

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III. Rapid defibrillation5,6 a. Only utilized for shockable rhythms b. Associated with increase in survival c. Biphasic vs. monophasic

i. Biphasic preferred method ii. Energy (J) depends on device

1. Monophasic: 360 J 2. Biphasic: 120-200 J

iii. Higher doses may be considered for second and subsequent doses IV. Ventilation5,6

a. Bag-mask-valve with 100% FiO2 or advanced airway i. In absence of advanced airway: 2 breaths every 30 seconds ii. After placement of advanced airway: 1 breath every 6-8 seconds (10 breaths per minute)

V. Medications in ACLS CA algorithm5,6 a. Epinephrine (EPI)

i. 1 mg IV/IO every 3-5 minutes regardless of rhythm ii. Supporting evidence is controversial

b. Amiodarone i. 300 mg bolus followed by second dose of 150 mg IV/IO ii. Recommended only for refractory VF or pVT

c. Vasopressin (VASO) removed from ACLS algorithm in 2015 guideline update

I. Reasoning a. EPI and VASO have both shown improved ROSC during CA b. Literature review indicates no additional benefit from combining EPI + VASO c. For simplicity, VASO has been removed from the algorithm

I. Endogenous catecholamine9 a. Primarily synthesized and released, along with norepinephrine and dopamine, from adrenal medulla

VASO for resuscitation in ACLS6

One dose of VASO 40 units IV/IO may replace either the first or second dose of

EPI in the treatment of CA

VASO in combination with EPI offers no advantage as a substitute for

standard-dose EPI in CA

Epinephrine Review

2015 ACLS Guideline Update

2010 Algorithm 2015 Algorithm

Figure 5. Comparison of ACLS guideline recommendations

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b. Phenylethanolamine N-methyltransferase converts norepinephrine to epinephrine in select cells II. Mechanism of action10

a. Non-selective α1, α2, β1, & β2 -adrenergic receptor agonist

III. Physiologic effects during CA a. Positive effects11

i. Increases systemic vascular resistance (SVR) ii. Increases coronary perfusion pressure (CoPP) iii. Increases cerebral perfusion pressure (CPP) iv. Increases myocardial oxygen delivery

b. Negative effects11,12 i. Decreased cardiac output ii. Increases myocardial oxygen consumption and lower systemic oxygen delivery iii. Myocardial dysfunction post-resuscitation iv. Increased intrapulmonary shunting v. Ventricular arrhythmias vi. Ischemia and activates inflammatory response vii. Decrease cerebral microvascular blood flow and increase severity of cerebral ischemia

IV. Early use of EPI10

Adrenergic agonism effects

α1

arterial vasoconstrictioninotropic

chronotropiccoronary vasoconstriction

α2 venoconstriction

β1

coronary vasodilationpositive inotropy

positive chronotropy

β2 bronchodilation

Figure 6. Mechanism of action on adrenergic receptors

Adrenal extracts, containing EPI, were administered to animals and increased arterial tone, ventricular contractions, and blood pressure

EPI used for resuscitation after profound hypotension

EPI isolated/purified from sheep & oxen

adrenal glands

EPI synthesized in laboratory for first time

EPI injected directly into the heart

1874

1896

1901

1904

1906

Figure 7. Historical timeline of EPI

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V. Use in CA13

a. Studied in VF and asystole since 1947 b. Established CPR recommendation since 1974 c. Studied extensively in animals and humans over the past 50 years

VI. Common clinical endpoints

I. In 2010, the International Liaison Committee on Resuscitation (ILCOR) called for randomized control trials (RCTs) comparing EPI to placebo in OHCA14 but many entities refused participation due to ethical issues

II. Poorly assessable outcomes, small sample sizes, high mortality, and confounding variables make it difficult to create and execute a reliable study

III. EPI administration during CA has been strongly advocated for decades IV. Evidence supporting EPI in CA is conflicting due to disparities in trial methodology

I. Animal data a. EPI increases CoPP, myocardial blood flow (MBF), CPP, cerebral blood flow, and ROSC15 b. EPI increased MBF without altering systemic O2 consumption, plasma glucose, or lactate levels16 c. In rats, EPI was more important in ROSC attainment as duration of CA increased17

II. Decades of evidence a. Observational studies report improved short-term outcomes with EPI18-20 (Appendix B)

ROSCShort-term

survival (24 hr)

Survival to hospital

admission

Survival to hospital

discharge

Neurologic recovery

(CPC of 1-2)

Long-term survival

(30-60 days)

Should we use EPI in allOHCA without discrimination?

