Clinical Review

Targeted temperature management

after out-of-hospital cardiac arrest
Who, when, why, and how?
Brian E. Grunau MD  Jim Christenson MD  Steven C. Brooks MD MHSc

Abstract
Objective  To provide a succinct review of the evidence, framed for the emergency department clinician, for the
application of targeted temperature management (TTM) for patients after out-of-hospital cardiac arrest (OHCA).

Sources of information MEDLINE, EMBASE, and the Cochrane database were searched for prospective and
retrospective studies relevant to the indications of TTM, optimal timing of TTM initiation, method of cooling, and
target temperature.

Main message Two prospective

Editor’s key points interventional trials reported
• Although targeted temperature management (TTM) is a widely recommended improved neurologically intact
therapy for patients after out-of-hospital cardiac arrest (OHCA), many survival with the use of TTM (goal
questions remain regarding the patient populations who would benefit from temperatures of 32°C to 34°C)
this therapy, as well as the optimal time to initiate therapy, method of cooling, compared with no temperature
and goal temperature. management in comatose OHCA
patients with shockable initial
• Current evidence indicates that TTM within a comprehensive protocol for cardiac arrest rhythms. A more
resuscitated patients after OHCA, compared with usual care, is a beneficial recent, high-quality randomized
intervention for patients who are not responsive to verbal commands after OHCA. controlled trial including OHCA
patients with shockable and
• An organized protocol for resuscitated patients after OHCA including the use of TTM nonshockable initial rhythms
with a goal temperature of 32°C to 36°C should be implemented in all OHCA patients compared TTM at 33°C versus TTM
upon arrival to the ED, followed by timely transfer to a critical care environment. at 36°C. Despite the study being
well powered, superiority of one
POINTS DE REPÈRE DU RÉDACTEUR target temperature over the other
• Bien que la gestion ciblée de la température (GCT) soit un traitement was not demonstrated. The benefit
communément recommandé pour les patients ayant subi un arrêt cardiaque hors of TTM in patients with initial
de l’hôpital (ACHH), de nombreuses questions demeurent quant aux populations de nonshockable rhythms is not clear;
patients qui en bénéficieraient, au moment optimal pour amorcer le traitement, aux h o w e v e r, s o m e o b s e r v a t i o n a l
méthodes de refroidissement et aux valeurs de température ciblées. studies have suggested benefit.
There is no evidence that any
• Les données probantes actuelles indiquent que, comparativement aux soins particular method of temperature
habituels, la GCT suivant un protocole complet pour les patients réanimés ayant regulation is superior. The
subi un arrêt cardiaque hors de l’hôpital est une intervention bénéfique lorsque
relationship between time and
ces derniers ne réagissent pas aux commandes verbales après un ACHH.
TTM initiation has not been well
established.
• Un protocole structuré pour les patients réanimés après un ACHH, incluant
l’utilisation de la GCT visant des valeurs de de 32 °C à 36 °C, devrait être mis en
œuvre pour tous les patients dès leur arrivée à l’urgence, suivi d’un transfert aux Conclusion  Targeted temperature
soins intensifs en temps opportun. management, with a target
temperature between 32°C
and 36°C, as a component of
This article has been peer reviewed. comprehensive critical care is a
Cet article a fait l’objet d’une révision par des pairs.
beneficial intervention for comatose
Can Fam Physician 2015;61:129-34
patients with return of spontaneous
circulation after OHCA.

Vol 61:  february • février 2015 | Canadian Family Physician • Le Médecin de famille canadien  129
Clinical Review | Targeted temperature management after out-of-hospital cardiac arrest
Gestion ciblée de la
température après un arrêt
cardiaque hors de l’hôpital
Qui, quand, pourquoi et comment?
Résumé
O b j e c t i f   Présenter une synthèse des données
probantes, élaborée à l’intention des cliniciens des
services d’urgence, en ce qui concerne les mesures de
gestion ciblée de la température (GCT) chez les patients
ayant subi un arrêt cardiaque hors de l’hôpital (ACHH).
