Series

Out-of-hospital cardiac arrest 3

Out-of-hospital cardiac arrest: in-hospital intervention
strategies
Christian Hassager, Ken Nagao, David Hildick-Smith

The prognosis after out-of-hospital cardiac arrest (OHCA) has improved in the past few decades because of advances Lancet 2018; 391: 989–98
in interventions used outside and in hospital. About half of patients who have OHCA with initial ventricular This is the third in a Series of
tachycardia or ventricular fibrillation and who are admitted to hospital in coma after return of spontaneous circulation three papers about
out-of-hospital cardiac arrest
will survive to discharge with a reasonable neurological status. In this Series paper we discuss in-hospital management
of patients with post-cardiac-arrest syndrome. In most patients, the most important in-hospital interventions other Department of Cardiology,
Rigshospitalet, Copenhagen,
than routine intensive care are continuous active treatment (in non-comatose and comatose patients and including Denmark (Prof C Hassager MD);
circulatory support in selected patients), cooling of core temperature to 32–36°C by targeted temperature management Department of Clinical
for at least 24 h, immediate coronary angiography with or without percutaneous coronary intervention, and delay of Medicine, University of
Copenhagen, Copenhagen,
final prognosis until at least 72 h after OHCA. Prognosis should be based on clinical observations and multimodal
Denmark (Prof C Hassager);
testing, with focus on no residual sedation. Cardiovascular Centre, Nihon
University Hospital, Tokyo,
Introduction neurological damage. The in-hospital management of Japan (Prof K Nagao MD); and
Department of Cardiology,
Only about one in ten of all patients with out-of-hospital patients with post-cardiac-arrest syndrome is the focus of
Sussex Cardiac Centre, Brighton
cardiac arrest (OHCA) will survive,1 but of those who this Series paper. and Sussex University
have initial ventricular tachycardia or ventricular Hospitals, Brighton and Hove,
fibrillation and who are comatose on admission to How should we initially assess and stabilise UK (Prof D Hildick-Smith MD)
hospital after return of spontaneous circulation (ROSC), patients? Correspondence to:
Prof Christian Hassager,
about half will survive with a reasonable neurological In the early phase after ROSC, myocardial dysfunction
Department of Cardiology,
status.2,3 Historical nihilism towards these patients is, and microcirculatory dysfunction from global ischaemia Rigshospitalet, University of
therefore, no longer justified. Whole-body ischaemia and lead to rapid release of toxic enzymes and free radicals Copenhagen,
reperfusion in resuscitated patients with OHCA leads to into the cerebrospinal fluid and blood. Cerebral and DK-2100 Copenhagen, Denmark
hassager@dadlnet.dk
so-called post-cardiac-arrest syndrome.4 This complex microvascular abnormalities persist while metabolic
combination of pathophysiological processes has four disorders progress to varying degrees, for which no
key components: brain injury, myocardial dysfunction, specific therapy has proven efficacy. Initial stabilisation
systemic ischaemia and reperfusion response, and the of resuscitated patients includes sedation when needed
underlying precipitating pathological process that caused (eg, violent or non-cooperative patients in severe distress,
the cardiac arrest (table). or hypoxic patients) and intubation for ventilation in
The severity of post-cardiac-arrest syndrome after comatose patients. The optimum haemodynamic goals
ROSC, and thereby survival and neurological function, remain undefined.6,7 Most centres advocate achieving
varies depending on the severity of the ischaemic insult, mean arterial pressure of 65–80 mm Hg by use of
the cause of cardiac arrest, out-of-hospital interventions, norepinephrine, with or without inotropes, and fluid.
and the patient’s prearrest state of health (figure 1).5 Heart rate is judged to be less important than achieving
The incidence of serious post-cardiac-arrest syndrome sufficient blood pressure, lactate clearance, and urine
leading to death or unfavourable neurological outcomes output, although might be increased to improve blood
at 30 days after OHCA is roughly 36–47% in shockable pressure if other methods fail.6,7 Early use of targeted
patients (ie, those with initial ventricular tachycardia or temperature management is also important.6,7
ventricular fibrillation) and 86–89% in non-shockable
patients (ie, those with asystole or pulseless electrical
activity).5 Important features in the occurrence of Search strategy and selection criteria
post-cardiac-arrest syndrome, therefore, are the initial We searched the Cochrane Library without date restrictions
cardiac rhythm and whether bystander cardiopulmonary and MEDLINE for papers published in the past 10 years.
resuscitation (CPR) was given. Care after OHCA has We used the search term “out of hospital cardiac arrest” to
improved early mortality due to post-cardiac-arrest identify papers with this phrase in the title. We largely selected
syndrome, but short time from arrest to ROSC remains those published in the past 5 years, but did not exclude
extremely important. Patients who die within 1 day of commonly referenced and highly regarded older publications.
OHCA mainly do so because of circulatory failure, but We also searched the reference lists of articles identified by this
the major cause of later death in resuscitated patients search strategy and selected those we judged to be relevant.
in hospital is withdrawal of life support due to severe

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Pathophysiology Clinical findings Potential treatment

Brain injury Disrupted electrophysiology and calcium
homoeostasis, free-radical formation, cell death
Myocardial dysfunction Myocardial stunning with reduced myocardial
contraction
Systemic ischaemia- Reperfusion injury, systemic inflammation,
reperfusion response endothelial activation, clotting cascade activation
Underlying Disease-specific features: plaque rupture,
precipitating pathology pulmonary embolus, electrolyte disturbances,
cardiomyopathies, channelopathies
Coma, seizures
Global myocardial hypokinesis,
acute heart failure
Hypotension, reperfusion injury
Disease-specific features:
myocardial infarction, acute heart diuretics, thrombolysis, haemofiltration
failure, repeated cardiac arrhythmia
Targeted temperature management,
sedation or antiepileptic drugs, optimised
ventilation and circulation
Inotropes and diuretics, mechanical
circulatory support
Intravenous fluids, vasopressors,
haemofiltration, general intensive care
Disease-specific features: PCI, inotropes and

PCI=percutaneous coronary intervention.