Should we abandon it altogether?

Is there a niche for EPI administration in OHCA?

THE BIG PICTURE: What do we know about EPI?

THE CLINICAL QUESTION: What do we need to decide about EPI?

OR OR

Figure 8. Common clinical endpoints in EPI trials

Figure 9. Clinical question

EPI Evidence

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b. Evidence for improved long-term outcomes is lacking18,19,21-24 (Appendix C) III. Meta-analysis: Lin et al. (2014)25

Table 2. Characteristics of Lin et al. meta-analysis Objective • Systematically review EPI efficacy for adult OHCA

Inclusion Criteria • Randomized and quasi-randomized trials

o Evaluated non-traumatic adult OHCA’s o Treated by EMS personnel

Exclusion Criteria

• Observational studies • Commentaries and reviews • Editorials or letters to the editor • Animal studies

Population

• 14 randomized control trials (RCTs) including 12,246 patients o One compared standard-dose EPI to placebo (n=534) o Six compared standard-dose EPI to high-dose EPI (n=6,174) o One compared standard-dose EPI to VASO (n=336) o Six compared standard-dose EPI to EPI + VASO (n=5,202)

Outcomes • Primary: survival to hospital discharge • Secondary: ROSC, survival to hospital admission, neurological outcome

Table 3. Study characteristics of included EPI trials EPI vs. placebo trial

Author [Location] Participants Setting Intervention Dose Max

(mg)

Jacobs et al.14 (2011)

[Australia]

Adult OHCA (n=534) Prehospital

EPI 1mg or

placebo 10

Standard-dose EPI (SDE) vs. High-dose EPI (HDE) trials Brown et al.26

(1992) [USA]

Adult OHCA (n=1,280) Prehospital

EPI 0.02 mg/kg or

EPI 0.2 mg/kg

Single dose

Callaham et al.27

(1992)

[USA] Adult OHCA

(n=816) Prehospital

EPI 1 mg or

EPI 15 mg or

NE 1 mg

3

Choux et al.28 (1995)

[France] Adult OHCA

(n=536) Prehospital EPI 1 mg

or EPI 5 mg

15

Gueugniaud et al.29 (1998) [France & Belgium]

Adult OHCA (n=3,327) Prehospital

EPI 1 mg or

EPI 5 mg 15

Sherman et al.30

(1997) [USA]

Adult OHCA (n=140) ED

EPI 0.01 mg/kg or

EPI 0.1 mg/kg 4

Stiell et al. 31

(1992) Adult OHCA

(n=335) ED EPI 1 mg 5

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[Canada] or EPI 7 mg

Table 4. Results of reported outcomes of included studies Author (Year) (n) ROSC Hospital

admission Hospital

discharge/ 30 day survival

CPC of 1-2

EPI vs. placebo Jacobs et al.14

(2011) 534 No difference No difference

HDE vs. SDE Brown et al.26

(1992) 1,280 No difference No difference No difference No difference

Callaham et al.27

(1992) 816 No difference No difference

Choux et al.28

(1995) 536 No difference No difference No difference¥ NR

Gueugniaud et al.29

(1998) 3,327 No difference No difference

Sherman et al.30

(1997) 140 NR No difference

Stiell et al. 31

(1992) 335 NR No difference£ No difference No difference

Systematic review and meta-analysis of EPI in OHCA

Pooled analysis25

NO DIFFERENCE NO DIFFERENCE

-Significantly better; NR-not reported; ¥-6 month survival; -No patient discharged; £-1 hour survival

