Resuscitation 80 (2009) 418–424
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/resuscitation
Early goal-directed hemodynamic optimization combined with therapeutic
hypothermia in comatose survivors of out-of-hospital cardiac arrest?,??
David F. Gaieskia,b,∗, Roger A. Banda,b, Benjamin S. Abellaa,b, Robert W. Neumara,b, Barry D. Fuchsc,
Daniel M. Kolanskyd, Raina M. Merchanta,b, Brendan G. Carra,b, Lance B. Beckera,b,
Cheryl Maguiree, Amandeep Klaira, Julie Hyltona, Munish Goyala,b
aDepartment of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
bCenter for Resuscitation Science, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States
cDepartment of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States
dDepartment of Internal Medicine, Division of Cardiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States
eUniversity of Pennsylvania School of Nursing, Nurse Manager, Medical Intensive Care Unit, United States
a r t i c l ei n f o
Received 29 July 2008
Received in revised form
10 November 2008
Accepted 25 December 2008
Post-cardiac arrest care
a b s t r a c t
Background: Comatose survivors of out-of-hospital cardiac arrest (OHCA) have high in-hospital mortality
brain injury and persistence of the precipitating pathology. Therapeutic hypothermia (TH) is the only
intervention that has been shown to improve outcomes in this patient population. Due to the similarities
between the post-cardiac arrest state and severe sepsis, it has been postulated that early goal-directed
hemodyamic optimization (EGDHO) combined with TH would improve outcome of comatose cardiac
Objective: We examined the feasibility of establishing an integrated post-cardiac arrest resuscitation
(PCAR) algorithm combining TH and EGDHO within 6h of emergency department (ED) presentation.
Methods: In May, 2005 we began prospectively identifying comatose (Glasgow Motor Score<6) survivors
of OHCA treated with our PCAR protocol. The PCAR patients were compared to matched historic controls
from a cardiac arrest database maintained at our institution.
Results: Between May, 2005 and January, 2008, 18/20 (90%) eligible patients were enrolled in the PCAR
protocol. They were compared to historic controls from 2001 to 2005, during which time 18 patients met
inclusion criteria for the PCAR protocol. Mean time from initiation of TH to target temperature (33◦C)
was 2.8h (range 0.8–23.2; SD=h); 78% (14/18) had interventions based upon EGDHO parameters; 72%
(13/18) of patients achieved their EGDHO goals within 6h of return of spontaneous circulation (ROSC).
Mortality for historic controls who qualified for the PCAR protocol was 78% (14/18); mortality for those
treated with the PCAR protocol was 50% (9/18) (p=0.15).
Conclusions: In patients with ROSC after OHCA, EGDHO and TH can be implemented simultaneously.
© 2009 Elsevier Ireland Ltd. All rights reserved.
There are more than 300000 cardiac arrests per year in the
?A Spanish translated version of the summary of this article appears as Appendix
in the final online version at doi:10.1016/j.resuscitation.2008.12.015.
??This work has been supported by an unrestricted research grant from Gaymar
Industries (Orchard Park, New York).
Street, Ground Ravdin, Philadelphia, PA 19104, United States. Tel.: +1 215 349 5241;
fax: +1 215 662 3953.
E-mail address: email@example.com (D.F. Gaieski).