Table: Characteristics of post-cardiac-arrest syndrome

70 A
90
favourable neurological function (%)

60 80

Proportion of adults (%)

70
50
30-day survival with

60
40 50
40
30 30
20
20
10
10 0

0 B
0 Shockable arrest Shockable arrest Non-shockable arrest Non-shockable arrest 90
with without with without 80
Proportion of adults (%)

bystander CPR bystander CPR bystander CPR bystander CPR 70

(n=7140) (n=4827) (n=9038) (n=11 180)
Figure 1: Neurologically intact survival in 32 185 adult patients who achieved return of spontaneous
circulation before arrival at hospital after bystander-witnessed out-of-hospital cardiac arrest
Witnessed refers to emergency medical service responders or bystanders. CPR=cardiopulmonary resuscitation.
The most common cause of OHCA in adults with ROSC,
particularly those who survive to 30 days with favourable
neurological function, is cardiovascular disease (figure 2),
and especially coronary heart disease.5 Therefore, in
patients with ROSC, assessment with 12-lead electro­
cardiography and echocardiography, if available, should be
done as soon as possible. Acute coronary angiography,
should be done in all patients who have ST-segment
elevation, but should also be considered for those without
ST-segment elevation because the results on out-of-hospital
electro­cardiograms (ECGs) after ROSC are insufficient to
predict an occluded major coronary vessel.8 Percutaneous
coronary intervention should be considered used if acute
occlusion occurs. An echocardiogram showing substantial
right ventricle enlargement might indicate a large
pulmonary embolus. Completely normal findings on the
ECG and echocardiogram should lead to additional
diagnostic investigations, which might include cerebral or
other CT, search for bleeding, and testing for infections or
poisons, and other causes.
Patients without ROSC who have favourable prog­
nostic factors out of hospital should be considered for
immediate extracorporeal CPR with mechanical circu­
latory support and extracorporeal membrane oxygenation
with cannulation of the femoral vein and artery. A review
60
50
40
30
20
10
0
Cardiac External Respiratory Cerebrovascular Other
cause cause failure accident
Cause
Figure 2: Causes of witnessed out-of-hospital cardiac arrest in adults
achieving return of spontaneous circulation
Witnessed refers to emergency medical service responders or bystanders.
(A) 62 085 adults who had return of spontaneous circulation before arrival at
hospital after cardiac arrest. (B) 14 264 adults who survived with favourable
neurological function at 30 days after cardiac arrest.
of cohort studies indicated that overall survival is about
20% in patients without ROSC after OHCA who receive
extracorporeal CPR, but the values varied widely between
individual studies and no randomised trials were
assessed.9 Furthermore, many of these patients will
have cerebral sequelae. The simpler percutaneous left
ventricular assist devices, such as the intra-aortic balloon
pump and the Impella heart pump (Abiomed, Aachen,
Germany), might not be adequate support in patients
with cardiogenic shock after OHCA (figure 3).10–12 Cardiac
diagnostic tests other than ECG, enzyme concentrations,
coronary angiography, and echocardiography are rarely
needed in the acute phase after OHCA, and may be
postponed until after the patient wakes and is in a
stable condition.

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Should all patients proceed to immediate out-of-hospital character­ istics, such as unwitnessed
coronary angiography? OHCA, delayed arrival of emergency medical services
ST-segment elevation on electrocardiogram after (EMS) in the absence of bystander CPR, and known
resuscitation pre-existing comorbidities, should be taken into
Most randomised trials of primary percutaneous consideration (figure 4).21–25 See Online for appendix
coronary intervention for ST-segment elevation myo­
cardial infarction (STEMI) have excluded patients
presenting with cardiac arrest. Furthermore, we found Patient with out-of-hospital cardiac arrest arrives
at hospital
no randomised trials of immediate invasive strategies
in STEMI patients resuscitated after OHCA. Most
studies have been small, single-centre, retrospective, Routine ABC stabilisation, ECG, TTE, and TTM
observational series and, therefore, are highly vulnerable initiation
Consider reversible causes (4H + 4T)
to unmeasured confounders and selection or reporting
biases (appendix).13–18 Nevertheless, these studies show
that early revascularisation after cardiac arrest in patients
with ST-segment elevation is feasible, safe, associated No ROSC ROSC
with optimum coronary flow, and can translate to
improved clinical and neurological outcomes in the short
and medium terms.13,15,18
STEMI or shock Stable circulation and no STEMI
The 2015 American Heart Association guidelines for
care after cardiac arrest advocate emergency angio­graphy
for patients with OHCA and ST-segment elevation on Consider extracorporeal CPR Immediate coronary Consider brain CT or further
angiography ± PCI* diagnostics, including coronary
the ECG after ROSC.6 The 2017 European Society angiography ± PCI*
of Cardiology19 and 2013 US guidelines for treatment
of STEMI20 assign a class I (level of evidence B)
recommendation for the use of percutaneous coronary
intervention in patients resuscitated after cardiac arrest Admit to intensive care for:
with ST-segment elevation on their ECG. Furthermore, • Routine intensive-care management with optimised ventilation, circulation, renal
function, electrolytes, blood glucose, etc
in a consensus statement on invasive treatment strategies • TTM for 24 h and rewarming at 0·5°C/h
for OHCA issued by the European Association for • Diagnose and treat seizures
• Wean sedation and attempt to wake at normothermia
Percutaneous Cardiovascular Interventions,21 immediate
angiography was endorsed in patients who wake
immediately after cardiac arrest and those who stay in a
coma and have STEMI on ECG (irrespective of Glasgow No signs of awakening Wakes up with contact
Coma Scale on arrival at the interventional centre).
Contemporary guidelines suggest that neurological
function should not be used as a determinant of • Delay prognosis for at least Routine treatment, coronary
72 h after arrest angiography ± PCI or CABG if
whether to do emergency coronary angiography.6,19,21 • Consider prevention against not yet done, plus secondary
Never­theless, human and departmental resources are fever for 72 h after arrest prevention
not inexhaustible, and a balance must be struck between
the likelihood of a positive outcome and the use of
Pupillary and corneal reflexes Consider stopping treatment
resources at the expense of other services. Unfavourable absent, bilaterally absent N20 Yes
on SSEP, or both, >72 h after
arrest
Figure 3: Algorithm for care after resuscitation for out-of-hospital cardiac
arrest due to shockable rhythm No
The algorithm may also be applicable to selected patients with out-of-hospital
Reassess after ≥24 h for two or Consider stopping treatment
cardiac arrest without a primary shockable rhythm. ABC=airway, breathing,
more of:
circulation. ECG=electrocardiography. TTE=transthoracic echocardiography. • Status myoclonus <48 h after
TTM=targeted temperature management at a constant temperature arrest Yes
of 32–36°C. 4H + 4T=hypoxia, hypovolaemia, hypokalaemia or hyperkalaemia, • High neuron-specific enolase
and hypothermia or hyperthermia plus thrombosis (coronary or pulmonary), concentration in serum
tension pneumothorax, tamponade, and toxins. ROSC=return of spontaneous • Highly malignant EEG†
circulation. STEMI=ST-segment-elevation myocardial infarction. • Severe anoxic injury on brain
Extracorporeal CPR=cardiopulmonary resuscitation by venoarterial CT or MRI
extracorporeal membrane oxygenation. PCI=percutaneous coronary No
intervention. CABG=coronary artery bypass graft. N20 on SSEP=bilateral
absence of peaks at 20 ms on somatosensory evoked potential testing. Observe and reassess with
EEG=electroencephalogram. *Depending on coronary anatomy, acute coronary multiple methods, including
bypass surgery might be preferred to PCI. †Suppressed background without MRI
discharges or with periodic discharges, or burst-suppression background.12

