Resuscitation 83 (2012) 932 939
Contents lists available at SciVerse ScienceDirect
Resuscitation
j ourna l h o me pag e: www. elsevier.com/locate/resuscitation
Review
Vasopressors in cardiac arrest: A systematic review ,
Todd M. Larabeea,", Kirsten Y. Liub, Jenny A. Campbella, Charles M. Littlea
a
Department of Emergency Medicine, University of Colorado Denver School of Medicine, 12401 East 17th Avenue, B215, Denver, CO 80045, United States
b
Department of Emergency Medicine, Denver Health Medical Center, Residency in Emergency Medicine, 777 Bannock Street, Denver, CO 80204, United States
a r t i c l e i n f o a b s t r a c t
Article history:
Objectives: To review the literature addressing whether the use of vasopressors improves outcomes in
Received 30 November 2011
patients who suffer cardiac arrest.
Received in revised form 15 February 2012
Methods: Databases were searched using the terms:  (adrenaline or noradrenaline or vasopressor) and
Accepted 27 February 2012
(heart arrest or cardiac arrest) and therapy . Inclusion criteria were human studies, controlled trials,
meta-analysis or case series. Exclusion criteria were articles with no abstract, abstract-only citations
without accompanying article, non-English abstracts, vasopressor studies without human clinical trials,
Keywords:
case reports, reviews, and articles addressing traumatic arrest.
Vasopressor
Results: 1603 papers were identified of which 53 articles were included for review. The literature
Cardiac arrest
addressed 5 main therapeutic questions. (1) Outcomes comparing any vasopressor to placebo. (2) Out-
Advanced life support
comes comparing vasopressin (alone or in combination with epinephrine) to epinephrine. (3) Outcomes
Resuscitation
Pediatric resuscitation comparing high dose epinephrine to standard dose epinephrine. (4) Outcomes comparing any alternative
vasopressor to epinephrine. (5) Outcomes examining vasopressor use in pediatric cardiac arrest.
Conclusion: There are few studies that compare vasopressors to placebo in resuscitation from cardiac
arrest. Epinephrine is associated with improvement in short term survival outcomes as compared to
placebo, but no long-term survival benefit has been demonstrated. Vasopressin is equivalent for use as
an initial vasopressor when compared to epinephrine during resuscitation from cardiac arrest. There is
a short-term, but no long-term, survival benefit when using high dose vs. standard dose epinephrine
during resuscitation from cardiac arrest. There are no alternative vasopressors that provide a long-term
survival benefit when compared to epinephrine. There is limited data on the use of vasopressors in the
pediatric population.
© 2012 Elsevier Ireland Ltd. All rights reserved.
1. Background
Cardiac arrest is a medical emergency with very poor progno-
sis. The reported incidence of cardiac arrest ranges from 165,000 to
450,000 per year in the United States.1 3 Survival to hospital dis-
charge in pre-hospital arrests is estimated at 5 8% in the United

A Spanish translated version of the abstract of this article appears as Appendix States, and less than 1% worldwide.1,4 6 For in-hospital cardiac
in the final online version at doi:10.1016/j.resuscitation.2012.02.029.
arrest, the rate of survival to hospital discharge is slightly better

This review includes information on resuscitation questions developed
at 12%.7
through the C2010 Consensus on Science and Treatment Recommendations
The use of vasopressors during resuscitation from cardiac arrest
(CoSTR) process, managed by the International Liaison Committee on Resuscitation
has long been a mainstay of therapy.3,8 However, vasopressor
(http://www.americanheart.org//ILCOR). The questions were developed by ILCOR
Task Forces, using strict conflict of interest guidelines. In general, each question was
effectiveness as a therapy remains controversial due to the poor
assigned to two experts to complete a detailed structured review of the literature,
neurologic and survival outcome data routinely published in the
and complete a detailed worksheet. Worksheets are discussed at ILCOR meetings to
literature. Furthermore, there is the possibility that epinephrine is
reach consensus and will be published in 2010 as the CoSTR. The conclusions pub-
associated with adverse changes in cerebral perfusion, microcu-
lished in the final CoSTR consensus document may differ from the conclusions of this
review because the CoSTR consensus will reflect input from other worksheet authors lation and myocardial function post-arrest.9 11We systematically
and discussants at the conference, and will take into consideration implementation
review the literature for evidence regarding the use of vaso-
and feasibility issues as well as new relevant research.
pressors in cardiac arrest. This review was undertaken as part
"
Corresponding author. Tel.: [phone]; fax: [phone].
of the C2010 International Liaison Committee on Resuscitation
E-mail address: [e-mail] (T.M. Larabee).