Corresponding author at: Department of Emergency Medicine, 3400 Spruce
have significant neurologic deficits. Therapeutic hypothermia cur-
rently represents the most efficacious treatment option to reduce
neurologic injury and mortality in comatose patients who have
apies used in concert with TH further improve outcomes.5
Clinical and laboratory investigations support the concept that
the immediate post-arrest period exhibits a number of similari-
ties to the sepsis syndrome, with elevated serologic markers of
global inflammation, endothelial dysfunction and microcirculatory
hypoperfusion.6Some investigators have referred to this patho-
goal-directed therapy (EGDT), an early goal-directed hemodyamic
optimization (EGDHO) strategy applied at the most proximal
phase of critical illness, Rivers and colleagues reduced in-hospital
0300-9572/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
D.F. Gaieski et al. / Resuscitation 80 (2009) 418–424
mortality from 46.5% to 30.5% in patients with severe sepsis and
septic shock.8This resuscitation strategy was endorsed by the
Surviving Sepsis Campaign and incorporated into its sepsis care
bundles.9Subsequent publications describing the feasibility of
have demonstrated similar mortality reductions.10–13
Given the similarities between the inflammatory responses
associated with septic shock and the post-resuscitation syndrome,
it is plausible that EGDHO may result in similar survival benefits
in patients with ROSC after cardiac arrest. A post-resuscitation care
bundle may benefit post-arrest patients in a similar fashion as sep-
sis care bundles have benefited patients with severe sepsis and
septic shock.14In fact, several recent publications have addressed
other aspects of post-resuscitation care in addition to TH, including
early percutaneous coronary intervention (PCI), intra-aortic bal-
loon pumps for treatment of cardiogenic shock, EGDHO strategies,
glucose and ventilator management strategies, and evaluation for
relative adrenal insufficiency.15–21
However, none of these implementation studies have exam-
ined a specifically defined hemodynamic optimization strategy
implemented at the most proximal phase of the post-resuscitation
syndrome. We sought to evaluate the feasibility of implement-
ing a comprehensive EGDHO protocol during induction of TH in
patients immediately after ROSC. Our protocol incorporates clearly
defined resuscitation endpoints and mandates implementation of
EGDHO simultaneous with induction of TH and continuation of
hemodynamic monitoring throughout the period on therapeu-
tic cooling. We hypothesized that hemodynamic optimization of
key physiologic endpoints—mean arterial pressure (MAP), cen-
tral venous pressure (CVP), and central venous oxygen saturation
(ScvO2)–could be achieved within 6h of ROSC while implementing
In this study, we performed an analysis of a prospectively col-
lected database of cardiac arrest patients with ROSC treated with a
combination of TH and EGDHO.
Establishment of hypothermia protocol
A PCAR protocol working group with members from Emergency
Medicine, Pulmonary and Critical Care Medicine, and Cardiology
was established in May, 2004 and regular meetings were held over
the next year to develop consensus recommendations for the man-
agement of comatose patients with ROSC after OHCA. The PCAR
protocol was implemented in May, 2005 at the Hospital of the
University of Pennsylvania (HUP), an urban, tertiary care teaching
hospital with 58,000 annual ED visits. Patients eligible for the PCAR
protocol were admitted from the ED to either the Medical Intensive
Care Unit (MICU) or the Cardiac Care Unit (CCU) and followed dur-
ing their inpatient stays by trained research staff. We also included
patients specifically transferred from outside hospitals to the CCU
for implementation of the PCAR protocol.
We aimed to enroll patients without severe pre-arrest condi-
criteria are detailed in Table 1). Determination of eligibility for and
initiation of the PCAR protocol were done in the ED, but various
steps of protocol implementation were completed in the ED, MICU
or CCU, depending on bed availability. If the patient was eligible
for emergent PCI, transfer to the catheterization laboratory was
not delayed to accomplish any of the initial steps of the protocol.
Inclusion and exclusion criteria for PCAR protocol.
Out-of-hospital or in-ED cardiac arrest
<60min, CPR prior to ROSC
Pre-arrest GCS=15 or independent ADLs
No written DNR/DNI
SBP ≥90mmHg post arrest (with or without vasopressors)
Head CT without mass or hemorrhage
Glasgow motor score<6
No other known reason for coma/arrest (e.g. septic shock, severe
acidosis, trauma, etc.)
Comatose prior to arrest
Unstable cardiac rhythms not terminated during initial management
In these instances, EGDHO and TH were initiated in the ED and
continued in the catheterization laboratory during PCI.
All patients eligible for the PCAR protocol were identified
through a combination of: real-time pager notification of study
team by ED clinical staff; and a regularly performed internet search
of the ED’s electronic medical record, designed to capture any eli-
gible patients who were not prospectively enrolled.