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angiography in patients without clearly defined

ROSC has returned, but patient ST-segment elevation on the ECG after ROSC if clinical
remains comatose
findings suggest that myocardial ischaemia is the likely
cause.6,19 The European Association for Percutaneous
Presence of multiple adverse features? Unlikely to benefit from acute Cardiovascular Interventions consensus statement21
• Unwitnessed cardiac arrest coronary interventions
• Initial rhythm not VT/VF Individualise patient’s care
advises that coronary angiography should be done within
• No bystander CPR and continue interventional 2 h of admission to hospital in patients without STEMI.
• >30 min to ROSC cardiology consultation This approach is intended to allow time in the emergency
• Ongoing CPR
• Regional cerebral oxygen saturation department or intensive-care unit to obtain important
<62% Yes history from bystanders and family to exclude non-coronary
• pH <7·2
• Plasma lactate concentration
causes and for additional testing if needed. This strategy
>7 mmol/L helps to conserve health-care resources and limit
• Plasma ammonia concentration unnecessary additional risks to the patient.21
>64 µmol/L
• Age >85 years
• End-stage renal disease Potential pitfalls of immediate invasive strategies
• Non-cardiac cause for arrest
Immediate angiography is clearly associated with
No
potential risks. Patients in whom coronary anatomy is
ST-segment elevation on ECG? Yes Notify STEMI team not responsible for the OHCA are subjected to adverse
immediately for possible PCI mobilisation at a time of important monitoring, exposure
No to contrast (which can affect renal function), vascular risk
Consult with interventional
from an unnecessary procedure, and bleeding risk from
cardiology and intensive-care services adjunctive medication. The com­ bination of targeted
and consider coronary angiography if temperature management and percutaneous coronary
appropriate
intervention can also lead to problems. Apart from
the logistics of maintaining targeted temperature
Figure 4: Guidance on use of immediate coronary angiogram after
manage­ ment during transfer between locations, this
resuscitation of patients with out-of-hospital cardiac arrest patients
ROSC=return of spontaneous circulation. VT/VF=ventricular tachycardia or therapy has been be associated with cardiac dysrhythmias,
ventricular fibrillation. CPR=cardiopulmonary resuscitation. infection, and bleeding risk.27–30 Incidence of these
ECG=electrocardiogram. STEMI=ST-segment-elevation myocardial infarction. disorders, however, did not differ between patients
PCI=percutaneous coronary intervention.
maintained at 33°C or 36°C.31 Small clinical series also
suggest that stent thrombosis is more frequent when
Resuscitated patients without ST-segment elevation targeted temperature management and percutaneous
The role of emergency coronary angiography in re­ coronary intervention are combined (appendix),32–35
suscitated patients presenting without ST-segment possibly due to multiorgan failure associ­ ated with
elevation on the ECG after ROSC is not clear-cut because attenuated absorption and impaired liver metabolism of
whether this finding reliably excludes haemodynamically drugs that inhibit the P2Y12 receptor and synthesis of
important coronary artery disease as the substrate for thromboxane A2.36,37 Prasugrel might be preferable to
cardiac arrest is unclear. In their seminal analysis of the clopidogrel if impaired liver function is suspected.
PROCAT Registry, Dumas and colleagues26 found in a
series of 435 patients with OHCA that the positive and Contemporary practice regarding coronary angiography
negative predictive values of ST-segment elevation for Most patients with OHCA have some degree of coronary
detecting substantial coronary lesions were 96% and 42%, artery disease, and many have plaque rupture.13,38–40
respectively. ST-segment elevation, therefore, is a good Emergency angiography to determine the most suitable
indicator of the presence of a coronary lesion requiring intervention, therefore, is important in the management
revascularisation, but the absence of this feature on of patients after cardiac arrest. Three meta-analyses
the ECG might also miss a proportion of patients who showed that in patients with OHCA outcomes and
would benefit from an invasive strategy.26 Around 25% of survival were improved with early coronary angiography
patients without ST-segment elevation will have an compared with no early coronary angiography.41–43
occluded coronary artery, and successful percutaneous Given the growing weight of evidence in favour of early
coronary intervention is an independent predictive use of coronary angiography and the endorsements
factor of survival, regardless of the ECG pattern after of international guidelines, invasive strategies have
resuscitation (appendix).26 been increasingly adopted. Moreover, an observational
Despite the paucity of randomised data, the American analysis of the US Nationwide Inpatient Sample database
Heart Association guidelines on care after cardiac arrest from January, 2000, to December, 2012, demonstrated
(class IIA, level of evidence B)6 and the European Society increased use of coronary angiography and percu­
of Cardiology STEMI guidelines (class IIa, level of taneous coronary intervention after OHCA secondary
evidence C)19 advocate consideration of emergency to ventricular tachycardia or ventricular fibrillation in

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patients with ST-segment elevation (from 54% to 87% and
from 30% to 77%, respectively) and without ST-segment
elevation (from 19% to 34%, and 4% to 12%, respectively).44
Can we protect the brain?
Targeted temperature management has been the
cornerstone of neuroprotection in patients resuscitated
but comatose after OHCA for the past 15 years. The exact
mechanism of action is unknown. Experimental data
suggest that targeted temperature management suppresses
pathways leading to delayed cell death and decreases the
cerebral metabolic rate, and consequently reduces the
release of excitatory aminoacids and free radicals.7 Neither
animal studies45 nor observational data from a randomised
trial in human beings,46 however, suggest that the
inflammatory response associated with post-cardiac-arrest
syndrome is reduced.
Inducing hypothermia before ischaemia was
introduced to preserve organ function during cardiac
surgery and the transportation of organs for trans­
plantation. Furthermore, people who have long-lasting
cardiac arrest due to severe accidental hypothermia
seem to have unexpectedly high survival.47 Finally, mild
hypothermia applied after a cardiac arrest mitigated
care. Little difference was seen between the two approaches
(figure 5). Prehospital cooling during resuscitation (also
called intra-arrest cooling)50,53,55 and cooling immediately
after achieving ROSC49,52,54 has been compared with in-
hospital cooling, but none of these trials showed any
benefit for prehospital cooling (figure 5).
Whether the target temperature affects outcomes has
also been tested. In the TTM trial,31 939 patients
resuscitated after OHCA were randomly assigned to be
maintained at 33°C or 36°C for 24 h. Prevention of fever
for the first 72 h was attempted in both groups. Mortality
at 6 months did not differ between the groups (hazard
ratio [HR] 1·06, 95% CI 0·89–1·28; figure 5). Further­
more, there were no indications of any difference
between groups in neurological function.3,31,56
The duration of targeted temperature management
has also been assessed. In the TTH trial,51 355 patients
resuscitated after OHCA were randomly assigned to be
maintained at 33°C for 24 or 48 h. The primary outcome
A HACA trial29 (n=273) Bernard and colleagues28
(n=77)
100 100
p=0·02 p=NS
Survival at discharge (%)
6-month survival (%)