0300-9572/$  see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.resuscitation.2012.02.029
T.M. Larabee et al. / Resuscitation 83 (2012) 932 939 933
Table 1
(ILCOR) Consensus on Science and Treatment Recommendations
ILCOR levels of evidence for therapeutic outcomes.
(COSTR) conference to generate recommendations for the 2010
American Heart Association (AHA) Advanced Cardiac Life Sup- LOE 1 Randomized controlled trials (or
meta-analyzes of RCTs)
port (ACLS) guidelines. The review was further enhanced in the
LOE 2 Studies using concurrent controls without
years following the submitted recommendations for the 2010
randomization
guidelines.
LOE 3 Studies using retrospective controls
LOE 4 Studies without a control group (e.g. case
series)
2. Methods
LOE 5 Studies non directly related to the specific
patient/population (e.g. different
The review was conducted in accordance with the International
patient/population; animal models,
Liaison Committee on Resuscitation (ILCOR) 2010 evidence evalu-
mechanical models, etc.)
ation process.
2.1. PICO question supported, was neutral, or opposed the use of vasopressors in the
final reported outcome related to cardiac arrest.12
This review sought to identify evidence to address the follow-
ing PICO (patient/population, intervention, comparator, outcome)
2.6. Data analysis
question:  In patients in cardiac arrest (asystole, pulseless electrical
activity (PEA), pulseless ventricular tachycardia (VT) and ventricu-
All reported numeric data was taken directly from the reviewed
lar fibrillation (VF)) (P), does the use of vasopressors (epinephrine,
manuscripts. Outcomes with p-values <0.05 were considered sig-
norepinephrine, others) or combination of vasopressors (I), com-
nificant.
pared with not using vasopressors (or a standard drug regimen) (C),
improve outcomes (e.g. return of spontaneous circulation (ROSC),
3. Results
survival) (O) .
The electronic search identified 1603 manuscripts for review.
2.2. Search strategy
All articles were reviewed by the authors, leaving 53 articles for
inclusion in this detailed review. After analysis, the articles were
The electronic databases PubMed (all dates), EmBASE (all dates)
broadly categorized into one of five therapeutic questions:
and the Cochrane Library were searched for eligible studies using
the terms (adrenaline or norepinephrine or vasopressor) and (heart
1. Outcomes comparing any vasopressor to placebo.
arrest or cardiac arrest) and therapy, as both MeSH and subjective
2. Outcomes comparing vasopressin (alone or in combination with
terms. For a more comprehensive search, the authors also reviewed
epinephrine) to epinephrine.
C2005 ILCOR worksheets related to this topic for past references.
3. Outcomes comparing high dose epinephrine (HDE) to standard
The ECC master library was searched using the terms vasopress*
dose epinephrine (SDE).
(all) and epinephrine (all). The superscript  * denotes the wild-
4. Outcomes comparing any alternative vasopressor (other than
card marker to search for all derivative possibilities. Bibliographies
vasopressin or various doses of epinephrine) to epinephrine.
of selected articles were reviewed for any missed articles as well.
5. Outcomes examining vasopressors in pediatric cardiac arrest.
The final search for this manuscript was undertaken on October 15,
2011.
Reported therapeutic outcomes were also recorded for each
All articles identified by the combined search strategy were con-
study (Table 2). These included ROSC, survival of event, survival to
sidered and hand reviewed by the authors (TL/CL). All manuscripts
hospital discharge, neurologic outcome, and other study endpoints.
that met the inclusion and exclusion criteria underwent a detailed
review.
3.1. Outcomes comparing any vasopressor to placebo
2.3. Inclusion criteria
Few randomized controlled trials (RCTs) have compared vaso-
pressors to placebo (Table 3). A recent trial by Olasveengen et al.
Review was undertaken of the manuscripts that met the
randomized cardiac arrest patients on scene to either ACLS with
following criteria: human studies and either controlled trials, meta-
intravenous (IV) access (and medications including epinephrine,
analyses, or case series.
atropine and amiodarone) or without IV access (n = 851).13 The
authors reported that the group with IV drug administration had
2.4. Exclusion criteria
significantly higher rates of achieving ROSC (p < 0.001, 95% CI
1.48 2.67) and surviving to hospital admission (p < 0.001, 95% CI
Articles were excluded if: (1) no abstract was present, (2) an
1.48 2.67), but this short-term survival did not correlate with a
abstract existed without an associated manuscript, (3) reference
significant improvement in survival to hospital discharge (p = 0.61,
was a non-English abstract or manuscript, (4) the study was a non-
95% CI 0.74 1.82) or survival with favorable neurologic outcomes
human trial (animal trial), (5) case report, (6) literature review, (7)
(p = 0.45, 95% CI 0.77 1.98). This study did not directly address the
vasopressor used in traumatic cardiac arrest.
contribution of epinephrine to these outcomes.