Induction and maintenance of hypothermia
Therapeutic hypothermia was accomplished by three means
used in concert: chilled saline infusion, surface cooling devices,
and ice packs. Initial induction of TH was by 2L bolus of 4◦C nor-
mal saline solution (NSS) via peripheral intravenous catheter(s).
Induction of hypothermia was completed and maintained using
surface cooling with either a water blanket temperature transfer
system (Meditherm III & Rapr.Round; Gaymar Industries, Orchard
Park, NY), or a gel adhesive pad temperature transfer device (Artic
Sun; Medivance Corporation, Louisville, CO). Ice packs, placed in
the axillae and groin, were used if there was difficulty achieving
a goal of rewarming over a minimum of 8h.
Early goal-directed hemodynamic optimization
Coincident with induction of TH, an arterial catheter was placed
for continuous blood pressure monitoring and a continuous oxi-
metric triple lumen central venous catheter (PreSep; Edwards
Lifesciences, Irvine, CA) was placed for CVP and ScvO2monitoring.
End-points of EGDHO were addressed in an algorithmic fashion,
beginning with MAP, then addressing CVP, and then ScvO2(see
Other components to the PCAR protocol
Several other changes in ICU management were incorporated in
the PCAR protocol, including evaluation for relative adrenal insuffi-
ciency; protocolized management to keep serum glucose less than
150mg/dL; and low tidal volume (6–8cc/kg) ventilator manage-
ment strategies where applicable.
Data collection for our clinical treatment intervention was
approved by the Institutional Review Board at the University of
Pennsylvania. A database was constructed following the Utstein
D.F. Gaieski et al. / Resuscitation 80 (2009) 418–424
Figure 1. The Hospital of the University of Pennsylvania’s post-cardiac arrest resuscitation treatment protocol.
style,22using standard database software (Access; Microsoft Cor-
poration, Redmond, WA). For mortality comparisons, the patients
eligible for and enrolled in the PCAR protocol were compared to
historic controls, seen in the ED from January 2001 through April
2005, who, on chart review, would have been eligible for the PCAR
protocol. The classification of historic controls was performed by
two of the investigators (DFG and JH) with 95% agreement (K=.90).
Continuous variables were analyzed by means with stan-
dard deviations and ranges, compared using Student’s t-test, and
expressed in unadjusted odds ratios with 95% confidence intervals
as well as p values; time variables were recorded in 24h time for-
mat; non-continuous variables were compared using Fisher’s exact
test and also were expressed in unadjusted odds ratios with 95%
confidence intervals as well as p values.
Between May, 2005 and January, 2008, 208 patients with
OHCA presented to our ED; 132/208 (64%) were of presumed car-
diac etiology. Non-cardiac etiologies included hemorrhagic shock,
intracranial hemorrhage, and environmental hypothermia. Of the
presumed cardiac etiology subgroup, 38/132 (29%) had ROSC, and
34/132 (26%) survived to hospital admission. Of those admit-
ted, 20/34 (59%) met inclusion criteria for the PCAR protocol;
18/20 (90%) of these patients were recognized prospectively by the
D.F. Gaieski et al. / Resuscitation 80 (2009) 418–424
Historic controls (N=18)PCAR protocol
Qualified PCAR (%)
Treated PCAR (%)
Age (years) (range)67 (35–87) 57 (20–86)
clinical team managing patient care and were enrolled in the pro-
tocol; 2/20 (10%) were not recognized as candidates for the PCAR
protocol and were treated neither with TH nor EGDHO. In the his-
toric database, 230 OHCA patients presented to our ED; 156/230
(68%) of these were of cardiac etiology. Of these, 56/156 (36%) had
ROSC, and 46/156 (30%) survived to hospital admission. Less than
half (18/46, 39%) would have met inclusion criteria for the PCAR
protocol and were included as controls (see Table 2 for complete
data and basic demographic information).