80 80
brain damage in dogs.48 Several clinical trials have
60 60
studied the effects of mild hypothermia achieved by
targeted temperature management after OHCA. Cohort 40 40
studies and before-and-after studies on the implemen­ 20 20
tation of targeted temperature management are difficult
0 0
to interpret because of other changes in post-cardiac TTM (33°C) No TTM TTM (33°C) No TTM
arrest care that occurred simultaneously over the past
two decades. The first published randomised multicentre B Kim and colleagues49 RINSE trial50 (n=1198)
(n=1359)
trial of targeted temperature management was the 100 100
HACA trial.29 Resuscitated patients after OHCA with p=NS p=NS
Survival at discharge (%)

Survival at discharge (%)

80 80
ventricular fibrillation were randomised to receive
targeted temp­erature management (target temperature 60 60
32–34°C for 24 h) or standard therapy. The trial was 40 40
stopped after 273 patients were enrolled because of slow
20 20
recruitment and lack of funding. Mortality at 6 months
was 41% in the hypothermia group and 55% in the group 0 0
Prehospital Standard Intra-arrest Standard
that did not receive targeted tempterature management cooling care cooling care
(risk ratio 0·74, 95% CI 0·58–0·95; figure 5). The
findings of this study were supported by those from a C TTM trial31 (n=939) TTH trial51 (n=351)
100 100
smaller quasirandomised trial of 77 patients treated with
p=NS p=NS
targeted temperature management to maintain core
6-month survival (%)

6-month survival (%)

80 80
temperature at 32–34°C for 12 h.28 In-hospital mortality 60 60
was 51% in the hypothermia group and 68% in the
40 40
group that did not receive targeted temperature
management. Based on this evidence, treat­ment with 20 20

targeted temperature manage­ment entered the guide­ 0 0

lines as standard therapy for OHCA due to ventricular
fibrillation.
The median time from OHCA to target temperature was
8 h in the HACA trial.29 Several midsize52–55 and two large
(>1000 patients)49,50 randomised trials assessed whether
rapid cooling, achieved by starting cooling out of hospital
would affect mortality compared with standard in-hospital
TTM (33°C) TTM (36°C) TTM TTM
33°C for 24 h 33°C for 48 h
Figure 5: Comparisons of mortality by different approaches to targeted
temperature management in major randomised clinical trial
(A) TTM at 33°C vs no TTM. (B) Starting TTM out of hospital vs in hospital in the
two largest trials (>1000 patients). (C) TTM dose (target temperature and
duration of treatment) in the largest trials. NS=not significant. TTM=targeted
temperature management with a constant core temperature of 32–36°C.

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of favourable neurological outcome at 6 months did not
differ significantly between groups (HR 1·08, 95% CI
0·93–1·25; figure 5).
Cooling as part of targeted temperature management
can be achieved in several ways. Initial cooling of
about 1°C may be achieved by intravenous infusion of
1–2 L of ice-cold fluid. Simple surface cooling can be
done with ice packs (although this approach might
lead to substantial temperature fluctuations over time),
or with water-circulating blankets or gel-coated pads.
Intravascular heat exchange by a catheter placed in the
femoral, subclavian, or jugular veins is also an option.
None of these methods has been shown to be superior to
the others in terms of clinical endpoints. For example, a
randomised trial involving 400 OHCA patients showed
no difference in neurological outcomes despite better
temperature control with endovascular cooling than
basic surface cooling.57
Taken together, the evidence suggests that targeted
temperature management is beneficial in patients re­
suscitated after OHCA, but no dose-response relation­
ships have been established for target temperature, time
to target temperature, or time maintained at target
temperature. Furthermore, fever has been associated
with poor neurological outcomes after OHCA in
observational studies.58,59 Fever was allowed in the
control groups in the two positive trials published
in 2002,28,29 and 33°C and 36°C resulted in equal outcome
in the TTM trial.31 Targeted temperature management
is, therefore, speculated to act solely by preventing fever,
but no randomised data are yet available to support this
theory. Based on the above trials, the 2015 European
Resuscitation Council guidelines7 downgraded the
evidence for targeted temperature management therapy
to low quality, but its use for 24 h in comatose patients
resuscitated after OHCA with a target temperature
between 32°C and 36°C was still classified as a strong
recommendation.
Neuroprotection through pharmacological intervention
is not supported by convincing results. Several different
treatment pathways have been tested in randomised
controlled trials. None of sedation and seizure control
with thiopental60 or diazepam,61 calcium entry blockade62
and use of calcium antagonists to lessen ischaemic insult
and cerebral vasomotor effects, or use of glucagon-like
peptide 1,63 erythropoietin,64 or ciclosporin65 to protect
against reperfusion injury have improved outcomes in
patients with OHCA.
When and how should we assess the neurological
prognosis?
Most patients with OHCA who die after hospital admission
while in a coma after resuscitation do so from neurological
injury and active withdrawal of life-sustaining treatment.66
Reaching a valid neurological prognosis is, therefore,
extremely important. Bilateral absence of corneal and
pupillary light reflex at 72 h from ROSC predicts poor
994 www.thelancet.com Vol 391 March 10, 2018
outcome with high specificity but low sensitivity. Likewise,
a status myoclonus within 48 h from ROSC is associated
with a poor outcome, but in these patients, clinical
examination must be supported by additional measures,
such as brain imaging and electrophysiology.7
Brain CT done shortly after OHCA is often used to
diagnose or exclude a cerebral bleed. A normal CT scan
at this time is not prognostically useful, but severe
changes indicate a poor outcome.67,68 Later on (>24 h),
cerebral oedema, appearing as a reduction in the depth
of cerebral sulci and an attenuation of the interface
between grey and white matter, clearly indicates a poor
outcome.68 MRI of the brain has a better sensitivity for
identifying ischaemic brain injury, but only small studies
have been done so far. Use of grey-matter morphometry,69
obtained with standard brain T1-weighted MRI, and
especially diffusion-weighted imaging,70 provides useful
prognostic information. MRI seems to provide the most
information 2–10 days after cardiac arrest.71
Electroencephalograms (EEGs) are commonly obtained
to assess neurological prognosis. A highly malignant
EEG (suppressed background without discharges or with
continuous periodic discharges, or burst-suppression
background) 48–72 h after OHCA with no residual
sedation suggested a poor outcome without false-positive
predic­tions in about half of patients.12 Furthermore, EEG
without malignant features in this time period predicted
a good outcome.12 Finally, an EEG might uncover a status
epilepticus that in rare cases can be treated. Bilateral
absence of peaks at 20 ms (known as N20 signals) in
short-latency somatosensory evoked potentials is deemed
to be close to 100% specific of a poor prognosis, but with
low sensitivity.12
Neuron-specific enolase, protein S-100B, and the
axonal injury marker tau are biomarkers of brain damage
that can be measured in blood. Values 48–72 h after
OHCA correlate with the neurological outcome, with the
prog­ nosis worsening as concentrations increase.72–74
Cutoff values, however, vary between studies and
knowing the specific characteristics of the local assay
used is important. These biomarkers should not be used
alone but can be included as part of multimodal
prognostic assessments.
The final prognosis should not be decided until at least
72 h after OHCA if the decision relies solely on clinical
signs, and more observation time is often needed
(figure 3). Over 90% of patients who wake up do so
within 1 week, but good outcomes might be seen in those
waking later.75 As no features are perfect predictors of
outcome, multiple approaches should be used in the
prognostic assessment whenever possible.7
Should there be cardiac arrest centres?
The final link in the chain of survival after OHCA is
increasingly being seen as the next real opportunity to
improve long-term survival. In 2010, the American
Heart Association published a policy statement