Table 5. Results of individual outcomes in pooled meta-analysis25

Outcome Meta-analysis EPI vs. placebo Standard-Dose EPI vs. High-Dose EPI

ROSC RR 2.80

95% CI 1.78-4.41 p=<0.00001

RR 0.85 95% CI 0.75-0.97

p=0.02

Hospital admission

RR 1.95 95% CI 1.34-2.84

p=0.0004

RR 0.87 95% CI 0.76-1.00

p= 0.049

Hospital discharge/

30 day survival

RR 2.12 95% CI 0.75-6.02

p=0.16

RR 1.04 95% CI 0.76-1.42

p=0.83

CPC of 1-2 RR 1.73

95% CI 0.59-5.11 p=0.32

RR 1.20 95% CI 0.74-1.96

p=0.46

a. Strengths

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i. Relevant outcomes ii. Randomized controlled trials iii. Large population size

b. Limitations i. Only one trial compared EPI to placebo ii. Administration time to EPI not reported in all trials iii. Dose average varied widely between trials iv. Two trials contributed approximately half of the patient population v. HDE vs. SDE trials all published prior to 2000

1. Chest compression ratios and quality emphasis has changed 2. Routine use of targeted temperature management or percutaneous coronary

intervention (PCI) during post-resuscitation care vi. Plethora of unmeasured cofounders

1. Patient-specific: comorbidities, arrest duration 2. Situational-specific: arrest location, witness status, bystander CPR, CPR quality,

EMS response times, in-hospital care, other drugs, cumulative dose of EPI c. Bottom-line

i. EPI improved survival to admission and ROSC in RCT comparing EPI and placebo ii. Results when comparing SDE to HDE, in ROSC and survival to admission were variable iii. No difference in hospital discharge or cal outcomes when SDE was compared to placebo or

HDE II. Meta-analysis: Atiksawedparit et al. (2014)32

Table 6. Characteristics of Atiksawedparit et al. meta-analysis Objective • Determine effects of prehospital EPI in patients experiencing OHCA

Inclusion Criteria • Any type of study with OHCA patients who received EPI or placebo

o RCT or quasi-RCT o Cohort study o Cross-sectional study

Exclusion Criteria • Insufficient data for pooling • Authors who did not provide additional information after being contacted twice

Population • 14 observational studies and 1 RCT

o RCT was not included in any pooled analysis o One trial was conducted in children and not included in pooled analysis

Outcomes

• ROSC • Survival to hospital admission • Survival to hospital discharge • Neurological outcome (CPC of 1-2)

Table 7. Description of study and subject characteristics of included studies Author (Year) Study Design Country Setting Participants (n)

Herlitz et al.33 (1994) Cohort Sweden Prehospital Adult M asystole (1,222)

Herlitz et al.34 (1995) Cohort Sweden Prehospital Adult M VF (1,203)

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Herlitz et al.35 (1995) Cohort Sweden Prehospital Adult M PEA (748)

Guyette et al.36 (2004) Cohort USA Prehospital Adult NT OHCA (298)

Ong et al.37 (2007) Cohort Singapore Prehospital Adult NT OHCA (681)

Vayrynen et al.38 (2008) Cohort Finland Prehospital Adult M PEA (789) Yanagawa et al.39

(201078 Cohort Japan Prehospital Adult M OHCA (713)

Hagihara et al.40 (2012) Cohort Japan Prehospital Adult M OHCA (417,188)

Hayashi et al.41 (2012) Cohort Japan Prehospital Adult NT OHCA (3,161)

Machida et al.42 (2012) Cohort Japan Hospital Adult M OHCA (492)

Nordseth et al.43 (2012) Cohort Sweden Prehospital Adult NT PEA (174)

Neset et al.44 (2013) Cohort Sweden Prehospital Adult NT OHCA (233)

Goto et al.45 (2013) Cohort Japan Prehospital Adult M OHCA (209,577) M-mixed traumatic and non-traumatic; NT-non-traumatic