2.5. Evidence appraisal
Table 2
Selected articles were reviewed in detail and classified by level Outcome definitions.
of evidence (LOE) according to the guidelines put forth by ILCOR
A Return of spontaneous circulation (ROSC)
regarding the evaluation of evidence for studies of therapeutic
B Survival of event
interventions (Table 1).12 The quality of the studies was also graded C Survival to hospital discharge
D Intact neurologic survival
as good, fair or poor based on previously established criteria for
E Other study endpoint
each LOE.12 Studies were further classified as to whether the data
934 T.M. Larabee et al. / Resuscitation 83 (2012) 932 939
Table 3
Outcomes comparing any vasopressor to placebo.
LOE Quality Study outcome Outcomes reported Number of patients
Woodhouse et al. (1995)14 1 Poor Neutral A D 194
Herlitz et al. (1995)15 2 Fair Neutral A C 1203
Ong et al. (2007)16 3 Poor Neutral A D 1296
Olasveengen et al. (2010)13 1 Good Neutral A D 851
Jacobs et al. (2011)17 1 Fair Neutral A D 534
A randomized control trial by Woodhouse et al. looked at sur- pressure post-resuscitation thereby decreasing other vasopressor
vival outcomes in HDE vs. SDE vs. placebo in all patients who requirements,19,20 and increased end-tidal carbon dioxide during
presented in either asystole or VF arrest (n = 339).14 In the original CPR.20 One recent randomized controlled study found no difference
design, patients were blindly randomized to receive HDE (10 mg) or in end-diastolic pressures during CPR at 15 min after placement of
placebo (saline) during the first 5-10 min of arrest, followed by 1 mg a intravenous line when comparing the three treatment groups of
doses of epinephrine as per standard ACLS protocol at that time. epinephrine alone vs. epinephrine plus vasopressin vs. epinephrine
However, there were many protocol violations where 1 mg doses plus vasopressin plus nitroglycerin.21 This study is underpowered
were given in place of blinded drugs, so a third study arm was cre- to detect a true difference (n = 44). A small prospective descrip-
ated post hoc to include the 1 mg aliquot group. The authors found tive study by Lindner et al. reported that ROSC correlated with
no difference in survival to hospital admission (p = 0.3) and hospi- higher concentrations of serum vasopressin.22 These investigated
tal discharge (p = NS) between any of the groups. At the conclusion parameters are all thought to correlate with improved survival.
of this study, patients had not been systematically randomized, Although a small, early case series (n = 8) showed improved
clinicians were not blinded, and patient groups were not treated rates of ROSC and survival to hospital discharge after 40 units
equally. of vasopressin,23 three randomized controlled trials in both
Herlitz et al. conducted a retrospective review that examined OOHCA24,25 and in-hospital cardiac arrests (IHCA)26 showed no
patients with VF arrest who did or did not receive epinephrine change in survival rates. These three study designs randomized
by EMS during resuscitation (n = 1203).15 Those patients with sus- patients to either 1 dose24,26 or 2 doses25 of either 1 mg of
tained VF treated with epinephrine (after 3 shocks) had higher rates epinephrine or 40 units of vasopressin as first-line agents in cardiac
of ROSC (p < 0.001) and survival to hospital admission (p < 0.001), arrest, then followed by rescue epinephrine per ACLS guidelines
but no benefit in survival to hospital discharge. This conclusion was if ROSC was not achieved. All three studies found similar rates of
similar in patients who converted from VF to PEA or asystole (9/246 survival to hospital admission24,25 or 1-h after the event,26 and
vs. 6/671). This study is limited by poor confounder control. survival to hospital discharge between the two groups. Wenzel
A prospective observational study analyzed survival out- et al. reported during secondary analysis that, when analyzed by
comes from cardiac arrest before and after implementation presenting rhythm, patients with asystole had improved survival
of epinephrine in out-of-hospital cardiac arrests (OOHCA) in rates to hospital admission (p = 0.02) and discharge (p = 0.04) when
Singapore (n = 1296).16 Only 1 dose of 1 mg epinephrine was treated with vasopressin vs. epinephrine.25 Furthermore, some evi-
allowed prior to transport, followed by 1 mg doses in the ED dence suggested that patients in refractory arrest treated with
according to ACLS guidelines. Pre-hospital atropine, amiodarone vasopressin had improved rates of survival to hospital admission
and lidocaine were not allowed to be given. The authors found no and discharge.24,25
significant difference in ROSC (OR = 0.9, 95% CI 0.6 1.2), survival to A systematic review was undertaken using the three random-
hospital admission (OR = 1.0, 95% CI 0.7 1.5) and survival to hos- ized trials discussed above.27 This meta-analysis of 1519 patients
pital discharge (OR = 1.7, 95% CI 0.6 4.5). However, this study has revealed no difference between vasopressin and epinephrine
methodological concerns regarding untreated patients in the treat- groups regarding the failure of ROSC (risk ratio (RR) 0.81, 95%
ment arm, poor confounder control, and poor group selection. CI 0.58 1.12), death before hospital admission (RR 0.72, 95% CI
Jacobs et al. most recently published a randomized, double- 0.38 1.39), death within 24 h (RR 0.74, 95% CI 0.38 1.43) and death
blinded clinical trial comparing survival to hospital discharge in before hospital discharge (RR 0.96, 95% CI 0.87 1.05). Subgroup
patients who received prehospital doses of either epinephrine analysis based on presenting rhythms (VF or VT, PEA, asystole) also
or placebo using current ACLS protocols after suffering OOHCA showed no differences in rate of death before hospital discharge.