supporting the idea of regional systems of care for
OHCA.76 Recognising the success of public health
initiatives, such as regional systems of care for STEMI
and trauma, this statement strongly supported
development of similar regional systems for OHCA
patients resuscitated out of hospital. Admission of
patients resuscitated after OHCA to tertiary centres is
associated with lower mortality than in non-tertiary
hospitals.77,78 Thus, a centralised strategy for immediate
care after resuscitation seems reasonable if geography
allows it. However, one solution is unlikely to be
globally applicable because emergency medical care
systems vary around the world. For instance, in Japan,
EMS responders must immediately start resuscitation
efforts for all OHCA patients, except when the victim is
obviously deceased, and must continue resuscitation
efforts until ROSC or arrival at hospital. The EMS
responders cannot make the decision to stop
resuscitation efforts. Therefore, each year in Japan,
more than 110 000 OHCA patients are transported
to emergency hospitals, which might be distant, by
high-speed ambulance or helicopter (both presenting
potential hazards to other people), irrespective of
outlook. Field termination reduces transport to the
hospital, but the optimum prehospital CPR duration to
maximise the number of patients with favourable
neurological outcomes has not previously been
established.5 Medical doctors being part of the EMS
response system might help to prevent futile trans­
portation of patients without ROSC after OHCA and a
poor prognosis to cardiac arrest centres far away. To
achieve the best possible regional networks for patients
with OHCA, therefore, systems need to be adapted
to the facilities available. Changes can only be
accomplished by close collabor­ ation between EMS,
intensive-care, and interventional cardiology teams.
What will we learn in the near future?
Several ongoing randomised clinical trials are comparing
subacute or immediate coronary angiography with delayed
coronary angiography in patients with OHCA but without
ST-segment elevation (NCT02387398, NCT02641626,
NCT02750462, and NCT02876458). Randomised trials
are also assessing extracorporeal CPR started out of hos­
pital (NCT02527031) and in hospital (NCT03101787 and
NCT01511666) for patients with no ROSC after OHCA.
Optimum haemodynamic goals after achieving ROSC
might be clarified from ongoing studies (NCT02541591
and NCT03141099). Regarding pharmacological neuro­
protection, inhaled xenon has showed a positive effect on
MRI indices of brain damage in a phase 2 trial,79 and a
phase 3 trial is planned (NCT03176186).
Most studies of cooling after ROSC28,29,31,49,80 showed
median or mean times from cardiac arrest to ROSC of
22–26 min. Stratification by time to ROSC should be
considered for future cooling studies. Finally, cooling
started during resuscitation might protect the
www.thelancet.com Vol 391 March 10, 2018 995
Series
myocardium and the brain from lethal reperfusion
injury if it can be delivered without delaying
resuscitation and without complications. After onset of
STEMI, early and successful myocardial reperfusion is
the most effective strategy for reducing myocardial
infarct size and improving the clinical outcome.
However, the process of restoring blood flow to the
ischaemic myocardium can induce injury.81 Myocardial
reperfusion injury can paradoxically reduce the
beneficial effects of myocardial reperfusion. Hypo­
thermia applied before reperfusion reduced the risk of
reperfusion injury in animal studies.82 A subgroup
analysis from a clinical trial found that patients with
anterior STEMI who underwent early cooling to achieve
a core temperature of less than 35°C before coronary
reperfusion had significantly smaller infarct sizes and
lower incidence of heart failure than patients who
received standard care.83 Other observational data84 and a
subgroup analysis from a clinical trial53 suggest that
cooling during resuscitation protects cardiomyocytes
and brain cells and improves outcomes after OHCA.
This effect is not yet proven, but a randomised trial
involving 900 patients that is due to finish soon might
provide useful data (NCT01400373). Finally, the whole
concept behind targeted temperature manage­ment is
being challenged in the TTM2 trial (NCT02908308),
which is comparing 24 h of cooling to 33°C with just
fever control (<37·8°C).
Conclusions
Survival after OHCA remains low. Immediate
bystander resuscitation, ROSC, and a clear treatable
cardiac cause are the best markers of a positive
outcome. Immediate echocardiography on arrival at
hospital can help to identify possible causes and aid
triage of patients. Patients with ECG evidence of
ST-segment elevation on arrival at hospital should usually
go directly for coronary angiography unless they have
severe adverse markers relating to acid-base balance.
In patients without ST-segment elevation, time should
be taken to gather key information. Coronary
angiography in such patients is not free from risk, and
its usefulness remains uncertain, but is being assessed
in trials. Neuroprotection with targeted temperature
management has been widely embraced, although the
data are not clear. Development of cerebral oedema
during treatment in hospital remains a poor prognostic
sign. Management of patients with OHCA uses
substantial resources, and results are improved by
treatment in dedicated facilities. Improvement in
overall outcome among patients with OHCA might
need regional networks of dedicated cardiac arrest
centres able to offer all treatment options.
Contributors
All authours contributed to the literature search. CH wrote the initial
draft of the paper with substantial contributions from KN and DH-S.
All authours reviewed and accepted the final draft.
 Series