The mean age of patients treated with the PCAR protocol was
57 years (SD=18 years); 12/18 (67%) were male; 8/18 (44%) were
African-American; 8/18 (44%) were Caucasian; and 2/18 (11%) were
Asian. In comparison, for historic controls the mean age was 67
years (SD=13 years); 50% (9/18) were male; 11/18 (61%) were
African-American and 7/18 (39%) were Caucasian.
Median time from ROSC to implementation of TH was 1.7h
(IQR 1.1–2.8h); mean starting temperature was 35.8◦C (range
31.0–37.0◦C; SD=1.4◦C); median time from initiation of TH to
achievement of target temperature was 2.5h (IQR 2.0–5.3h);
median time from ROSC to achievement of target temperature was
4.2h (IQR 3.1–8.1h); mean rate of cooling during induction of TH
was 0.8◦C/h; mean length of time patients were cooled for was
19.3h (range 17.0–29.0h; SD=8.3h), excluding two patients who
had care withdrawn by their families at hours 7 and 9, at which
PCI was performed in 17% (3/18) of patients in the PCAR protocol
group versus 11% (2/18) of patients in the historic control group.
Thirty-nine percent (7/18) of the patients in the PCAR group had
PCI during their hospital stay versus 11% (2/18) of the historic con-
trols. Immediate echocardiogram (during the first 6h after ROSC)
was performed in 85% (15/18) of the PCAR patients (mean EF=39%;
median EF=45%; IQR=25–65%) versus 38% (7/18) of the historic
controls (mean EF=31%; median EF=25%; IQR=13–50%); follow
up echocardiograms were performed in 58% (10/17) of the surviv-
ing EGDHO patients by 72h post-ROSC (mean EF=43%; median
EF=43%; IQR=25–50%) versus 20% (2/10) of the historic control
patients (mean EF=63%).
For patients treated with the PCAR protocol, the mean ini-
tial CVP was 12.8mmHg (range 5–26; SD=5.8mmHg); the mean
initial MAP was 95.1mmHg (range 67–147; SD=21.1mmHg); the
TH and EGDHO variables.
Mean (range) Number (%)
Starting T (◦C)
Time from ROSC to goal T (◦C)
Time, induction to goal T
Length of cooling
Time of rewarming
Initial CVP (mmHg)
Initial MAP (mmHg)
Achieved EGDHO endpoints in ≤6h
Interventions based on EGDHO variables
Intravenous fluid (mL), 1st 12h
mean initial ScvO2was 79.1% (range 54–90; SD=9.8%); 7/18 (39%)
patients required vasopressor infusions for greater than 6h; aver-
age intravenous fluid infusion volume over the first 12h was
5761mL (range 2250–14795mL); 14/18 (78%) had interventions
based upon EGDHO parameters; 13/18 (72%) of patients achieved
their EGDHO goals within 6h of implementation of TH and EGDHO.
For historic controls, the mean initial MAP was 81mmHg (range
41–106mmHg); 22% (4/18) required vasopressors initially; average
intravenous fluid infusion volume over the first 12h was 1451mL
(range 658–4305mL) (see Tables 3, 4 and 5A).
Pre-implementation mortality was 14/18 (78%) for historic
control patients who qualified for the PCAR protocol; post-
implementation mortality for patients who qualified for and were
treated with the PCAR protocol was 10/20 (50%) and 9/18 (50%),
respectively (p=0.16); 4/18 (22%) historic controls and 9/18 (50%)
patients treated with PCAR protocol survived to hospital discharge;
two patients enrolled in TH protocol had care withdrawn by fam-
ily at hours 7 and 9; mortality for patients who completed TH was
44% (7/16; p<0.05); 4/4 (100%) of surviving historic controls and
8/9 (89%) of surviving patients treated with the PCAR protocol had
good neurologic outcomes, defined as cerebral performance cate-
gory (CPC) 1 or 2 (see Table 5B for details).