Sources des données On a effectué une recherche
dans MEDLINE, EMBASE et la base de données
Cochrane pour trouver des études prospectives et
rétrospectives concernant les indications de la GCT, le
moment optimal pour amorcer la GCT, les méthodes de
refroidissement et les valeurs de température ciblées.
Message principal Dans deux études interventionnelles
prospectives, on a signalé une amélioration du taux
de survie sans lésion neurologique avec l’utilisation
de la GCT (températures ciblées de 32  °C à 34  °C)
comparativement à celui des patients comateux victimes
d’un ACHH et présentant des rythmes initiaux à l’arrêt
cardiaque justifiant une défibrillation dont la température
n’avait pas été prise en charge. Plus récemment, une
étude randomisée contrôlée de grande qualité portant
sur des patients victimes d’un ACHH et présentant des
rythmes initiaux justifiant ou non une défibrillation
comparait la GCT à 33  °C à la GCT à 36  °C. Bien que
l’étude ait été bien menée, elle n’a pas démontré la
supériorité de l’une ou l’autre des températures ciblées.
Les avantages de la GCT chez les patients présentant
des rythmes initiaux ne justifiant pas une défibrillation
ne sont pas clairs même si, dans certaines études
observationnelles, on a fait valoir certains bienfaits.
Il n’y a pas de données probantes établissant qu’une
méthode particulière de régulation de la température soit
supérieure à une autre. Le moment opportun d’amorcer
la GCT n’a pas été bien établi.
Conclusion  La gestion ciblée de la température, visant
des valeurs entre 32 °C et 36 °C, en tant que composante
des soins intensifs complets est une intervention bénéfique
pour les patients comateux qui ont eu un rétablissement
de la circulation spontanée après un ACHH.
C
ardiac arrest affects approximately 40 000 victims
per year in Canada1 and is associated with low
rates of survival to hospital discharge.2,3 Targeted
temperature management (TTM) has been used for
patients after out-of-hospital cardiac arrest (OHCA)
130  Canadian Family Physician • Le Médecin de famille canadien
with the objective of improving neurologic outcomes
and lowering rates of mortality. In spite of numerous
studies examining the use of TTM, questions remain
in terms of the patient populations who would benefit
from this therapy, as well as the optimal time to ini-
tiate therapy, method of cooling, and goal tempera-
ture. In light of this, we sought to provide a succinct
review of the evidence related to TTM, framed for the
emergency department (ED) clinician, for resuscitated
patients after OHCA.
Case description
A 55-year-old patient arrived at a 10-bed rural
ED with emergency medical services (EMS). His
wife heard him fall to the ground at home and
when she found him unresponsive she immedi-
ately performed cardiopulmonary resuscitation
(CPR). Emergency medical services arrived at the
scene, confirmed pulselessness, continued CPR, and
applied an automated external defibrillator (AED).
The AED advised, “No shock.” After one cycle of
CPR was performed, the AED delivered a defibril-
latory shock, which resulted in a sustained return
of spontaneous circulation (ROSC). On arrival in
the ED, the patient’s vital signs were as follows:
blood pressure of 135/70 mm Hg, heart rate of
50 beats per minute, temperature of 36.9°C, oxy-
gen saturation of 92%, and a Glasgow Coma Scale
score of 3 (eye opening = 1, verbal response = 1,
motor response = 1). The patient was not intubated.
Pupillary response was absent and there was no
corneal reflex.
Sources of information
We performed a MEDLINE search from January 1, 1900,
to December 31, 2013, to identify all studies examin-
ing neurologic outcomes or mortality in patients with
OHCA of presumed cardiac causes relevant to the fol-
lowing questions.
• Does TTM improve outcomes and, if so, in which pop-
ulations have studies shown benefits? (Trials compar-
ing TTM to usual care and those comparing TTM of
different temperature targets were included.)