Declaration of interests
We declare no competing interests.
Acknowledgments
We thank Aung Myat, Brighton and Sussex University Hospitals NHS
Trust and Brighton and Sussex Medical School, Brighton and Hove, UK,
for developing the series and contributing substantially to the direction
and delivery of this paper.
References
1 Wissenberg M, Lippert FK, Folke F, et al. Association of national
initiatives to improve cardiac arrest management with rates of
bystander intervention and patient survival after out-of-hospital
cardiac arrest. JAMA 2013; 310: 1377–84.
2 Bro-Jeppesen J, Kjaergaard J, Horsted TI, et al. The impact of
therapeutic hypothermia on neurological function and quality of life
after cardiac arrest. Resuscitation 2009; 80: 171–76.
3 Cronberg T, Lilja G, Horn J, et al. Neurologic function and
health-related quality of life in patients following targeted
temperature management at 33°C versus 36°C after
out-of-hospital cardiac arrest: a randomized clinical trial.
JAMA Neurol 2015; 72: 634–41.
4 Stub D, Bernard S, Duffy SJ, Kaye DM. Post cardiac arrest syndrome:
a review of therapeutic strategies. Circulation 2011; 123: 1428–35.
5 Nagao K, Nonogi H, Yonemoto N, et al. Duration of prehospital
resuscitation efforts after out-of-hospital cardiac arrest.
Circulation 2016; 133: 1386–96.
6 Callaway CW, Donnino MW, Fink EL, et al. Part 8: post-cardiac arrest
care: 2015 American Heart Association guidelines update for
cardiopulmonary resuscitation and emergency cardiovascular care.
Circulation 2015; 132 (suppl 2): S465–82.
7 Nolan JP, Soar J, Cariou A, et al. European Resuscitation Council
and European Society of Intensive Care Medicine guidelines for
post-resuscitation care 2015: section 5 of the European Resuscitation
Council guidelines for resuscitation 2015. Resuscitation 2015;
95: 202–22.
8 Salam I, Hassager C, Thomsen JH, et al. Editor’s choice—is the
pre-hospital ECG after out-of-hospital cardiac arrest accurate for the
diagnosis of ST-elevation myocardial infarction?
Eur Heart J Acute Cardiovasc Care 2016; 5: 317–26.
9 Ortega-Deballon I, Hornby L, Shemie SD, Bhanji F, Guadagno E.
Extracorporeal resuscitation for refractory out-of-hospital cardiac
arrest in adults: a systematic review of international practices and
outcomes. Resuscitation 2016; 101: 12–20.
10 Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support
for myocardial infarction with cardiogenic shock. N Engl J Med 2012;
367: 1287–96.
11 Ouweneel DM, Eriksen E, Sjauw KD, et al. Percutaneous mechanical
circulatory support versus intra-aortic balloon pump in cardiogenic
shock after acute myocardial infarction. J Am Coll Cardiol 2017;
69: 278–87.
12 Westhall E, Rossetti AO, van Rootselaar AF, et al. Standardized EEG
interpretation accurately predicts prognosis after cardiac arrest.
Neurology 2016; 86: 1482–90.
13 Garot P, Lefevre T, Eltchaninoff H, et al. Six-month outcome of
emergency percutaneous coronary intervention in resuscitated
patients after cardiac arrest complicating ST-elevation myocardial
infarction. Circulation 2007; 115: 1354–62.
14 Peels HO, Jessurun GA, van der Horst IC, Arnold AE, Piers LH,
Zijlstra F. Outcome in transferred and nontransferred patients after
primary percutaneous coronary intervention for ischaemic
out-of-hospital cardiac arrest. Catheter Cardiovasc Interv 2008;
71: 147–51.
15 Hosmane VR, Mustafa NG, Reddy VK, et al. Survival and neurologic
recovery in patients with ST-segment elevation myocardial infarction
resuscitated from cardiac arrest. J Am Coll Cardiol 2009; 53: 409–15.
16 Lettieri C, Savonitto S, De Servi S, et al. Emergency percutaneous
coronary intervention in patients with ST-elevation myocardial
infarction complicated by out-of-hospital cardiac arrest: early and
medium-term outcome. Am Heart J 2009; 157: 569–75.
17 Mylotte D, Morice MC, Eltchaninoff H, et al. Primary percutaneous
coronary intervention in patients with acute myocardial infarction,
resuscitated cardiac arrest, and cardiogenic shock: the role of
primary multivessel revascularization. JACC Cardiovasc Interv 2013;
6: 115–25.
18 Shavelle DM, Bosson N, Thomas JL, et al. Outcomes of ST elevation
myocardial infarction complicated by out-of-hospital cardiac arrest
(from the Los Angeles County regional system). Am J Cardiol 2017;
120: 729–33.
19 Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the
management of acute myocardial infarction in patients presenting
with ST-segment elevation: the Task Force for the management of
acute myocardial infarction in patients presenting with
ST-segment elevation of the European Society of Cardiology (ESC).
Eur Heart J 2018; 39: 119–77 .
20 O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA
guideline for the management of ST-elevation myocardial
infarction: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice
Guidelines. J Am Coll Cardiol 2013; 61: e78–140.
21 Noc M, Fajadet J, Lassen JF, et al. Invasive coronary treatment
strategies for out-of-hospital cardiac arrest: a consensus statement
from the European association for percutaneous cardiovascular
interventions (EAPCI)/stent for life (SFL) groups.
EuroIntervention 2014; 10: 31–37.
22 Rab T, Kern KB, Tamis-Holland JE, et al. Cardiac arrest:
a treatment algorithm for emergent invasive cardiac procedures
in the resuscitated comatose patient. J Am Coll Cardiol 2015;
66: 62–73.
23 SOS-KANTO 2012 Study Group. Initial blood ammonia level is a
useful prognostication tool in out-of-hospital cardiac arrest—
multicenter prospective study (SOS-KANTO 2012 Study).
Circ J 2017; 81: 1839–45.
24 Nishiyama K, Ito N, Orita T, et al. Regional cerebral oxygen
saturation monitoring for predicting interventional outcomes in
patients following out-of-hospital cardiac arrest of presumed
cardiac cause: a prospective, observational, multicentre study.
Resuscitation 2015; 96: 135–41.
25 Ito N, Nishiyama K, Callaway CW, et al. Noninvasive regional
cerebral oxygen saturation for neurological prognostication of
patients with out-of-hospital cardiac arrest: a prospective
multicenter observational study. Resuscitation 2014; 85: 778–84.
26 Dumas F, Cariou A, Manzo-Silberman S, et al. Immediate
percutaneous coronary intervention is associated with better
survival after out-of-hospital cardiac arrest: insights from the
PROCAT (Parisian Region Out of hospital Cardiac ArresT)
registry. Circ Cardiovasc Interv 2010; 3: 200–07.
27 Batista LM, Lima FO, Januzzi JL Jr, Donahue V, Snydeman C,
Greer DM. Feasibility and safety of combined percutaneous
coronary intervention and therapeutic hypothermia following
cardiac arrest. Resuscitation 2010; 81: 398–403.
28 Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose
survivors of out-of-hospital cardiac arrest with induced
hypothermia. N Engl J Med 2002; 346: 557–63.
29 Hypothermia after Cardiac Arrest Study G. Mild therapeutic
hypothermia to improve the neurologic outcome after cardiac
arrest. N Engl J Med 2002; 346: 549–56.
30 Nielsen N, Hovdenes J, Nilsson F, et al. Outcome, timing and
adverse events in therapeutic hypothermia after out-of-hospital
cardiac arrest. Acta Anaesthesiol Scand 2009; 53: 926–34.
31 Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature
management at 33°C versus 36°C after cardiac arrest.
N Engl J Med 2013; 369: 2197–206.
32 Knafelj R, Radsel P, Ploj T, Noc M. Primary percutaneous coronary
intervention and mild induced hypothermia in comatose survivors
of ventricular fibrillation with ST-elevation acute myocardial
infarction. Resuscitation 2007; 74: 227–34.
33 Wolfrum S, Pierau C, Radke PW, Schunkert H, Kurowski V.
Mild therapeutic hypothermia in patients after out-of-hospital
cardiac arrest due to acute ST-segment elevation myocardial
infarction undergoing immediate percutaneous coronary
intervention. Crit Care Med 2008; 36: 1780–86.
34 Penela D, Magaldi M, Fontanals J, et al. Hypothermia in acute
coronary syndrome: brain salvage versus stent thrombosis?
J Am Coll Cardiol 2013; 61: 686–87.
35 Joffre J, Varenne O, Bougouin W, Rosencher J, Mira JP, Cariou A.
Stent thrombosis: an increased adverse event after angioplasty
following resuscitated cardiac arrest. Resuscitation 2014;
85: 769–73.