Our study demonstrates successful implementation of TH and
EGDHO in a hospital employing a multi-disciplinary post-cardiac
arrest resuscitation protocol. We found that 78% of patients
required interventions based upon our treatment algorithm and
that 72% of patients were able to achieve EGDHO goals within 6h
of ROSC. We demonstrated a 28% absolute reduction in mortal-
ity when compared with historic controls, though the study was
underpowered for the results to reach statistical significance.
Therapeutic hypothermia has been demonstrated to improve
neurologic function and survival in a number of clinical trials. One
of the benefits of hypothermia is a decrease in systemic and cere-
bral metabolic rates of oxygen consumption. This may be especially
helpful when systemic oxygen delivery does not meet metabolic
demands and may prevent recurring oxygen debt.
In the original early goal-directed therapy trial, by correcting
CVP, MAP, and ScvO2in a stepwise fashion within 6h of presen-
tation, Rivers et al.8reduced in-hospital mortality from 46.5% to
30.5% in patients with severe sepsis and septic shock. Subsequent
publications describing the feasibility of implementing EGDT along
with other aspects of a sepsis care bundle have demonstrated simi-
lar mortality reductions.10–13While the mechanisms for improved
optimizes hemodynamics at the proximal phase of critical illness,
which may prevent sudden cardiovascular collapse. In addition, in
D.F. Gaieski et al. / Resuscitation 80 (2009) 418–424
EGDHO end-points and target temperature over time.
Percentage of patients reaching resuscitation end-point at specific time intervals
Hour 0Hour 1 Hour 2Hour 3 Hour 4Hour 5Hour 6
Target temperature 32–34◦C
14/18 (78%)2/18 (11%) 8/18 (44%)10/18 56% 11/18 (61%)12/18 (67%)
Vasoactive agents and fluids over time.
Pressors 1h Pressors 6h Pressors 24hInotrope 1h Inotrope 6h Inotrope 24h Vasodilators 1hVasodilators 6h Vasodilators 24h
Input ED Output ED Balance ED (+/−)
Input 12h Output 12h Balance 12h (+/−)
Input 24h Output 24h Balance 24h (+/−)
688mL (+) 1451mL
276mL (−) 4203mL
post-hoc serologic analysis, patients treated with EGDT had lower
TNF-? receptor antagonists, IL-1, IL-6, IL-8, and IL-10, suggesting
achieved with EGDHO.23
The efficacy of EGDHO has been demonstrated in a number
of disease states and clinical settings.4,11–13,24–26
profile of patients who have ROSC after cardiac arrest is very simi-
lar to that of patients with septic shock, characterized by elevated
serologic markers of global inflammation, endothelial dysfunction
and microcirculatory hypoperfusion.
Mortality and neurologic outcomes.
PCAR Qualified 14/18 (78%)
Surviving historic controls
Surviving PCAR patients
Recognizing this, investigators have theorized that EGDHO
may be beneficial in the management of the post-resuscitation
syndrome.31,32In addition, the International Liaison Committee on
Resuscitation (ILCOR) and the American Heart Association (AHA)
have suggested using EGDHO to normalize oxygen content and
oxygen transport in patients post-cardiac arrest.33Despite this
evidence and the ILCOR/AHA recommendations, a 2007 literature
search found no clinical trials examining clearly specified hemody-
those of a standard therapy group.34
In a study published shortly after this literature review, Sunde
et al.15incorporated hemodynamic optimization and TH in their
standardized treatment protocol for post-resuscitation care of
post-arrest patients and demonstrated a 30% absolute increase in
survival to hospital discharge with favorable neurological outcome
when compared to historic controls. They implemented multiple
interventions simultaneously including an aggressive PCI strategy,
TH, and control of hemodynamics, blood glucose, ventilation, and
seizures. Not all patients received all interventions and the time
tributions of these different treatment modalities to the mortality
reduction cannot be determined and the ability to simultaneously
implement multiple treatment modalities in the proximal phase of
the post-resuscitation syndrome is unclear.