in Western Australia (n = 534).17 Upon arrival to an emergency A prospective RCT analyzed the effectiveness of 4 doses of either
department, patients received all standard ACLS resuscitative 40 units of vasopressin or 1 mg of epinephrine as the only vasopres-
efforts. Although an improvement in ROSC was demonstrated in sor in OOHCA (n = 336).28 Excluding any patient who received either
the prehospital epinephrine group (OR = 3.4, 95% CI 2.0 5.6), as well medication prior to arrival to ED, the authors found no significant
as an improvement in hospital admission (OR = 2.3, 95% CI 1.4 3.6), difference between groups regarding ROSC (p = 0.76), 24 h survival
there was no difference between groups in the primary study out- (p = 0.42), or survival to hospital discharge (p = 0.43). However, this
come of survival to hospital discharge (OR = 2.2, 95% CI 0.7 6.3). study had incomplete reporting of neurologic outcome data and
This study was limited by enrolment issues (planned n = 2213 per the average time to first dose of vasopressor exceeded 30 min for
group), alternative trial center recruitment issues, and willingness both groups.
of EMS to participate. Another prospective cohort study compared outcomes after
administration of 40 units of vasopressin following 3 rounds of 1 mg
epinephrine vs. 40 units vasopressin as first-line therapy vs. a ret-
3.2. Outcomes comparing vasopressin (alone or in combination
rospective control group of 3 rounds of epinephrine in patients
with epinephrine) to epinephrine
who suffered VF or pulseless VT (n = 109).29 Patients treated with
vasopressin (as first- or second-line therapy) had significantly
There is a large body of literature regarding the use of
higher rates of ROSC (p < 0.05) and 24-h survival (p < 0.05) than
vasopressin in cardiac arrest (Table 4). Small studies have doc-
epinephrine-only treated patients, but this benefit did not correlate
umented its physiologic effects, including increased coronary
with a significant improvement in survival to hospital discharge
perfusion pressure in 40% of patients,18 increased mean arterial
T.M. Larabee et al. / Resuscitation 83 (2012) 932 939 935
Table 4
Outcomes comparing vasopressin vs. epinephrine (alone or in combination).
LOE Quality Study outcome Outcomes reported Number of patients
Vasopressin vs. epinephrine
Morris et al. (1997)18 2 Poor Neutral E 10
Malley et al. (2007)20 3 Poor Neutral A C, E 598
Lindner et al. (1996)23 4 Good Supporting A D 8
Grmec et al. (2006)29 3 Good Supporting A C 109
Lindner et al. (1997)24 1 Good Neutral A D 40
Wenzel et al. (2004)25 1 Good Neutral A D 1186
Stiell et al. (2001)26 1 Good Neutral A E 200
Mukoyama et al. (2009)28 1 Fair Neutral A D 336
Aung et al. (2005)27 1 Good Neutral A D Meta-analysis
Vasopressin/epinephrine vs. epinephrine
Guyette et al. (2004)32 3 Poor Supporting A, E 298
Callaway et al. (2006)30 1 Good Neutral A D 336
Gueugniaud et al. (2008)31 1 Good Neutral A D 2984
Mentzelopoulos et al. (2009)33 1 Good Supporting A C, E 100
Cody et al. (2010)34 3 Good Neutral A C 191
Ducros et al. (2010)21 1 Good Neutral E 44
between groups (p = 0.21) and in neurologic outcomes. This study hospital discharge.38 Another early study looked at complications
was grossly underpowered for the latter assessment. from HDE vs. SDE and found that HDE did not increase potential
Two randomized clinical trials30,31 have examined combina- complication rates when compared to SDE group.39
tion therapy (vasopressin plus epinephrine) vs. epinephrine alone Other studies demonstrated deleterious effects of using HDE.