996 www.thelancet.com Vol 391 March 10, 2018


36 Ibrahim K, Christoph M, Schmeinck S, et al. High rates of
prasugrel and ticagrelor non-responder in patients treated with
therapeutic hypothermia after cardiac arrest. Resuscitation 2014;
85: 649–56.
37 Bjelland TW, Hjertner O, Klepstad P, Kaisen K, Dale O,
Haugen BO. Antiplatelet effect of clopidogrel is reduced in
patients treated with therapeutic hypothermia after cardiac arrest.
Resuscitation 2010; 81: 1627–31.
38 Spaulding CM, Joly LM, Rosenberg A, et al. Immediate coronary
angiography in survivors of out-of-hospital cardiac arrest.
N Engl J Med 1997; 336: 1629–33.
39 Radsel P, Knafelj R, Kocjancic S, Noc M. Angiographic
characteristics of coronary disease and postresuscitation
electrocardiograms in patients with aborted cardiac arrest outside
a hospital. Am J Cardiol 2011; 108: 634–38.
40 Sunde K, Pytte M, Jacobsen D, et al. Implementation of a
standardised treatment protocol for post resuscitation care after
out-of-hospital cardiac arrest. Resuscitation 2007; 73: 29–39.
41 Larsen JM, Ravkilde J. Acute coronary angiography in patients
resuscitated from out-of-hospital cardiac arrest—a systematic
review and meta-analysis. Resuscitation 2012; 83: 1427–33.
42 Camuglia AC, Randhawa VK, Lavi S, Walters DL.
Cardiac catheterization is associated with superior outcomes
for survivors of out of hospital cardiac arrest: review and
meta-analysis. Resuscitation 2014; 85: 1533–40.
43 Millin MG, Comer AC, Nable JV, et al. Patients without ST
elevation after return of spontaneous circulation may benefit from
emergent percutaneous intervention: a systematic review and
meta-analysis. Resuscitation 2016; 108: 54–60.
44 Patel N, Patel NJ, Macon CJ, et al. Trends and outcomes of
coronary angiography and percutaneous coronary
intervention after out-of-hospital cardiac arrest associated with
ventricular fibrillation or pulseless ventricular tachycardia.
JAMA Cardiol 2016; 1: 890–99.
45 Callaway CW, Rittenberger JC, Logue ES, McMichael MJ.
Hypothermia after cardiac arrest does not alter serum
inflammatory markers. Crit Care Med 2008; 36: 2607–12.
46 Bro-Jeppesen J, Kjaergaard J, Wanscher M, et al. The inflammatory
response after out-of-hospital cardiac arrest is not modified by
targeted temperature management at 33°C or 36°C.
Resuscitation 2014; 85: 1480–87.
47 Wanscher M, Agersnap L, Ravn J, et al. Outcome of accidental
hypothermia with or without circulatory arrest: experience from
the Danish Praesto Fjord boating accident. Resuscitation 2012;
83: 1078–84.
48 Safar P, Xiao F, Radovsky A, et al. Improved cerebral resuscitation
from cardiac arrest in dogs with mild hypothermia plus blood flow
promotion. Stroke 1996; 27: 105–13.
49 Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction
of mild hypothermia on survival and neurological status among
adults with cardiac arrest: a randomized clinical trial. JAMA 2014;
311: 45–52.
50 Bernard SA, Smith K, Finn J, et al. Induction of therapeutic
hypothermia during out-of-hospital cardiac arrest using a rapid
infusion of cold saline: the RINSE trial (Rapid Infusion of Cold
Normal Saline). Circulation 2016; 134: 797–805.
51 Kirkegaard H, Soreide E, de Haas I, et al. Targeted temperature
management for 48 vs 24 hours and neurologic outcome after
out-of-hospital cardiac arrest: a randomized clinical trial.
JAMA 2017; 318: 341–50.
52 Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic
hypothermia by paramedics after resuscitation from
out-of-hospital ventricular fibrillation cardiac arrest: a randomized
controlled trial. Circulation 2010; 122: 737–42.
53 Castren M, Nordberg P, Svensson L, et al. Intra-arrest transnasal
evaporative cooling: a randomized, prehospital, multicenter study
(PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness).
Circulation 2010; 122: 729–36.
54 Bernard SA, Smith K, Cameron P, et al. Induction of prehospital
therapeutic hypothermia after resuscitation from nonventricular
fibrillation cardiac arrest. Crit Care Med 2012; 40: 747–53.
55 Debaty G, Maignan M, Savary D, et al. Impact of intra-arrest
therapeutic hypothermia in outcomes of prehospital cardiac arrest:
a randomized controlled trial. Intensive Care Med 2014; 40: 1832–42.
www.thelancet.com Vol 391 March 10, 2018 997
Series
56 Lilja G, Nielsen N, Friberg H, et al. Cognitive function in survivors
of out-of-hospital cardiac arrest after target temperature
management at 33°C versus 36°C. Circulation 2015; 131: 1340–49.
57 Deye N, Cariou A, Girardie P, et al. Endovascular versus external
targeted temperature management for patients with out-of-hospital
cardiac arrest: a randomized, controlled study. Circulation 2015;
132: 182–93.
58 Bro-Jeppesen J, Hassager C, Wanscher M, et al. Post-hypothermia
fever is associated with increased mortality after out-of-hospital
cardiac arrest. Resuscitation 2013; 84: 1734–40.
59 Zeiner A, Holzer M, Sterz F, et al. Hyperthermia after cardiac
arrest is associated with an unfavorable neurologic outcome.
Arch Intern Med 2001; 161: 2007–12.
60 Brain Resuscitation Clinical Trial I Study Group. Randomized
clinical study of thiopental loading in comatose survivors of cardiac