Table 8. Results of reported outcomes of EPI vs. placebo in included studies Author (Year) (n) ROSC Hospital

admission Hospital

discharge/ 30 day survival

CPC of 1-2

Herlitz et al.33 (1994) Asystole

1,222 NR No difference NR

Herlitz et al.34 (1995)

VF 1,203 No difference NR

Herlitz et al.35 (1995)

PEA 748 NR No difference No difference NR

Guyette et al.36 (2004) 298 NR NR NR

Ong et al.37 (2007) 681 No difference No difference No difference NR

Vayrynen et al.38 (2008) 789 NR NR

Yanagawa et al.39 (2010) 713 NR NR No difference

Hagihara et al.40 (2012) 417,188 NR No difference No difference

Hayashi et al.41 (2012) 3,161 £

No difference§ No difference No difference No difference

Machida et al.42 (2012) 492 No difference No difference No difference No difference

Nordseth et al.43 (2012) 174 NR

Neset et al.44 (2013) 233 No difference No difference No difference NR

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Pooled analysis32 £ NO

DIFFERENCE§

NO DIFFERENCE

NO DIFFERENCE NR

Significantly better; data not available; significantly worse; NR-not reported €-initial shockable rhythms; ¥-initial non-shockable rhythms £-prehospital ROSC §-overall ROSC

a. Limitations i. Observational data

1. Results were unadjusted for known and unknown confounders 2. Lacked randomization

ii. Subgroup analysis could not be done because of small number of included studies iii. Two studies comprised a large number of patients iv. Neurological outcomes could not be assessed because of limited studies included

b. Bottom-line i. EPI significantly increased pROSC but did not show benefit in overall ROSC attainment ii. EPI did not increase survival to hospital admission and discharge

I. Numerous trials analyzed outcomes based on time to EPI administration

Table 9. Summary of trials with time to EPI administration outcomes Trial Intervention Result

Stiell et al.31 (1992) [n=335]

HDE vs. SDE (RCT)

Those who received their first dose of EPI >10 minutes after CA had poorer rates of resuscitation

[11.4% vs. 24%; p=0.004]

Brown et al.26 (1992) [n=1,280]

HDE vs. SDE (RCT)

EPI was administered within 10 minutes of CA onset improved survival to hospital discharge [HDE (23% vs. 5%), SDE (11% vs. 4%)]

Hayashi et al.41 (2012)

[n=3,161]

EPI vs. placebo (Observational)

In VF arrests, early EPI group (<10 min) had significantly higher rate of neurologically intact

1-month survival compared to non-EPI group [66.7% vs. 24.9%]

Donnino et al. (2014)46

[n=25,095]

EPI vs. placebo (Observational, registry data)

In patients with non-shockable cardiac arrest in a hospital, early administration of EPI is associated with higher

probability of ROSC, survival in hospital, and neurologically intact survival

Does time to EPI administration matter?

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II. Goto et al. (2013)45

Table 10. Summary of Goto et al. (2013)

Objective • Examine initial cardiac rhythm as a factor to predict survival and neurological outcomes • Determine if prehospital EPI (pEPI) improves 1-month survival in OHCA patients (non-shockable

rhythms)

Population

209,577 OHCA adult patients (>18 years) between January 1, 2009 and December 31, 2010 were divided into two major cohorts:

1. Initial shockable rhythm (n=15,492) a. Prehospital EPI (n=3,136) b. No prehospital EPI (n=12,356)

2. Initial non-shockable rhythm (n=194,085) a. Prehospital EPI (n=20,540) b. No prehospital EPI (n=173,545)

Study Design Methods

• Prospective, observational study of OHCA patients who received EMS services in Japan • EMS personnel collected data and transferred information into a nationwide database

Outcomes • Primary: survival at one month • Secondary: pROSC, one month survival with favorable neurologic outcome (CPC of 1-2)

Results

Outcomes of patients according to initial rhythm and prehospital EPI administration

Outcome n (%)

Shockable Rhythm Non-shockable Rhythm EPI

(n=3,136) No EPI

(n=12,356) p-value EPI (n=20,540)