as first-line vasopressors during cardiac arrest after some ini- One retrospective cohort study targeted neurologic outcomes in
tial supportive data had been reported.32 The studies differ in VF arrest patients treated with HDE vs. SDE, and concluded that
size (n = 325,30 n = 295631) and dosage. Callaway et al. adminis- higher cumulative doses of epinephrine were independently asso-
tered repeat injections of the same dosages; Gueugniaud et al. ciated with unfavorable neurologic outcomes.40 Another study
administered successive injections at increasing dosages of tar- compared SDE from a retrospective control group (repeat boluses
geted drugs. These studies show no differences in rates of ROSC of 1 mg epinephrine; 4 mg maximum) to HDE in a prospective
(p = 0.88,30 p = 0.6231), pulses at arrival to hospital (p = 0.28)30 or study group (5 mg, 10 mg and 15 mg successive boluses; 30 mg
survival to hospital admission (p = 0.69),31 survival to hospital dis- maximum; n = 1674), and found no differences in rates of hospi-
charge (p = 0.24),31 1-year survival (p = 0.09),31 duration of survival tal admission and discharge between the 2 study arms.41 Rivers
(p = 0.23),30 and good neurologic recovery at discharge (p = 0.29).31 et al. reported that using HDE (more than 15 mg total dose) resulted
A double-blinded trial randomized 100 consecutive patients in inadvertent catecholamine toxicity that was associated with
with in-hospital cardiac arrests to either combination therapy adverse effects, including lower cardiac indices, lower systemic
(20 units of vasopressin, 1 mg of epinephrine) with 1 dose of oxygen consumption and delivery, increase in lactate levels and
40 mg of methylprednisolone or epinephrine-only therapy.33 Post- decrease in rates of survival at 24-h.42 An observational study34
resuscitation care involved stress-dose hydrocortisone (300 mg found that doses of epinephrine greater than 5 mg were associated
daily for 7 days maximum) in study group patients vs. placebo in with post-resuscitation left ventricular dysfunction.43
control group. This study reported significantly higher rates of ROSC Eight well-designed clinical trials evaluated the benefit of HDE
in study population (p = 0.03), higher MAPs during and 20 min after in cardiac arrest.38,44 50 Of these 8 studies, three demonstrated sig-
CPR (p = 0.01, p = 0.02, respectively), and improved survival to hos- nificantly improved rates of ROSC38,46,47 and two demonstrated
pital discharge (p = 0.02) than the control population. It is unclear improvement in rates of hospital admission46,47 in patients who
if these findings were related to the treatment benefits of vaso- received HDE. No study demonstrated a difference in survival to
pressin, methylprednisolone, hydrocortisone or the combination. hospital discharge. The remaining five RCTs uniformly showed no
Most recently, a small retrospective cohort study compared the significant differences in ROSC, survival to hospital admission, sur-
use of epinephrine or vasopressin in combination with epinephrine vival to hospital discharge, and neurologic outcomes in HDE vs.
in pulseless electrical activity (PEA) cardiac arrest (n = 191).34 No SDE. A meta-analysis of 5 of these 8 studies confirmed no sur-
differences in survival to emergency department arrival (OR 1.42, vival benefit to hospital discharge in the pooled analysis.51 The
95% CI = 0.73, 2.76; p = 0.26), 24 h survival (OR 0.54, 95% CI = 0.22, authors concluded that if there were a trend, it favored standard-
1.30; p = 0.13), or survival to discharge (OR 1.81, 95% CI = 0.49, 6.88; dose epinephrine in cardiac arrest.51
p = 0.32) were noted.
3.4. Outcomes comparing any alternative vasopressor to
3.3. Outcomes comparing high-dose epinephrine (HDE) to epinephrine
standard-dose epinephrine (SDE)
Several alternative vasopressors have been studied in compari-
The use of epinephrine as a standard 1 mg dose dates to son to, or as an adjunct with, the use of epinephrine (Table 6).
the 1960s. Animal studies suggested that the use of high dose Three randomized clinical trials compared outcomes using
epinephrine (HDE) may improve outcomes over standard dose methoxamine to epinephrine.52 54 Although the study designs
epinephrine (SDE). Initial human trials also suggested improved were similar, these studies are difficult to compare since a wide
outcomes with HDE, including dose-dependent increases in blood range of doses were used (Olson et al.: 0.5 mg epinephrine vs. 5 mg
pressure and decreases in arterial carbon dioxide,35 higher rates of methoxamine; Patrick et al.: 2 mg epinephrine vs. 40 mg methox-
ROSC,36 and improved aortic and coronary perfusion pressures37 amine; Turner et al.: 1 mg epinephrine vs. 10 mg methoxamine).