Our study demonstrated that when compared to historic con-
trols, patients treated with the PCAR protocol were given larger
volumes of intravenous fluids, a similar amount of vasopressors,
more inotropes and more vasodilators. These differences appear
to reflect more attention to maintenance of optimal hemodynamic
that the addition of hemodynamic optimization to TH during the
immediate post-resuscitation phase helps to modulate the inflam-
matory response, decrease apoptosis, and minimize reperfusion
injury. Further, by improving systemic oxygen delivery, EGDHO
ing outcomes post-arrest.35In a subset of patients, EGDHO may be
vasopressor-sparing, improving microvascular flow, and possibly
contributing to improved survival.36
On the other hand, it is also possible that EGDHO had no
positive impact on outcomes. In contrast to the “resuscitation
opportunities” identified by Rivers’ group, which were corrected
by EGDT (i.e. marked deficits in preload, afterload, and contractility
D.F. Gaieski et al. / Resuscitation 80 (2009) 418–424
leading to a deficit in global O2delivery), we observed less marked
initial deviation from normal values for the measured hemody-
namic parameters (CVP; MAP) and infrequent evidence of global
tissue hypoxia (ScvO2) requiring correction through transfusion
or administration of an inotrope. Ongoing efforts at maintaining
hemodynamic optimization continued throughout the period of
induced TH, however. Indeed, at 24h post-ROSC, 29% (5/17) of the
patients remained on vasopressors, 38% (6/17) on inotropes, and
18% (3/17) on vasodilators. This suggests that the period of hemo-
dynamic optimization opportunities extends beyond the initial 6h
of algorithmic resuscitation.
This study was performed at a single, academic medical center
with a dedicated research and clinical staff to assist in the identifi-
cation, enrollment, and management of patients eligible for TH and
post-arrest EGDHO and, therefore, these results may not be gen-
eralizable to other institutions with different infrastructures and
available resources. In addition, while 18/20 (90.0%) of the patients
who qualified for the protocol were enrolled, this still may have
Similar concerns apply to the historic control group. Further, his-
toric charts had more missing data on vasopressors, fluid infusion,
urine output, and other variables and only 8/18 (44.4%) had com-
plete records in this regard. The small number of patients enrolled
in the protocol – a reflection of the large number of hospitals in
the Philadelphia area and the policy of Philadelphia Fire Rescue
to transport cardiac arrest patients to the nearest hospital – does
not power the study sufficiently for outcome results to reach sta-
tistical significance. Because of the before–after design employed
in this study, other care issues changed in the same time period
(including low tidal volume ventilator strategies; steroid therapy
for relative adrenal insufficiency; and tight glucose control) and
these may have contributed to our results. Along with these clini-
changed, impacting on outcomes by increasing the level of aggres-
siveness in care, including more expeditious PCI, more attention to
minute to minute clinical details, neurologic assessment, and 1:1
nursing. Further, the contribution of TH cannot be separated from
reduction and neurologic benefit achieved by TH alone. Finally, the
to better quality CPR, not to improved post-resuscitation care.
Our study demonstrated that performance of EGDHO opti-
mization combined with TH is feasible in comatose cardiac arrest
survivors. Using an algorithmic protocol, both hemodynamic and
if EGDHO combined with TH improves outcome compared to ther-
apeutic hypothermia alone in comatose cardiac arrest survivors.
Conflict of interest
Data collection and research assistants involved in the proto-
col were supported by an unrestricted research grant from Gaymar
of this manuscript and did not review the manuscript prior to its
submission. Dr. Gaieski has received consulting fees and honoraria
Gaymar Industries and honoraria from Edwards Lifesciences; Dr.
Abella has received honoraria from Gaymar Industries, Alsius Corp,
and Medivance Corp. No author declares intellectual property or
equity ownership conflicts of interest.
We would like to acknowledge the invaluable contributions of
the following persons to the development and implementation of
the PCAR protocol: Linda Hoke, RN, Gail Delfin, RN, Jennifer Barger,
mitment of the entire nursing staffs of the ED, CCU, and MICU. We
are indebted to Fran Shofer, PhD, for her statistical analyses and
contributions to the methodology of the paper.
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