No EPI (n=173,545) p-value

pROSC 716 (22.8) 3426 (27.7) <0.0001

3847 (18.7) 5248 (3.0) <0.0001 1-month survival 482 (15.4) 3338 (27) 795 (3.9) 3819 (2.2) 1-month CPC 1-2 219 (7) 2301 (18.6) 121 (0.59) 1078 (0.62) 0.605

Results of multivariate logistic regression analysis based on administration time and rhythm

EPI Timing

Shockable Rhythm OR (95 % CI)

Non-shockable Rhythm OR (95% CI)

pROSC 1-month survival

1-month CPC 1-2 pROSC 1-month

survival 1-month CPC 1-2

<9 min 1.45 (1.2-1.75)

0.95 (0.77-1.16)

0.71 (0.54-0.92)

8.83 (8.01-9.73)

1.78 (1.5-2.1)

0.95 (0.62-1.37)

10-19 min 0.88 (0.78-1.00)

0.51 (0.44-0.59)

0.34 (0.28-0.42)

6.18 (5.82-6.56)

1.29 (1.17-1.43)

0.63 (0.48-0.8)

> 20 min 0.63 (0.52-0.77)

0.33 (0.25-0.42)

0.21 (0,14-0.31)

4.32 (3.98-4.69)

0.79 (0.66-0.93)

0.49 (0.32-0.71)

Author’s Conclusions

• Initial shockable rhythm is associated with improved one-month survival and favorable neurological outcomes

• No beneficial effects of prehospital EPI on one-month outcomes in initial shockable rhythms • pEPI improved one-month survival in initial non-shockable rhythms if given within 20 minutes • pEPI decreased positive one-month neurological outcomes in both cohorts when administered

after 10 minutes

Strengths • Exclusive OHCA population • Large sample size

Limitations

• Observational data (no randomization) • Uncontrollable confounders potentially influence outcomes • EPI use only indicated in patients refractory to chest compressions or initial shock • Variables which influence outcomes not assessed (CPR quality, in-hospital care)

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• Compliance to Japanese CPR guidelines was assumed and not assessed • Outcomes not assessed based on cumulative dose of EPI • Patients without prehospital EPI may have received EPI at the hospital • Solely Japanese population may limit external validity • Patients who achieved ROSC quickly, before requiring EPI, would be placed in non-EPI group

which could cause EPI group to appear to have worse outcomes Bottom-line • EPI showed most benefit in non-shockable rhythms when it was administered within 10 minutes

Table 11. Summary of trials with cumulative EPI dose outcomes Rivers et al. (1994)48

Objective Population [n] Results Conclusion

Measured effect of total cumulative EPI dose during ACLS on hemodynamic, O2

transport, & utilization variables in post-

resuscitation period

<15 mg EPI [n=20] or

>15 mg EPI [n=29]

• Both groups had similar: o MAP o Mixed venous O2 sat

• HDE had significantly: o ↓ CI, O2 consumption &

delivery o ↑ SVR & lactic acid o ↓ 24 hour survival

Higher cumulative doses of EPI may be associated with

post-resuscitation complications

Arrich et al. (2012)51

Investigate association between cumulative dose

of EPI used during resuscitation and poor

functional outcome and in-hospital mortality in patients with PEA or

asystole

< 2 mg EPI [n=492] Or

>2 mg EPI [n=454]

• Died during hospital stay: o < 2 mg: 287/492 (58.3%) o > 2 mg: 362/454 (79.7%) o P value: <0.001

• Never reached CPC < 3: o < 2 mg: 274/492 (55.7%) o > 2 mg: 369/454 (81.3%) o P value: <0.001

Multivariable analysis found statistically significant ↑ in poor functional outcome and in-hospital mortality

with ↑ cumulative doses of EPI

I. Hagihara et al. (2012)40

Table 12. Summary of Hagihara et al. (2012) Objective • Evaluate prehospital EPI administration on short and long-term mortality in OHCA patients

Population

• 417,188 adult patients included (>18 years old) o EPI (n=15,030) o No-EPI (n=402,158)

• All patients experienced OHCA before EMS arrival, treated by EMS, and transported to hospital

Study Design Methods

• Non-randomized, observational propensity analysis of Japanese OHCA patients from 2005-2008

• Data was collected from a national registry • A propensity score was developed to control potential confounding and selection bias which

matched patients given EPI with unique non-EPI control patients o 13,401 patients who received EPI were matched with 13,401 patients who did not

But is it harmful?