(Table 5). An early randomized trial of 68 patients showed improve- All three studies demonstrated no benefit of methoxamine com-
ment in ROSC for asystole and PEA patients treated with HDE pared to epinephrine in regards to ROSC or survival rates. Patrick
(n = 28) vs. SDE (n = 40) (p < 0.001), with a trend toward survival to et al. found a trend favoring epinephrine in ROSC rates53 and Olson
936 T.M. Larabee et al. / Resuscitation 83 (2012) 932 939
Table 5
Outcomes comparing adult high dose epinephrine vs. standard dose epinephrine.
LOE Quality Study outcome Outcomes reported Number of patients
Gonzales et al. (1989)35 4 Good Supporting E 10
Barton et al. (1991)36 4 Fair Supporting A 49
Paradis et al. (1991)37 2 Fair Supporting E 32
Lindner et al. (1991)38 1 Good Neutral A C 68
Carvolth et al. (1996)41 3 Good Neutral A C 1174
Brown et al. (1992)44 1 Good Neutral A D 1280
Callaham et al. (1991)39 3 Poor Neutral B E 68
Choux et al. (1995)45 1 Good Neutral A D 536
Callaham et al. (1992)46 1 Good Neutral A D 816
Gueugniaud et al. (1998)47 1 Good Neutral A D 3327
Lipman et al. (1993)48 1 Good Neutral A, B, E 35
Sherman et al. (1997)50 1 Good Neutral A C 140
Stiell et al. (1992)49 1 Good Neutral A D 650
Vandycke et al. (2000)51 1 Fair Neutral A D Meta-analysis
Rivers et al. (1994)42 2 Poor Opposing A, B, E 49
Chang et al. (2007)43 4 Poor Opposing E 58
Behringer et al. (1998)40 3 Good Opposing A, D 151
et al. demonstrated a significant advantage of epinephrine over less than 0.1 mg/kg in SDE; more than 0.1 mg/kg up to 0.2 mg/kg
methoxamine in ROSC (p < 0.02) and survival to hospital discharge in HDE) compared the use of HDE to SDE in pediatric cardiac
(p = 0.01).52 arrest.58 63 Two of these studies were small retrospective out-
Norepinephrine (NE) was studied in two randomized trials. The of-hospital studies,58,59 two were prospective randomized control
first compared NE (1 mg, n = 25) to SDE (1 mg, n = 25)55 and the sec- trials of out-of-hospital62 and in-hospital cardiac arrests,63 one was
ond compared NE (11 mg/dose, n = 270) to SDE (1 mg/dose, n = 260) a case series60 and one was a cohort study.61 Five of the six stud-
and HDE (15 mg/dose, n = 26).46 Initial ROSC was higher with NE in ies showed similar outcomes between groups in terms of ROSC,
both studies, but there was no difference in long-term survival46,55 survival to hospital admission, survival to hospital discharge, and
or neurologic outcomes,46 with a trend toward worse cerebral per- neurologic outcomes.58,59,61 63 The case series by Goetting and
formance category (CPC) scores with NE.46 Paradis describe two series of patients using HDE after the admin-
The addition of a dopamine infusion (15 mcg/kg/min) in con- istration of 2 doses of SDE in small cohorts (n = 7 in one series, n = 20
junction with escalating epinephrine boluses (1 mg, 3 mg, 5 mg) in the other series).60 They found significant improvement in ROSC
was compared to the use of epinephrine boluses alone in 9 and survival to discharge in those treated with HDE.
cardiac arrest patients.56 The addition of dopamine did not gen- Only one case-series has been published to date on vasopressin
erate additional increases in blood pressure compared to the in the pediatric population.64 Sixty-four patients who received
epinephrine-only arm. No other outcome data was collected or vasopressin in an uncontrolled fashion during in-hospital car-
recorded during this study. diac arrests (IHCA) were included, which showed worsened ROSC
Phenylephrine, a potent alpha-agonist, was compared to rates with vasopressin (adjusted OR 0.49, 95% CI 0.27 0.88), but
epinephrine by administering 2 doses of either 1 mg phenyle- no difference between survival in 24 h (adjusted OR 0.52, 95%
phrine (n = 29) or 0.5 mg epinephrine (n = 36) in cardiac arrest, CI 0.27 1.03), at hospital discharge (adjusted OR 0.48, 95% CI
followed by rescue epinephrine per ACLS protocol in a single, 0.21 1.11), and favorable neurologic outcomes (adjusted OR 0.36,
prospective double-blinded study.57 The authors reported sim- 95% CI 0.13 9.04). The vasopressin group was confounded by
ilar rates of ROSC in both groups, but no survival data was longer arrest duration, and more than 98% of this group received
reported. epinephrine. No data was reported on timing of vasopressin admin-
istration.