• Does earlier initiation of TTM improve outcomes com-
pared with later initiation?
• Are certain techniques of patient cooling, for the pur-
pose of TTM, associated with improved outcomes?
Studies were included regardless of language of pub-
lication. The search strategy used and combined the fol-
lowing MeSH terms: heart arrest, induced hypothermia,
humans, and adult. A similar search was performed in
EMBASE. The Cochrane database of systematic reviews
was searched using the term hypothermia. We included
all prospective and retrospective human adult studies
of randomized, pseudo-randomized, and observational
| Vol 61:  february • février 2015
 Targeted temperature management after out-of-hospital cardiac arrest | Clinical Review
designs. References of studies examined were also
reviewed to widen the search.
Main message
Our search yielded 445 citations. After review for rel-
evance by title and abstract, we reviewed 145 articles in
full. We included 57 of these in the final review.
Indications for TTM
Initial shockable rhythms (ventricular fibrillation
[VF] and pulseless ventricular tachycardia):  Two pro-
spective interventional trials, both published in 2002,
examined the use of TTM after OHCA with a presumed
cardiac cause, with goal temperatures of 32°C to 34°C.
Bernard et al enrolled 77 patients (men older than 17
and women older than 49 years of age) with an ini-
tial rhythm of VF in “persistent coma” after OHCA
and compared TTM with those receiving usual care.4
Targeted temperature management was initiated by
EMS in the intervention group and continued for 12
hours. Forty-nine percent of patients in the TTM group
had a “good outcome” (discharged to a rehabilita-
tion facility or home) compared with 26% in the con-
trol group (P = .046). The Hypothermia after Cardiac
Arrest Study Group randomized 273 patients aged
18 to 75 years after witnessed OHCA with an initial
rhythm of VF or nonperfusing ventricular tachycar-
dia who had no “response to verbal commands” and
an interval time of collapse to EMS arrival of 5 to 15
minutes. 5 The intervention group received TTM for
24 hours, commencing in hospital; 55% of patients
had favourable outcomes (cerebral performance cate-
gory score of 1 or 2) compared with 39% among those
who received usual care (P = .009). Further, there was
a reduction in mortality. In addition, several obser-
vational studies have reported benefits in mortality
and neurologic outcomes when comparing the use
of TTM with historical controls in patients with initial
shockable rhythms.6-10
The protocols of the initial 2 studies examin-
ing TTM4,5 used target temperatures of 32°C to 34°C.
Subsequent widespread implementation of TTM and
guidelines endorsed this strategy11,12; however, evi-
dence supporting these specific temperature goals was
lacking. It was theorized by some that the true benefit
of TTM was in its ability to prevent hyperthermia after
cardiac arrest, as opposed to a benefit of subnormal
temperatures.13 Nielsen et al performed a multicentre
randomized controlled trial, enrolling 950 unconscious
patients after OHCA, comparing targeted temperature
groups of 33°C and 36°C.14 Patients of all initial rhythms,
with the exception of unwitnessed asystole, were consid-
ered for inclusion; however, 79% of participants had shock-
able initial cardiac rhythms. The study was powered to
detect an absolute reduction in mortality of 11%. Targeted
Vol 61:  february • février 2015
temperature management was initiated within 240 min-
utes of ROSC and was continued, with mandatory seda-
tion, for 28 hours followed by slow rewarming. Measures
to avoid hyperthermia continued for a total of 72 hours. An
assessor-blinded standardized evaluation for neuroprog-
nostication took place 72 hours after the rewarming phase
to make recommendations for further life-sustaining treat-
ment. Despite being well powered, superiority of one tar-
get temperature over the other was not demonstrated in
terms of neurologic outcomes or mortality.
There have been no studies comparing patients
with a TTM goal of 36°C with usual care.