Does cumulative dose matter?

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o Predictor variables matched, indicating difference between patients was EPI administration

Outcomes

• pROSC • One-month survival • One-month survival with favorable CPC of 1-2 • Survival with no, mild, or moderate neurological disability (Overall Performance Category 1-2)

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Results

Conditional logistic regression analysis of EPI vs, no-EPI of propensity matched OHCA patients

Analysis OR (95% CI)

ROSC 1-month survival CPC 1-2 OPC 1-2

Unadjusted 1.91 (1.78-2.05) 0.71 (0.64-0.79) 0.41 (0.34-0.49) 0.43 (0.36-0.51)

Adjusted for Propensity 2.01 (1.83-2.21) 0.71 (0.62-0.81) 0.41 (0.33-0.52) 0.43 (0.34-0.54)

Selected variables 2.24 (2.03-2.48) 0.60 (0.49-0.74) 0.40 (0.26-0.63) 0.43 (0.28-0.66)

All covariates 2.51 (2.24-2.8) 0.54 (0.43-0.68) 0.21 (0.10-0.44) 0.23 (0.11-0.45)

Author’s Conclusion

• Prehospital EPI significantly increased pROSC • Prehospital EPI significantly decreased one-month survival and one-month survival with good

neurological outcome

Strengths • Large sample size • Attempted to adjust for confounders

Limitations

• Observational data (no randomization) • Patients without prehospital EPI may have received EPI at the hospital • Uncontrollable confounders, not adjusted for, may influence outcomes • Variables which influence outcomes not assessed (CPR quality, in-hospital care) • Outcomes not assessed based on cumulative dose of EPI • Patients who achieved ROSC quickly, before requiring EPI, would be placed in non-EPI group

which could cause EPI group to appear to have worse outcomes • Solely Japanese population may limit external validity

Bottom-line • Observational nature of this trial makes it difficult to associate results with EPI administration • A RCT is needed to corroborate these results

II. Jacobs et al. (2011)14

Table 13.Summary of Jacobs et al. (2011) Objective • Determine effect of EPI on survival to hospital discharge in OHCA Population • 534 OHCA patients underwent randomization from August 11, 2006-November 30, 2009

o EPI (n=272) o Placebo (n=262)

Study Design Methods

• Double-blind, randomized, placebo-controlled trial • Patients were randomized at the time of EPI qualification to receive EPI 1 mg or NaCl 0.9%

Outcomes • Primary: survival to hospital discharge • Secondary: pROSC and neurologic outcomes (CPC of 1-2)

Results Outcomes for patients receiving placebo vs. EPI

Outcome Placebo (n=262) n(%)

EPI (n=272) n(%) p-value

pROSC 22 (8.4%) 64 (23.5%) <0.001 Hospital admission 34 (13%) 69 (25.4%) <0.001 Hospital discharge 5 (1.9%) 11 (4.0%) 0.15

CPC 1-2 5 (100%) 9 (81.8%) 0.31 Author’s Conclusion

• EPI improved pROSC and survival to hospital admission but did not improve long-term outcomes

Strengths • Primary outcome was a long-term clinical endpoint • RCT • Placebo-controlled

Limitations • Study was drastically underpowered • CPR quality and time to EPI administration not assessed

Bottom-line • The results of this study are similar to previous findings

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• If the study had met power, it would be more useful in answering our EPI question