3.5. Outcomes examining vasopressors in pediatric cardiac Terlipressin, a long-acting analog of arginine vasopressin,
arrests was studied in a case series of 7 pediatric patients who
experienced 8 episodes of refractory cardiac arrest.65 Stan-
There is limited human data in the pediatric literature regarding dard ACLS was first attempted, and then 15 20 g/kg of
the use of vasopressors in cardiac arrest for this patient population terlipressin was given in 3 5 min as indicated. The primary
(Table 7). diagnosis in four of these patients was congenital cardiac
The majority of available data looked at HDE vs. SDE in pediatric surgery, 2 congenital diaphragmatic hernias and 1 sepsis. The
cardiac arrest. Six studies of differing designs and doses (0.01 to authors found that, with terlipressin, ROSC occurred in 6 of
Table 6
Outcomes comparing any alternative vasopressor vs. epinephrine.
LOE Quality Study outcome Outcomes reported Number of patients
Methoxamine
Olson et al. (1989)52 1 Good Neutral A C 51
Patrick et al. (1995)53 1 Good Neutral A D 145
Turner et al. (1988)54 1 Good Neutral A C 80
Norepinephrine
Callaham et al. (1992)46 1 Good Neutral A D 2667
Lindner et al. (1991)55 1 Good Neutral A C 50
Dopamine
Gonzales et al. (1988)56 4 Poor Neutral E 9
Phenylephrine
Silfvast et al. (1985)57 1 Fair Neutral A 65
T.M. Larabee et al. / Resuscitation 83 (2012) 932 939 937
Table 7
Outcomes examining vasopressors in pediatric cardiac arrest.
LOE Quality Study outcome Outcomes reported Number of patients
HDE vs. SDE
Carpenter et al. (1997)58 3 Fair Neutral A D 51
Dieckmann et al. (1995)59 3 Poor Neutral A D 65
Goetting et al. (1989)60 4 Poor Supporting A 7
Goetting et al. (1991)61 3 Good Supporting A D 40
Patterson et al. (2005)62 1 Fair Neutral A D 154
Perondi et al. (2004)63 1 Good Neutral A C 68
Vasopressin
Duncan et al. (2009)64 4 Poor Opposing A E 1293
Terlipressin
Matok et al. (2007)65 4 Fair Supporting A C 7
Yildisdas et al. (2011)66 4 Fair Supporting A, C, D 9
Carroll et al. (Epub)67 3 Good Neutral A D 30
8 cardiac arrest episodes, survival to hospital discharge in time whether these findings were related to methylprednisolone
4 of 7 patients and good neurologic outcomes in 4 of 7 or a combination of the medications used.33
patients. The literature demonstrates that HDE confers no long-term
A second retrospective case series examined the use of terli- survival benefit when compared to SDE. However, three of eight
pressin in 9 pediatric patients who suffered 12 cardiac arrests.66 In studies, including the largest trial, demonstrate improved rates
this group, terlipressin (20 g/kg) was given after failure of stan- of ROSC when using HDE compared to SDE.38,46,47 Furthermore,
dard advanced life support (at least 2 doses of epinephrine). ROSC no alternative adrenergic vasopressor has been shown to be
was achieved in 6 of the 12 arrests, and 5 of 9 patients were dis- more effective than standard dose epinephrine for long-term
charged home with good neurologic status (CPC 1). survival during resuscitation from cardiac arrest. Two smaller
A recent prospective feasibility pilot study examined the use studies demonstrated improvement in ROSC when comparing
of vasopressin (0.8 units/kg) for refractory in-patient pediatric car- norepinephrine to SDE.46,55
diac arrest, as defined by failed ROSC despite CPR and one dose There is no data supporting the use of HDE or other vasopressors
of epinephrine (0.1 mg/kg).67 Ten study patients were compared in resuscitation of pediatric cardiac arrests. The literature pertain-
to 20 matched retrospective controls who did not receive vaso- ing to vasopressors in pediatric resuscitation is quite limited. There
pressin. Although improvement in ROSC was noted (OR 9.33, 95% is evolving literature on the use of terlipressin in this population.
CI = 1.51, 57.65), no difference in other outcome measures was This review raised two key issues in the assessment of the liter-
demonstrated. This study does demonstrate that a prospective, ran- ature. It is clear that the majority of the reviewed manuscripts are
domized trial is warranted and feasible. generally underpowered to demonstrate a difference in the pri-
mary study outcome. Developing prospective regional or national
systems and databases for analysis of cardiac arrest outcomes will
4. Discussion
likely be the only way in which to capture an appropriate sample
size to examine intended outcomes.