Initial nonshockable rhythms (pulseless electrical activ-
ity and asystole):  No large prospective randomized
studies have examined the use of TTM in patients with
nonshockable initial rhythms in comparison with usual
care; however, several retrospective studies, all with
target temperatures of 32°C to 34°C, have indicated
benefit.15,16 Testori et al reviewed 374 cases with non-
shockable initial rhythms and reported better neuro-
logic outcomes and a lower mortality rate in those
treated with TTM. 16 Conversely, in other similarly
designed studies, including one study examining 1145
consecutive cardiac arrests,17 benefit was limited to
only those with initial shockable rhythms.18-22 Nielsen
and colleagues compared temperature targets of 33°C
and 36°C in patients with initial nonshockable rhythms
in a subgroup analysis and reported no benefit seen
with the more aggressive TTM goal.14
Given the low survival rate of OHCA patients with
nonshockable initial rhythms, extremely large sam-
ple sizes would be required to detect benefit.23 Several
observational studies have examined the implemen-
tation of TTM in all resuscitated patients after OHCA,
regardless of initial rhythm, and have reported ben-
efit in neurologic outcomes or mortality.24-32 To isolate
the effect of TTM on nonshockable rhythms, Kim et al
performed a meta-analysis incorporating data pertain-
ing only to these rhythms from 10 non-randomized
studies involving 1292 patients. They concluded that
TTM was associated with reduced in-hospital mortality
(relative risk 0.84; 95% CI 0.78 to 0.92); however, there
was no statistical benefit seen in neurologic outcomes
at hospital discharge.23 The authors concluded that the
quality of evidence was low and that high-quality ran-
domized trials were required.
It is unclear why patients with initial non-
shockable rhythms have a worse prognosis con-
sidering that the pathophysiology of anoxic brain
injury is likely similar in all instances of cerebral
hypoperfusion.33 Resuscitated patients after OHCA with
initial non-shockable rhythms are much more likely to
have had longer collapse-to-ROSC durations,34 which
might play a role in the worse outcomes observed. 4
| Canadian Family Physician • Le Médecin de famille canadien  131
Clinical Review | Targeted temperature management after out-of-hospital cardiac arrest
Oddo et al performed a multivariable analysis on pro-
spective data from 74 resuscitated patients after OHCA
treated with TTM to assess for predictors of outcomes.34
They reported that initial arrest rhythm, in contrast to
time from collapse to ROSC, was not independently
associated with neurologic outcomes or mortality. Soga
et al reported similar outcomes for patients with shock-
able and nonshockable rhythms whose collapse-to-
ROSC interval was 16 minutes or less.35 The sole data
point of shockable versus nonshockable initial rhythms
for the decision on whether to initiate TTM in a patient
is likely overly simplistic and negates other variables
that might play a large role in the success of this treat-
ment and patient outcomes.
Issues of timing
Time to initiation of cooling and time to target
temperature in studies investigating TTM, with goal
temperatures of 32°C to 34°C, vary widely. Multiple
animal models have shown benefits of earlier and
faster cooling strategies 36-40 ; however, the impor-
tance of this variable on outcomes in humans remains
unknown. Four retrospective studies have reported
benefits of earlier cooling, including improved neu-
rologic outcomes and mortality rates.41-44 Conversely,
some studies have indicated a lack of benefit for
shorter time to target temperature,45,46 and 4 studies
reported worse outcomes.47-50
Five RCTs examined the effects of prehospital TTM
induction using cold saline. 51-55 No study found sig-
nificant differences in patient neurologic outcomes or
mortality; however, differences in mean patient tem-
peratures between intervention and control groups at
hospital arrival were modest (0.8°C to 1.3°C).