I. Summary a. EPI has been the drug of choice in CPR since the 1970’s despite weak and conflicting evidence b. Evidence indicates EPI improves short-term outcomes (ROSC and survival to hospital admission)

after OHCA c. Current literature has failed to find benefit from EPI in long-term outcomes (survival to hospital

discharge and good neurological outcomes) d. Several studies report improved survival to hospital discharge from early administration of EPI (< 10

minutes) but no mortality benefit has been discovered e. Several studies reported increased mortality and neurological function in patients receiving either

EPI administration or late EPI (> 10 minutes) but data was retrospective and contained numerous uncontrollable confounders

II. Conclusion a. There are two plausible explanations for EPI’s true effect in resuscitation:

i. EPI temporarily resuscitates patients who already have injuries not compatible with life ii. EPI contributes to post-resuscitation complications and increases chance of death

b. Currently, it is difficult to prove EPI worsens long-term outcomes due to poor trial methodology, retrospective data, ethical issues, and uncontrollable factors

c. A well-designed, adequately-powered RCT is essential to determine if EPI has side effects which worsen long-term outcomes or patients receiving EPI would die anyway despite temporary resuscitation

III. Unanswered questions a. Is an EPI dose of 1 mg the most appropriate dose or would lower doses yield similar results? b. Is a continuous infusion of EPI an option in this patient population? c. Is there a true mortality benefit if EPI is used in OHCA? d. Does EPI administration directly contribute to patient death?

IV. Recommendation a. Focus on providing immediate, quality CPR and early defibrillation in qualified patients

i. These interventions increase a patient’s chance of survival ii. They should NOT be interrupted to gain IV access and administer medications

b. EPI should ONLY be considered if it can be administered early (<10 minutes) and it does not interrupt CPR and defibrillation

i. Early administration has been associated with improved survival to discharge and improved neurological survival

ii. Benefit in longer resuscitations has not been clearly identified c. If utilized, administer EPI in 1 mg doses for 2-3 cycles

i. HDE did not improve long-term outcomes and is associated with increased premature ventricular contractions26, post-resuscitation VT27, post-resuscitation anti-arrhythmic pharmacological treatment compared to SDE28

ii. Cumulative EPI doses > 2 mg may be associated with poor outcomes 1. Repeated doses may increase anoxic damage in brain through prolonged ischemia

and increased post-resuscitation arrhythmias 2. In prolonged resuscitations, there is limited data to guide EPI administration and care

should focus on high-quality CPR and defibrillation

Summary and Recommendation

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Appendix A

Table 13. Cerebral performance category scale and overall performance category score scale Cerebral Performance Category Score Scale Overall Performance Category Score Scale 1 Full recovery or mild disability 1 No or mild neurologic disability

2 Moderate disability; independent in activities of daily living 2 Moderate neurologic disability

3 Severe disability; dependent in activities of daily living 3 Severe cerebral disability

4 Persistent vegetative state 4 Coma or vegetative state 5 Dead 5 Dead

Appendix B

Table 14. Studies reporting improved short-term outcomes with EPI use Author [n] Intervention Result

Olasveengen et al. (2009)18 851 EPI vs. placebo EPI improved ROSC and survival to hospital admission

Larabee et al. (2012)19 4,078 SDE vs. placebo or HDE EPI improved short-term outcomes

Vandycke et al. (2000)20 3,327 SDE vs. HDE SDE improved ROSC compared to HDE

Appendix C

Table 15. Studies reporting EPI did not improve long-term outcomes Author [n] Intervention Result

Woodhouse et al. (1995)21 339 EPI 10 mg vs. placebo No difference in survival to hospital discharge

Olasveengen et al. (2009)18 851 EPI vs. placebo No difference in survival to hospital discharge or neurological outcomes

Patanwala et al. (2014)22 400,000+ EPI vs. placebo No difference in survival to hospital discharge or 30 day survival

Larabee et al. (2012)19 4,078 SDE vs. placebo or HDE EPI did not improve long-term outcomes or survival

Holmberg et al. (2002)23 10,966 EPI vs. placebo EPI did not improve survival

Nakahara et al. (2013)24 11,048 EPI vs. placebo EPI improved survival to

hospital discharge but not neurologically intact survival

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