arrest. N Engl J Med 1986; 314: 397–403.
61 Longstreth WT Jr, Fahrenbruch CE, Olsufka M, Walsh TR,
Copass MK, Cobb LA. Randomized clinical trial of magnesium,
diazepam, or both after out-of-hospital cardiac arrest. Neurology
2002; 59: 506–14.
62 Brain Resuscitation Clinical Trial II Study Group. A randomised
clinical study of a calcium-entry blocker (lidoflazine) in the
treatment of comatose survivors of cardiac arrest. N Engl J Med
1991; 324: 1225–31.
63 Wiberg S, Hassager C, Schmidt H, et al. Neuroprotective effects of
the glucagon-like peptide-1 analog exenatide after out-of-hospital
cardiac arrest: a randomized controlled trial. Circulation 2016;
134: 2115–24.
64 Cariou A, Deye N, Vivien B, et al. Early high-dose erythropoietin
therapy after out-of-hospital cardiac arrest: a multicenter,
randomized controlled trial. J Am Coll Cardiol 2016; 68: 40–49.
65 Argaud L, Cour M, Dubien PY, et al. Effect of cyclosporine in
nonshockable out-of-hospital cardiac arrest: the CYRUS
randomized clinical trial. JAMA Cardiol 2016; 1: 557–65.
66 Dragancea I, Wise MP, Al-Subaie N, et al. Protocol-driven
neurological prognostication and withdrawal of life-sustaining
therapy after cardiac arrest and targeted temperature management.
Resuscitation 2017; 117: 50–57.
67 Metter RB, Rittenberger JC, Guyette FX, Callaway CW. Association
between a quantitative CT scan measure of brain edema and
outcome after cardiac arrest. Resuscitation 2011; 82: 1180–85.
68 Langkjaer S, Hassager C, Kjaergaard J, et al. Prognostic value of
reduced discrimination and oedema on cerebral computed
tomography in a daily clinical cohort of out-of-hospital cardiac
arrest patients. Resuscitation 2015; 92: 141–47.
69 Silva S, Peran P, Kerhuel L, et al. Brain gray matter MRI
morphometry for neuroprognostication after cardiac arrest.
Crit Care Med 2017; 45: e763–71.
70 Wu O, Sorensen AG, Benner T, Singhal AB, Furie KL, Greer DM.
Comatose patients with cardiac arrest: predicting clinical outcome
with diffusion-weighted MR imaging. Radiology 2009; 252: 173–81.
71 Youn CS, Park KN, Kim JY, et al. Repeated diffusion weighted
imaging in comatose cardiac arrest patients with therapeutic
hypothermia. Resuscitation 2015; 96: 1–8.
72 Mattsson N, Zetterberg H, Nielsen N, et al. Serum tau and
neurological outcome in cardiac arrest. Ann Neurol 2017; 82: 665–75.
73 Stammet P, Collignon O, Hassager C, et al. Neuron-specific
enolase as a predictor of death or poor neurological outcome after
out-of-hospital cardiac arrest and targeted temperature
management at 33°C and 36°C. J Am Coll Cardiol 2015; 65: 2104–14.
74 Stammet P, Dankiewicz J, Nielsen N, et al. Protein S100 as
outcome predictor after out-of-hospital cardiac arrest and targeted
temperature management at 33°C and 36°C. Crit Care 2017; 21: 153.
75 Lybeck A, Cronberg T, Aneman A, et al. Time to awakening after
cardiac arrest and the association with target temperature
management. Resuscitation 2018; published online Feb 2.
DOI:10.1016/j.resuscitation.2018.01.027.
76 Nichol G, Aufderheide TP, Eigel B, et al. Regional systems of care
for out-of-hospital cardiac arrest: a policy statement from the
American Heart Association. Circulation 2010; 121: 709–29.
77 Soholm H, Wachtell K, Nielsen SL, et al. Tertiary centres have
improved survival compared to other hospitals in the Copenhagen
area after out-of-hospital cardiac arrest. Resuscitation 2013;
84: 162–67.
 Series
78 Tranberg T, Lippert FK, Christensen EF, et al. Distance to invasive
heart centre, performance of acute coronary angiography, and
angioplasty and associated outcome in out-of-hospital cardiac
arrest: a nationwide study. Eur Heart J 2017; 38: 1645–52.
79 Laitio R, Hynninen M, Arola O, et al. Effect of inhaled xenon on
cerebral white matter damage in comatose survivors of out-of-hospital
cardiac arrest: a randomized clinical trial. JAMA 2016; 315: 1120–28.
80 Yokoyama H, Nagao K, Hase M, et al. Impact of therapeutic
hypothermia in the treatment of patients with out-of-hospital cardiac
arrest from the J-PULSE-HYPO study registry. Circulation 2011;
75: 1063–70.
81 Yellon DM, Hausenloy DJ. Myocardial reperfusion injury.
N Engl J Med 2007; 357: 1121–35.
82 Dae MW, Gao DW, Sessler DI, Chair K, Stillsen CA. Effect of
endovascular cooling on myocardial temperature, infarct
size, and cardiac output in human-sized pigs.
Am J Physiol Hear Circ Phsyiol 2002; 282: H1584–91.
998 www.thelancet.com Vol 391 March 10, 2018
83 Erlinge D, Gotberg M, Lang I, et al. Rapid endovascular catheter
core cooling combined with cold saline as an adjunct to
percutaneous coronary intervention for the treatment of acute
myocardial infarction. The CHILL-MI trial: a randomized controlled
study of the use of central venous catheter core cooling combined
with cold saline as an adjunct to percutaneous coronary
intervention for the treatment of acute myocardial infarction.
J Am Coll Cardiol 2014; 63: 1857–65.
84 Nagao K, Kikushima K, Watanabe K, et al. Early induction of
hypothermia during cardiac arrest improves neurological outcomes
in patients with out-of-hospital cardiac arrest who undergo
emergency cardiopulmonary bypass and percutaneous coronary
intervention. Circ J 2010; 74: 77–85.