Methods of TTM
Multiple methods of cooling for TTM have been
described, including use of ice bags, cold saline infu-
sions, cooling blankets, and intravascular or intrana-
sal cooling devices. There is no evidence to suggest
that any one method is superior.11
Cold saline has been proposed as a favoured option
for induction of TTM owing to its relatively low cost,
convenience, universal availability, and ease of use
in patient transport. The American Heart Association
currently recommends a cold intravenous fluid bolus
to induce TTM. 11 Several studies, including 4 ran-
domized controlled trials, have reported cold saline
infusions to be safe and effective while not induc-
ing pulmonary edema. 51-53,56-65 However, a recent
large study that randomized patients to prehospital
administration of a rapid 2-L bolus of 4°C normal saline,
compared with usual care, reported increased prehospi-
tal recurrence of cardiac arrest and pulmonary edema
within the first 12 hours of hospitalization; there was no
132  Canadian Family Physician • Le Médecin de famille canadien
difference in overall mortality.55 Cold saline infusions are
effective induction agents but appear less effective in
the maintenance of a particular body temperature.56
Case resolution
The patient was moved to a resuscitation bay in the
ED with a cardiac monitor, 2 large-bore intravenous
catheters were placed, and oxygen was adminis-
tered to achieve an oxygen saturation of 94%. An
endotracheal tube was inserted and sedation was
commenced. A 500-mL bolus of 4°C normal saline
was initiated, with a goal temperature of 36°C, and
a bladder temperature catheter was inserted for
monitoring. A total of 1 g of acetaminophen was
given rectally. The regional cardiac referral centre
was contacted and arrangements were made for
urgent transport. Standard of care within the region
included delay of neuroprognostication until at least
72 hours for all patients after OHCA, regardless of
initial neurologic status. An additional 500-mL bolus
of cooled saline was given and a surface-cooling
blanket was applied until advanced care transport
paramedics arrived.
Conclusion
Unanswered questions remain with regard to the opti-
mal TTM strategy and the magnitude of its effectiveness.
However, there is compelling evidence that TTM pro-
tocols,* compared with the usual care before the TTM
era, lead to improved outcomes for patients with initial
shockable rhythms and nonshockable rhythms. Recent
data presented by Nielsen and colleagues support the
conclusion that when employing the protocol of 108
or more hours described in the study—including strict
temperature control, mandatory sedation, and delayed
standardized prognostication—TTM with a goal temper-
ature of 33°C is not superior to a goal of 36°C.14
Current evidence indicates that TTM within a com-
prehensive protocol for resuscitated patients after
OHCA, compared with usual care, is a beneficial inter-
vention for patients after OHCA who are not responsive
to verbal commands. Normal saline at 4°C is effective
for initial temperature regulation; however, until there is
further evidence supporting the safety of this technique,
it might be advisable to avoid large rapid boluses. An
organized protocol for resuscitated patients after OHCA
including the use of TTM with a goal temperature
of 32°C to 36°C should be implemented in all OHCA
patients upon arrival to the ED, followed by timely
transfer to a critical care environment. 
Dr Grunau is an emergency physician at St Paul’s Hospital in Vancouver, BC,
and Clinical Assistant Professor in the Department of Emergency Medicine
*Further information on targeted temperature management
protocols can be found at www.emergencymedicine.
utoronto.ca/research/ptmr/CS/SPARC.htm.
| Vol 61:  february • février 2015
 Targeted temperature management after out-of-hospital cardiac arrest | Clinical Review
at the University of British Columbia in Vancouver. Dr Christenson is an
emergency physician at St Paul’s Hospital and Professor in and Head of the
Department of Emergency Medicine at the University of British Columbia.
Dr Brooks is an emergency physician at Kingston General Hospital in Ontario
and Assistant Professor in the Department of Emergency Medicine at Queen’s
University in Kingston.
Contributors
All authors contributed to the literature review and interpretation, and to pre-
paring the manuscript for submission.
Competing interests
None declared
Correspondence
Dr Brian Grunau, Emergency Department, St Paul’s Hospital, 1081 Burrard St,
Vancouver, BC V6Z 1Y6; e-mail Brian.Grunau2@vch.ca
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