We found limited data that adequately addresses the use of
The second issue is related to the outcome being measured.
vasopressors compared to placebo in resuscitation from adult car-
Many of the studies have demonstrated an improvement in ROSC
diac arrests. Since vasopressor use has been considered a mainstay
when using vasopressors in cardiac arrest.13 15,17 The larger studies
in the treatment of cardiac arrest in North America and Europe,
involving HDE also demonstrate an improvement in ROSC com-
few placebo-controlled RCTs have been performed. Those trials that
pared to standard dose epinephrine.38,46,47 The current review
have been performed are methodologically flawed often due to the
targeted the longest reported outcome (ROSC, 24 h survival,
unwillingness of providers to randomize subjects to the placebo
survival to hospital discharge, or neurologic outcome) as the char-
arm, and thus limiting conclusions that can be drawn. The most
acteristic defining whether the manuscript supported, opposed or
recent RCT by Jacobs et al. comparing epinephrine to placebo in
was neutral to the benefit of the treatment group. As such, most
OOHCA cited these very issues, including difficulty in recruiting
of the larger studies in all categories are neutral, demonstrating no
multiple centers and getting EMS personnel to complete the pro-
benefit but no detriment in the treatment group as the measured
tocol despite appropriate human subject review approval.17 These
outcome was survival to discharge or neurologic outcome. When
same concerns were noted in the earlier Woodhouse study.14 The
considering the long-term outcomes, it is now clear that there are
studies do support an improvement in short-term outcomes (ROSC)
many other factors and interventions which play a role in survival to
when using epinephrine in patients who suffer cardiac arrest, as
hospital discharge with good neurologic outcome, some of which
does the Olasveengen study addressing the use of IV medications
are influenced by the components of post-resuscitative care and
early in resuscitation. However, the effect of epinephrine on neu-
innovations in cerebral protection such as therapeutic hypother-
rologically intact survival has not been demonstrated.
mia. It is not likely the case that the vasopressor therapy is the
Using vasopressin as the first-line agent during resuscitation
sole responsible agent effecting long-term outcomes, although we
offers no benefit related to short- and long-term survival when
cannot say that vasopressor use does not play some role. Issues
compared to epinephrine. In contrast to early, smaller studies,
related to brain edema formation, myocardial dysfunction and
no RCTs were able to demonstrate short or long term survival
other post-resuscitative complications are confounders when con-
benefits, and this conclusion is supported by a meta-analysis of
sidering long-term outcomes. None of the studies reviewed were
the data.27 Furthermore, the combination therapy vasopressin and
performed in the current era of post-resuscitative care, which is
epinephrine is not superior to epinephrine alone when compar-
a limitation of all the reviewed studies. Until it is clear that the
ing outcomes from cardiac arrest. One recent trial comparing the
use of vasopressors is directly detrimental to long-term outcomes
combination of vasopressin, epinephrine and methylprednisolone
related to cardiac arrest, the authors believe that there is enough
to epinephrine alone showed higher rates of ROSC and survival to
supporting evidence that demonstrate improvement in short-term
hospital discharge in the combination group, but it is unclear at this
938 T.M. Larabee et al. / Resuscitation 83 (2012) 932 939
outcomes when vasopressors are used during resuscitation. As 15. Herlitz J, Ekstrom L, Wennerblom B, Axelsson A, Bang A, Holmberg S. Adrenaline
in out-of-hospital ventricular fibrillation. Does it make any difference? Resusci-
such, vasopressors should continue to be included in ACLS algo-
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rithms.
16. Ong ME, Tan EH, Ng FS, et al. Survival outcomes with the introduction of intra-
Our review has several limitations. As this was an extensive venous epinephrine in the management of out-of-hospital cardiac arrest. Ann
Emerg Med 2007;50:635 42.
review with over 1600 manuscripts for consideration, it is possible
17. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on
we may have missed manuscripts that met the inclusion criteria
survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-
for this systematic review. Only studies written in English were
controlled trial. Resuscitation 2011;82:1138 43.
18. Morris DC, Dereczyk BE, Grzybowski M, et al. Vasopressin can increase coronary
included, and studies appropriate for consideration may have been
perfusion pressure during human cardiopulmonary resuscitation. Acad Emerg
written in another language. Also, we included only trials with pub-
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lished abstracts available for review and published manuscripts.
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diovascular failure during the post-resuscitation phase after cardiac arrest.
Either of these exclusions may have led to omission of potentially
Resuscitation 2007;72:35 44.
appropriate studies. This review relied on the data reported by
20. Mally S, Jelatancev A, Grmec S. Effects of epinephrine and vasopressin on end-
authors and data was not independently analyzed. As such, this
tidal carbon dioxide tension and mean arterial blood pressure in out-of-hospital
review may be susceptible to publication bias. cardiopulmonary resuscitation: an observational study. Crit Care 2007;11:R39.
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Conflict of interest statement
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